Pesticide Toxicity A Mechanistic Approach PDF

EXCLI Journal 2018;17:1101-1136 – ISSN 1611-2156
Received: September 14, 2018, accepted: October 24, 2018, published: November 08, 2018
Review article:
PESTICIDE TOXICITY: A MECHANISTIC APPROACH

Volodymyr I. Lushchaka*, Tetiana M. Matviishyna, Viktor V. Husaka, Janet M. Storeyb,
Kenneth B. Storeyb
a
Department of Biochemistry and Biotechnology, Vasyl Stefanyk Precarpathian National
University, 57 Shevchenko Str., Ivano-Frankivsk, 76018, Ukraine
b
Institute of Biochemistry, Carleton University, 1125 Colonel By Drive, Ottawa, Ontario
K1S 5B6, Canada
* Corresponding author: Department of Biochemistry and Biotechnology, Vasyl Stefanyk

Precarpathian National University, 57 Shevchenko Str., Ivano-Frankivsk 76018, Ukraine.
Tel/Fax.: +38 0342 714683. E-mail: lushchak@pu.if.ua (V.I. Lushchak),
orcid.org/0000-0001-5602-3330
http://dx.doi.org/10.17179/excli2018-1710
This is an Open Access article distributed under the terms of the Creative Commons Attribution License
(http://creativecommons.org/licenses/by/4.0/).
ABSTRACT
Pesticides are known for their high persistence and pervasiveness in the environment, and along with products of
their biotransformation, they may remain in and interact with the environment and living organisms in multiple
ways, according to their nature and chemical structure, dose and targets. In this review, the classifications of pes-
ticides based on their nature, use, physical state, pathophysiological effects, and sources are discussed. The ef-
fects of these xenobiotics on the environment, their biotransformation in terms of bioaccumulation are highlight-
ed with special focus on the molecular mechanisms deciphered to date. Basing on targeted organisms, most pes-
ticides are classified as herbicides, fungicides, and insecticides. Herbicides are known as growth regulators,
seedling growth inhibitors, photosynthesis inhibitors, inhibitors of amino acid and lipid biosynthesis, cell mem-
brane disrupters, and pigment biosynthesis inhibitors, whereas fungicides include inhibitors of ergosterol biosyn-
thesis, protein biosynthesis, and mitochondrial respiration. Insecticides mainly affect nerves and muscle, growth
and development, and energy production. Studying the impact of pesticides and other related chemicals is of
great interest to animal and human health risk assessment processes since potentially everyone can be exposed to
these compounds which may cause many diseases, including metabolic syndrome, malnutrition, atherosclerosis,
inflammation, pathogen invasion, nerve injury, and susceptibility to infectious diseases. Future studies should be
directed to investigate influence of long term effects of low pesticide doses and to minimize or eliminate influ-
ence of pesticides on non-target living organisms, produce more specific pesticides and using modern technolo-
gies to decrease contamination of food and other goods by pesticides.
Keywords: Bioaccumulation, biotransformation, pollutants, mechanisms, oxidative stress, xenobiotics
Abbreviations:
ALT, alanine aminotransferase; AST, aspartate aminotransferase; BchE, butyrylcholinesterase; 2,4-D, 2,4-
dichlorophenoxyacetic acid; 2,4-DCP, 2,4-dichlorophenol; AChE, acetylcholinesterase; DDT, 1,1,1-trichloro-
2,2-bis(4-chlorophenyl)ethane; DTC, dithiocarbamates; GPx, glutathione peroxidase; GSH, GSSG, reduced and
oxidized glutathione; GST, glutathione-S-transferases; LDH, lactate dehydrogenase; NF-kB, transcription factor
nuclear factor kappa B; OP, organophosphorous pesticide; ROS, reactive oxygen species; SOD, superoxide dis-
mutase.
1101
INTRODUCTION biotransformation, conjugation, isolation

and/or excretion into the environment or via
Pesticides are synthesized substances or
a combination of these mechanisms. All
biological agents used for attracting, seduc-
these efforts are directed to prevent or mini-
ing, destroying, or mitigating any pest. They
mize damage to the organism. Elimination of
are mainly applied in agriculture to protect
pesticides can be implemented in at least two
crops from insects, weeds, and bacterial or
ways: either by excretion in their original
fungal diseases during growth and to protect
form or after biotransformation and/or con-
foods during storage from rats, mice, insects
jugation with different compounds by the or-
or diverse biological contaminants (Bolo-
ganism (van der Oost et al., 2003). Interest-
gnesi and Merlo, 2011). Some pesticides,
ingly, sometimes biotransformation can re-
like herbicides, are applied to clear roadside
sult in more hazardous products than the ini-
weeds, trees, and shrubs and are commonly
tial pesticide. Processing of pesticides de-
applied in ponds and lakes to control un-
pending on their properties, dose, and routes
wanted aquatic plants. Others are used to kill
of entry can substantially affect the organ-
or inhibit growth of fungi or insects that par-
ism. For example, pesticides can cause endo-
asitize crops (Gupta, 2011). Thus, being a
crine disruptions and neurological disturb-
heterogeneous category, pesticides occupy a
ancіes, influence immune system, reproduc-
unique position among synthetic chemicals
tion, development (Khan and Law, 2005). In
that humans encounter daily. They can now
view of this, the toxicity of pesticide expo-
be found almost everywhere worldwide. Pes-
sure to non-target organisms is a substantial
ticides originating from human activity can
concern around the world.
also enter water bodies through surface run-
The mode of action of numerous pesti-
off, leaching, and/or erosion (Khan and Law,
cides is diverse and often cannot be specifi-
2005). Meanwhile, drift, evaporation, and
cally classified. It is well known that organ-
wind erosion can carry pesticide residues in-
ophosphorus pesticides are extremely neuro-
to the atmosphere, which can lead to contam-
toxic since they irreversibly inhibit acetyl-
ination of surface waters, soils, flora, and
cholinesterase, an enzyme that hydrolyzes
fauna via precipitation, often at sites distant
the neurotransmitter acetylcholine at neuro-
from their place of origin (Dubus et al.,
muscular junctions and brain cholinergic
2000).
synapses (Galloway and Handy, 2003; van
Pesticides are characterized by various
der Oost et al., 2003). Many dithiocarba-
degrees of toxicity to target and non-target
mates (DTC) induce intraneuronal oxidative
organisms (Bolognesi and Merlo, 2011;
stress leading to neuronal damage because
Khan and Law, 2005). Because of cumula-
the metal ions released during their biotrans-
tive properties of many pesticides (Wil-
formation can enhance the steady-state levels
kinson et al., 2000), they circulate in ecosys-
of reactive oxygen species (ROS) and stimu-
tems and may be accumulated by many liv-
late ROS-induced oxidation of lipids and
ing organisms and even migrate through
proteins, or inactivate certain enzymes re-
food chains. To recognize herbicide impact
sulting in neurotoxic effects (Fitsanakis et al.,
some biological subjects, individuals, spe-
2002; Nobel et al., 1995). A number of pes-
cies, or communities, are preferentially used
ticides cause endocrine disruption by inter-
as models for evaluation of hazardous influ-
fering with the production, release, transport,
ences. Pesticides may enter the body by dif-
ferent ways depending on species, metabolic metabolism, action, or elimination of hor-
peculiarities, and susceptibility to toxins mones (Bolognesi and Merlo, 2011; Khan
(Hodgson, 2010). However, if a chemical al- and Law, 2005). Pesticides also may increase
ready entered an organism, the organism steady-state ROS levels, stimulate ROS-
must be able to deal with it in order to neu- induced modification of cellular components,
tralize or minimize its deleterious effects via affect core homeostatic and regulatory pro-
1102
cesses, or deplete antioxidant defenses that GENERAL APPRAISAL”). The ability of

collectively result in the development of oxi- various pesticides to affect organisms in dif-
dative stress (Abdollahi et al., 2004; ferent ways complicates the risk assessment
Banerjee et al., 2001; Lushchak, 2011a, b). based on the environmental levels. Deleteri-
Since ROS interact with DNA in different ous effects are often difficult to detect in tar-
ways, an increase in their steady-state levels geted organisms since many of these effects
can enhance the chance to interact with the tend to manifest only after prolonged expo-
genetic material and cause genotoxicity lead- sure. When the effects finally become obvi-
ing to diverse mutations (Franco et al., ous, destructive processes may already be ir-
2010). reversible (van der Oost et al., 2003). Fur-
This review considers general mecha- thermore, due to the long-term persistence of
nisms of pesticide-promoted toxicity in tar- many pesticides (or products of their conver-
get and non-target organisms. Because pesti- sion) in the environment, resulting from non-
cides are present and circulate everywhere in controlled or poorly controlled use in agri-
the environment, we have analyzed the main culture and other human activities, ecosys-
routes of penetration and processing of these tems may be substantially modified. Because
chemicals in nature as well as the peculiari- of their cumulative properties, pesticides cir-
ties of their metabolism in living organisms. culate and become accumulated in many liv-
ing organisms some of which are used as
model subjects for investigation of their haz-
PERSISTENT STATUS OF
ardous effects.
PESTICIDES IN THE ENVIRONMENT
From the viewpoint of environmental
protection, ecotoxicological studies of the Pesticides and their circulation in the
natural environment have become very im- biosphere
Pesticides can be found almost every-
portant in recent decades since pesticides
where worldwide. Large numbers of pesti-
regularly enter the environment. They may
cides can persist in water bodies, air, fog,
disturb the natural balance of the ecosystem
rain, and soils (Bolognesi and Merlo, 2011).
and cause substantial ecological changes
The fate of a contaminant in the environment
even if used according to good agricultural
is affected by a variety of physical, chemical,
practices. Whereas problems arising from
and biological processes that can affect their
pesticide use are most often linked with agri-
processing as well as their interactions with
culture or forestry practices, they are also
environmental components. Pesticides most
present as a common component of urban
wastewater accumulating as the result of commonly enter bodies of water due to run-
weed treatment along roads or rail lines, as off from adjacent fields and roads (Figure 1).
well as from gardens, parks, and urban Other routes include direct spray, airborne
woodland areas. These include pesticides of drift, intentional dumping, improper mixing,
the triazine group, the phenyl urea group and contaminated groundwater. Pesticide
(e.g. chlorotoluron, isoproturon and diuron), penetration into groundwater is controlled by
the phenoxy acid group (e.g. 2,4- two factors: water applied and interaction
dichlorophenoxyacetic acid (2,4-D)), etc. with organisms and solid particles, i.e. a bal-
(Revitt et al., 1999) (for details see section ance between absorption and adsorption
“CLASSIFICATION OF PESTICIDES: (Huggenberger et al., 1973).
1103
Figure 1: The movement of pesticide in the hydrologic cycle. Diffuse water pollution through pesti-
cides occurs either due to evaporation (4) with short and long-distance transfer (5), surface runoff (8)
or leaching to groundwater (13). 1 – pesticide application; 2 – absorbed by crop; 3 – degraded by ul-
traviolet light; 4 – evaporation (vaporized to atmosphere); 5 – short and long-distance transport; 6 –
deposited by rainfall; 7 – runoff; 8 – surface runoff to lakes and rivers; 9 – polluted waters; 10 – seep-
age; 11 – adheres to soil particles; 12 – biodegradation (degraded by bacterial oxidation or chemical
hydrolysis); 13 – leaching (groundwater discharge to streams); 14 – pollution of surrounding territory.
Eventually, when chemicals enter eco- structures that can be decomposed by visible
systems, transformation occurs in various or UV light in a process called photolysis. If
ways depending upon their physical and the chemical possesses double bonds be-
chemical properties and interaction with oth- tween carbon atoms or other chemical ele-
er environmental components. For example, ments, and absorbs light at visible or UV
water solubility is a key characteristic of a wavelengths, it can potentially undergo di-
chemical but is affected by several parame- rect photolysis (Hemond and Fechner, 1994;
ters including temperature, pH, salinity, tur- Sparks and Nauen, 2015). Non-absorbing
bidity, and the presence of other chemicals in compounds may undergo indirect photolysis,
the microenvironment (Rand et al., 1995). where light-absorbing molecules commonly
Highly water-soluble pesticides, such as 2,4- persisting in water absorb photons and sub-
D, are less persistent in the environment, and sequently transfer their energy to non-
are most likely to biodegrade quickly. Be- absorbing compounds. Indirect photolysis
cause of this, they are not likely to be accu- can also occur when transient oxidants such
mulated in the soil or sediments, volatilize, as hydroxyl radicals or singlet oxygen attack
or bioconcentrate in organisms. Hydrolysis is pesticide molecules (Hemond and Fechner,
a common way to degrade many pesticides, 1994; Sparks and Nauen, 2015).
particularly those chemicals that possess Environmental temperature also plays a
chemical bonds that are potentially hydro- significant role since temperature determines
lyzable at environmental pH (Katagi, 2010). not only the level of dissolved oxygen in the
Some other contaminants have chemical water, but can also affect the behavior of di-
1104
verse chemicals in an aqueous environment Transfer and bioaccumulation of pesticides

by influencing solubility, volatility, and in the food chains
chemical activity of pesticides (Chovanec et Pesticides are known to be widespread
al., 2003). The bioaccumulation and toxicity environmental pollutants due to their bioac-
of chemicals are also influenced by tempera- cumulation and persistence in the ecosys-
ture. Increased contact time between the tems. Residues of these compounds have
body surface of an organism and a pesticide been detected in different biological media
will intensify bioconcentration, a form of bi- of test organisms (Bolognesi and Merlo,
oaccumulation in which the pesticide is ac- 2011). Because most organisms interact with
cumulated directly from the environment. In each other in the food web, knowledge about
water, pesticides may act either alone, or in pesticide migration and bioconcentration
concert with many biological, physical, or from dietary exposure is important for the
other chemical factors that can affect aquatic evaluation of their real environmental effects
organisms. Thus, it is not a simple matter to (Katagi, 2010). Runoff and erosion can be
determine the mechanisms of pesticide tox- major routes of chemical entry into surface
icity, which may be further complicated by waters (Giddings et al., 2005) and so, for
environmental factors such as elevated tem- aquatic organisms, persistent chemicals may
perature, low dissolved oxygen levels, or by also accumulate through other mechanisms
bacterial infections and parasite invasions including via the direct uptake from water by
(Khan and Law, 2005). Since the danger of gills or skin (bioconcentration), via uptake of
pesticide contamination is high, and many suspended particles (ingestion), and via the
other factors can act individually or in com- consumption of contaminated food (biomag-
bination to produce health harm, a clear pro- nification) (van der Oost et al., 2003). Ter-
tocol needs to be established to resolve these restrial wildlife can be exposed to pesticides
issues. via consumption of contaminated food or
Historically, chemical exposure in the water (Solomon et al., 2008).
workplace has been assessed through envi- The term “bioconcentration” is broadly
ronmental monitoring. Analytical procedures used to describe the process of pesticide en-
for the detection of pesticides and their me- trance into organisms. Katagi (2010)
tabolites in biological samples (blood, urine, disсussed three main factors determining bi-
saliva, sweat, leaves, roots, etc.) have been oconcentration processes: (i) physico-
developed to study patterns of absorption, chemical properties of the individual chemi-
transformation, and excretion of these com- cals, (ii) physiological disposition of the or-
pounds (Bolognesi and Merlo, 2011). Acute ganism penetrated, and (iii) surrounding en-
effects of pesticides have been adequately vironmental conditions. Since biological
evaluated in different test/model organisms membranes are the primary barriers for
(Atamaniuk et al., 2013; El-Sayed et al., chemicals, the physicochemical properties of
2007; Prusty et al., 2011). Although acute re- pesticides such as steric parameters (e.g. mo-
sponses to exposure are well known for lecular size and shape) and water or lipid
many pesticides, human data on their de- solubility are critically important (Landrum
layed effects are much more limited since and Fisher, 1998). Among the range of phys-
human exposure to pesticides is extremely iological properties that exist in organisms,
complex as a result of occupational or envi- lipid content is considered to be the most
ronmental influences. important determinant for pesticide biocon-
centration because lipid-soluble pesticides
are especially prone to bioaccumulation. Li-
pid influence on pesticide intake may be fol-
lowed by metabolism or excretion, which are
substantially affected by the physiological
1105
state of organisms (Katagi, 2010). Finally, Concentration of DDT in living organ-

the rate of bioconcentration also depends to isms results from imbalance between its ab-
some extent on environmental conditions. sorption, metabolization, and excretion.
Hence, for chemicals having a dissociable Thus, when a pesticide enters a water source,
functional group, bioconcentration may be it first accumulates in and contaminates
affected by the environmental pH value. The plankton. When small fish species eat plank-
hardness of water was also reported to affect ton, they are then contaminated and when
both uptake and elimination processes of bigger fish eat smaller ones, they are also
pesticides (Kawatski and Bittner, 1975). In contaminated. Such events lead to DDT ac-
the aquatic environment, the presence of bot- cumulation through food chains and its per-
tom sediments also substantially complicates sistence in these chains. Hence, food is the
an investigation of bioconcentration. Aquatic most significant source of toxicants that bio-
organisms usually ingest prey, sediment par- accumulate along food chains. It is common-
ticles, and detritus contaminated by chemi- ly accepted that if the levels of pesticides
cals, and this may affect bioaccumulation persisting in the organism are enhanced
rates (Katagi, 2010). Therefore, the biocon- through two or more trophic levels in a food
centration of pesticides often leads to their web, that the process is referred to as “bio-
bioaccumulation that includes added effects magnification” (Connell et al., 1988). There
of dietary uptake through food consumption are two different mechanisms providing bio-
and intake of sediments (Miyamoto et al., magnification: active and passive transporta-
1990). Figure 2 shows how DDT [1,1,1- tion. In the first case, specific systems are re-
trichloro-2,2-bis(4-chlorophenyl)ethane] be- sponsible for pesticide entrance.
comes concentrated in the tissues of organ-
isms.
Figure 2: Bioaccumulation of DDT in the food chain. Each successive consumer in the food chain ac-
cumulates contaminants to a higher level, thus magnifying the exposure when moving up the food
chain
1106
In the second case, however, biomagni- pesticide exposure (Hodgson and Goldstein,
fication can be related to some driving force 2001). Kidney is a secondary organ involved
for net passive chemical transport; i.e. every in detoxification related to big extent by its
penetrating organic chemical has a particular high blood flow and its ability to concentrate
chemical activity or chemical potential and convert pesticides due to which it is a
which promotes the tendency of the chemical target for xenobiotic toxicity (Husak et al.,
to be released from a phase when driving on 2014, 2017; Husak, 2015). Very little is
the food chain (Gobas et al., 1988). Biomag- known about xenobiotic detoxification in the
nification also can be determined as the ratio central nervous system although several
between the uptake of chemicals from food studies have demonstrated efficient relation-
and their clearance (Sijm et al., 1992). ships between development of neurotoxicity
and exposure to organophosphorus com-
Uptake and bioprocessing of pesticides pounds (Galloway and Handy, 2003; Vani et
Pesticides may enter organisms in differ- al., 2011).
ent ways. Due to differences in metabolism Biotransformation is one of the most im-
and other characteristics, species, strains, and portant factors governing bioconcentration,
individuals may vary greatly in their suscep- bioaccumulation, and detoxification of pesti-
tibility to pesticides. Aquatic organisms may cides (Katagi, 2010). Williams (1959) first
absorb dissolved chemicals directly from the suggested that the metabolism of xenobiotics
water across respiratory organs (e.g., gills), generally occurs in two stages that are now
the body surface, or via intake of contami- generally classified as phase I and phase II
nated food, suspended particles or sediments detoxification reactions that proceed succes-
(Katagi, 2010; Lushchak, 2011b). Most ter- sively to facilitate elimination of pesticides
restrial animals also absorb pesticides (Hodgson, 2010; Katagi, 2010). Phase I
through skin, respiratory and/or gastrointes- stage involves predominantly oxidation, re-
tinal tract surfaces. The skin and nasal muco- duction, and hydrolysis and serves to intro-
sa are the main portals of entry for different duce a polar group into hydrophobic mole-
pesticides (Hodgson, 2010). A few pesticides cules, i.e. produce derivatives containing -
are known to give rise to toxic endpoints in OH, -COOH, -NH2, and -SH functional
the nasal tissues; some of them have been groups (Figure 3). Such oxidation is usually
identified to cause nasal lesions or tumors in catalyzed by mixed function oxidases, in-
experimental animals (Hodgson, 2010). The cluding cytochrome P450 enzymes and has
lung is also a primary site of exposure to air- been extensively investigated (Watanabe,
borne environmental pollutants closely con- 2000). Located in endoplasmic reticulum
tacting with blood (Ding and Kaminsky, P450 enzymes usually function as terminal
2003). oxidases of electron-transport chains. Phe-
Pesticide acquisition from all routes of nols are thought to be primarily oxidized by
exposure eventually comes to the liver for monooxygenases to the corresponding cate-
disposition, liver being the primary site of chol derivatives followed by ring cleavage
pesticide biotransformation for facilitated by 2,3-dioxygenases (Semple et al., 1999).
clearance through excretion of water-soluble Lipoxygenases, dioxygenate mainly poly-
products of detoxification. However, the enoic fatty acids, but also take part in con-
high level of oxidative metabolism in liver version of different xenobiotics primary via a
also makes it a possible target for more toxic direct hydrogen abstraction in the reactions
metabolic products appearing due to bio- oxidation, epoxidation, hydroxylation, sul-
transformation of certain xenobiotics (Hodg- foxidation, desulfuration, dearylation, and N-
son and Goldstein, 2001). For example, pes- dealkylation as well as are capable of gluta-
ticide poisoning accompanied by acute liver thione conjugation of certain xenobiotics
intoxication has been associated with chronic (Kulkarni, 2001). Reductive dehalogenation
1107
and dehydrohalogenation, typical reactions cretable products (Figure 3) (Lushchak, 2011

for biotransformation of DDT, as well as re- b). Acetylation, formylation, and conjugation
duction of nitro- and S-oxide groups were al- with amino acids are mostly used for amino
so described. Hydrolysis, catalyzed by vari- and carboxyl groups after reduction of the
ous esterases, is common in the metabolism nitro group or ester bond cleavage. Glucose
of organophosphorus and pyrethroid pesti- conjugates can be further metabolized by
cides (Katagi, 2010; Mangas et al., 2017). acetylation or conjugation with malonic acid
Based on reaction profiles, esterases are or carbohydrates (Katagi, 2010). Glutathi-
classified functionally into three categories one-S-transferases (GSTs) are widely dis-
(Thompson, 1999; Wheelock et al., 2005): tributed in terrestrial and aquatic organisms
1. A-esterases that include phosphotriester and these enzymes catalyze the transfer of
hydrolases that hydrolyze organo- tripeptide GSH to electrophilic chemicals
phosphorus (OP) compounds and are not such as epoxides, halides, and arene oxides
inhibited by OPs. that are formed by phase I oxidation (James,
2. B-esterases including cholinesterases and 1994; Lushchak, 2012). The conjugates
carboxyesterases that are typically inhib- formed then undergo further metabolism via
ited by OPs as a result of the extremely catalysis by peptidases and N-acetyltrans-
slow dephosphorylation of tetrahedral in- ferase via two intermediates and finally to
termediates formed between OPs and a conjugates of mercapturic acid. Many chem-
serine residue at their active sites (Fukuto, icals (e.g. chlorophenol derivatives) are
1990). Carboxyesterases are well known known to inhibit a GST (LeBlanc and
to hydrolyze pyrethroids and carbamates. Cochrane, 1987). Such metabolic profiles
Among cholinesterases, acetylcholine may be common in all eukaryotic organisms,
(AchE) and butyrylcholine (BchE) ester- but the contribution of these reactions de-
ases have been found in neuromuscular pends on species.
junctions, whereas carboxyesterases are Reactions of phase II detoxification are
usually distributed in all tissues and hy- not the final stage of the overall process. The
drolyze a wide variety of endogeneous xenobiotic conjugates can be metabolized,
and exogeneous esters (Galloway et al., for example with glutathione, and excreted
2002). from the living organisms (Lushchak, 2012).
3. C-esterases that include acetylesterases The system responsible for excretion of
not inhibited by OPs. transformed and original pesticides has been
The phase II detoxification system, con- called phase III detoxification (Figure 3).
sisting primarily products of conjugation re- Specific ATP-binding cassette transporters
actions, includes the combination of the provide the ATP-dependent excretion of
products of phase I reactions with carbo- diverse hydrophilic anions to the extra-
hydrates, reduced glutathione (GSH), sulfate, cellular medium (Homolya et al., 2003; Nies
or amino acids to form water-soluble ex- and Keppler, 2007).
Figure 3: Biotransformation of pesticides. Description in the text. *glutathione, carbohydrates, amino

acids, sulfates, acetyl groups
1108
Organisms eliminate absorbed chemicals transporters providing release of pesticides

in two forms: they are either excreted in in environment (Bounds and Hutson, 2000;
original form (the parent compound) or as Kreuz et al., 1996). As in animals, plants
products of their biotransformation. The possess three defense systems or phases of
products of biotransformation generally are detoxification. Phase I reactions involve oxi-
more hydrophilic compounds and are more dation by P450 cytochromes and hydrolysis
readily excreted than parental ones (Ver- by carboxylesterases. Phase II includes con-
meulen, 1996). In animals, liver is the organ jugation of original or transformed xenobiot-
most commonly involved in biotransfor- ics with endogenous molecules such as GSH
mation of foreign compounds due to its func- in the reactions catalyzed by GSTs, glucu-
tion, position among other organs and exten- ronic acid in reactions involving UDP-
sive blood supply. Biotransformation usually glucuronosyltransferase, or sulfate in reac-
alters the toxicity of compounds making tions conducted by sulfotransferases. In
them either more or less toxic to the organ- phase III biotransformed xenobiotics alone
ism than the initial compound (van der Oost or in conjugated form are transported into
et al., 2003). The skin also contains many the vacuole or extruded from the plant by
xenobiotic metabolizing enzymes and some specific transport mechanisms. Interestingly,
are inducible, primarily by polycyclic hydro- plants are also capable of further processing
carbons (Baron et al., 2008). Because of kid- of conjugates such as by partial degradation,
ney role in the organism related with high secondary conjugations, or incorporation in-
blood flow and presence of renal xenobiotic to cell wall constituents (sometimes called
metabolizing systems, it is also the target for phase IV detoxification) (Riechers et al.,
xenobiotic toxicity (Speerschneider and 2010).
Dekant, 1995). Interestingly, among animals,
we know that the capacity for biotransfor- CLASSIFICATION OF PESTICIDES:
mation and elimination of xenobiotics is of- GENERAL APPRAISAL
ten positively correlated with an organism’s The term ”pesticide” indicates any sub-
capability to survive general stress condi- stance or mixture of substances used to kill,
tions. Usually, more stress-tolerant organ- repel, or otherwise control a ”pest”, includ-
isms demonstrate lower sensitivity to xeno- ing insects, snails, rodents, fungi, bacteria,
biotics (Banaszkiewicz, 2010). and weeds (Bolognesi and Merlo, 2011). The
Plants possess coordinated defense “green revolution” caused rapid growth in
mechanisms to natural and synthetic toxi- the application of pesticides which contrib-
cants (Zhang et al., 2007). Similarly to ani- uted significantly to increased production
mals, plants possess systems of biotransfor- and expansion of the range of pesticide
mation to cope with xenobiotics. Hence, the products. In this regard, there is an urgent
capacity of plants to detoxify herbicides need to develop a classification of pesticides
metabolically via complex multistep pro- that would provide essential clues to navi-
cesses clearly demonstrates their highly spe- gate the mass of existing compounds and
cific defense systems that also show extraor- choose the best one for the target application.
dinary diversity among species (Kreuz et al., When compiling the classification of pesti-
1996). In modern agriculture, selective herb- cides it is very difficult to meet one single
icides are widely used that are safe for use on principle, so in most cases, combined ap-
particular crops, but can efficiently control proaches are preferred. There are three gen-
associated weeds (Riechers et al., 2010). eral characteristics according to which pesti-
They frequently are claimed to be low toxic cides may be classified:
for non targeted organisms. (A) assignment (or type of pest, target
In plants, several groups of enzymes are group) – e.g., herbicides, fungicides etc;
used for herbicide detoxification along with
1109
(B) method of pesticide impact – con- 12) Synthetic pyrethroids and others
tact (in some cases acting externally to dry (e.g., allethrin, cypermethrin, fluva-
the body of the pest or to create a gas-tight linate).
film that blocks normal gas exchange, or in There are also other approaches that may
other cases penetrating through the integu- serve as important tools used for pesticide
ment to strike the nervous system, etc.), sys- classification. For example, their toxicity is
temic (pesticides easily penetrate the organ- of great interest to modern science. Howev-
ism barriers and affect all organs), fumigants er, this parameter is too changeable to be-
– chemical compounds that enter the body come a classification mechanism for pesti-
through inhalation to affect bloodstream, en- cides. Toxicity of pesticides depends on
zymes and nervous systems of living organ- temperature, dose, permeation rate, degrada-
isms, and complex preparations; tion time etc., usually with broad fluctuations
(C) chemical nature of the pesticide – that makes it difficult to use as a classifica-
is the most specific way to differentiate the tion parameter.
multiple classes and subclasses of com- Selectivity is known to be among the
pounds that exhibit a vast array of chemical- most desired properties of pesticides, i.e.
ly diverse structures (Franco et al., 2010), as ideally pesticides should act specifically
detailed in the Pesticide Manual published against certain target organisms without se-
by British Crop Protection Council (Tomlin, verely affecting others (Bolognesi and Merlo,
2000). From this, depending on chemical 2011). Theoretically, pesticide chemicals
structure, the most popular pesticides may be might be designed or selected that uniquely
divided into the following groups (Bolognesi attack a functional system or target mole-
and Merlo, 2011; Franco et al., 2010; Katagi, cules peculiar to the ”pest” with either absent
2010): or less critical in its effects on other organ-
1) Organochlorines (e.g., endosulfan, isms. For example, chitin synthetase inhibi-
hexachlorobenzene); tors are selectively toxic to invertebrates
2) Organophosphates (e.g., diazinon, with exoskeleton (Bolognesi and Merlo,
omethoate, glyphosate); 2011). Interestingly, the same approach can
3) Carbamic and thiocarbamide deriva- be used to treat fungi that also possess chitin.
tives (e.g., aldicarb, carbofuran, oxam- Such inhibitors can also potentially serve as
yl, carbaryl); fungicides, but the information on such ap-
4) Carboxylic acids and their derivatives plication is very old and scarce (Leighton et
(e.g., pentanal, butanamide, bu- al., 1981). Therefore, one may expect that
tanamide); inhibitors of chitin synthetase may affect
5) Urea derivatives (e.g., fenuron, me- both insects and fungi.
toxuron, diuron, linuron, monuron);
6) Heterocyclic compounds (e.g., benzim- Herbicides and their mode of action
idazole, triazole derivatives); Herbicides, or chemical weed killers,
7) Phenol and nitrophenol derivatives provide an effective and economical means
(e.g., dinocap, dinoseb); of weed control. The worldwide use of herb-
8) Hydrocarbons, ketones, aldehydes and icides accounts for almost 48 % of the total
their derivatives (e.g., benzene, tolu- pesticide usage. In the last three decades,
ene, cerenox); herbicides have represented the most rapidly
9) Fluorine-containing compounds (e.g., growing segment of the pesticide industry
cryolite, acetoprole, dichlofluanid); (Gupta, 2011). Similar to other pesticides,
10) Copper-containing compounds (e.g., herbicides may be classified according to
champion WP, caocobre, macc 80); specificity, chemical nature, time of applica-
11) Metal-organic compounds (e.g., tion, and mode of action (Peterson et al.,
mancozeb, maneb, zineb, nabam); 2013). Improper use of herbicides has result-
1110
ed in human health problems and the mecha- (including atrazine and simazine) are effec-
nisms of toxicity of many pesticides to non- tive and inexpensive herbicides used to con-
target organisms remain poorly studied. Re- trol a wide spectrum of broadleaf weeds and
search into understanding the mode of action selective grasses (Sathiakumar et al., 2011).
of herbicides may be an important tool to For example, atrazine inhibits photosynthesis
improve their efficiency, application meth- via competition with plastoquinone II at its
ods in various agricultural practices, handle binding site and blocks electron transport in
weed resistance problems, and explore toxic photosystem II (Devine et al., 1993). This
properties (Jablonkai, 2011). inhibition results in the cessation of carbo-
Since most herbicides are synthesized to hydrate synthesis, leading to a subsequent
target specific plant metabolic pathways (e.g. reduction in the carbon pool and a buildup of
photosynthesis, plant hormone action, regu- CO2 within the plant cell (Giddings et al.,
lation of cell division, etc.), they kill plants 2005). At high concentrations, copper or
in different ways (Bolognesi and Merlo, copper-containing pesticides can interrupt
2011; Peterson et al., 2013). However, be- electron transport through photosystem II.
fore killing the target, the herbicide must Jegerschöld et al. (1995) demonstrated that
contact the site of action in the weed other- copper ions blocked the electron donation
wise its actions are useless. Herbicides can from Tyrz to P680 (Figure 4). Moreoever,
affect various sites in plants and at the site of the central magnesium atom of chlorophyll
action each herbicide manifests different was found to be substituted by ions of mer-
mechanisms, which are grouped as follows cury, copper, or cadmium, inhibiting in this
(Peterson et al., 2013): manner operation of photosystem (Küpper et
1. Growth Regulators. This type of al., 1996). Copper ions were found to oxidize
herbicides is used to control broadleaf the low potential form cyt b559 at low con-
weeds. They influence plants stimulating centrations (1-10 µM) and the high potential
their growth like natural hormones shifting form at higher concentrations (10-100 µM),
in this manner hormone balance. For exam- probably by deprotonation of this labile cyt
ple, 2,4-dichlorophenoxiacetic acid belongs b559 form (Burda et al., 2003).
to this group. The mechanism found for her- 4. Inhibitors of Amino Acid Biosyn-
bicidal activity of 2,4-D is based on its aux- thesis. These herbicides block biosynthesis
in-like capacity. A receptor for auxin was re- of certain amino acids. For example, glypho-
ported to recognize synthetic auxin ana- sate [N-(phosphonomethyl)glycine], an ac-
logues such as 2,4-D (Jablonkai, 2011). tive ingredient of herbicide Roundup, inhib-
2. Seedling Growth Inhibitors. its plant biosynthesis of the aromatic amino
Among these herbicides, thiocarbamates and acids such as tyrosine, tryptophan, and phe-
acid amides act as powerful shoot and root nylalanine. There are some other targets for
growth inhibitors. These herbicides appear to these chemicals. Thus, several classes of
interfere with normal plant growth, especial- herbicides may inhibit acetohydroxyacid
ly at growth points. The herbicides that in- synthase, which catalyzes the first common
hibit cell division also belong to this catego- step in the biosynthesis of valine, leucine,
ry. They are frequently mitotic poisons and and isoleucine, or 4-hydroxyphenylpyruvate
are represented mostly by dinitroanilines. dioxygenase, a key enzyme in tyrosine ca-
3. Photosynthesis Inhibitors. These tabolism and carotenoid synthesis (Duggleby
herbicides (e.g. triazines, copper-containing et al., 2008; Garcia et al., 2017). Several
pesticides) block photosynthesis via disrup- compounds are potent inhibitors of gluta-
tion of biomembranes by highly active mole- mine synthase that catalyzes incorporation of
cules. The susceptible plants die from a ammonia onto glutamate (Jablonkai, 2011;
buildup of highly reactive molecules that de- Tarazona et al., 2017).
stroy cell membranes. Triazine herbicides
1111
Fungicides and their mode of action

Fungicides are agents that kill, repel,
prevent, or otherwise mitigate fungi and they
are used to protect tubers, fruits, and vegeta-
bles during storage and plant growth (Gupta,
2011). The mode of action of fungicides de-
pends on their protection role in plants.
Thus, there are preventive fungicides that
prevent infections, antisporulants that pre-
vent spore production, and curative fungi-
cides that inhibit the development of a dis-
ease following infection (Bolognesi and
Merlo, 2011). Moreover, some fungicides
are single-site active ones and affect a fungus
or a single critical enzyme or protein critical-
ly needed by fungus, whereas others are mul-
tisite ones that deal with different metabolic
sites within the fungus (Bolognesi and Merlo,
Figure 4: Cu-inhibitory sites and active sites of differ- 2011). Similar to herbicides, the mode of ac-
ent electron donors and acceptors in PSII-mediated tion of fungicides is closely related to
electron transport. PSII, photosystem II; D1 and D2,
bind the electron carriers involved in transfer of elec- specific fungal metabolic pathways, but this
trons from Tyrz to plastoquinone; b559, cytochrome task is more difficult due to certain similari-
b559; Tyrz, tyrosine residue active electron transfer ties between fungi and animals. Neverthe-
from the manganese complex to reaction centre P680;
Pheo, pheophytin; QA and QB, bound plastoquinone; less, a few general mechanisms of fungicide
P680, reaction center of chlorophyll (primary electron activity can be defined:
donor); PQ, reduced plastoquinone (Husak, 2015). 1. Ergosterol Biosynthesis Blockers.
Conazoles possess the ability to block the
5. Lipid Biosynthesis Inhibitors. synthesis of ergosterol that is an essential
Herbicides of this group such as fluazifop, component of the fungal cell membrane.
sethoxydim, are used mainly for postemer- These fungicides primarily inhibit the cyto-
gent grass suppression. They inhibit biosyn- chrome P450 (CYP-51) or lanosterol-14α-
thesis of lipids and it results, particularly, in demethylase, the only members of the cyto-
impossibility to form biological membranes. chrome family that are found in animals,
6. Cell Membrane Disrupters. These plants, fungi, and prokaryotes. Conazoles
chemicals are light-activated postemergence have a broad antifungal activity and are used
contact herbicides. Injury symptoms are rep- as pharmaceuticals to treat topical and sys-
resented by browning (necrosis) of the tissue temic fungal infections (Bolognesi and Mer-
appear first as water soaked foliage. Paraquat lo, 2011).
and diquat are the most typical representa- 2. Protein Biosynthesis Inhibitors. Di-
tives of this group. thianon acts as a multisite inhibitor of pro-
7. Pigment Biosynthesis Inhibitors. tein formation modifying the sulfhydryl
These herbicides (e.g. clomazone) inhibit bi- groups of many proteins. This protein syn-
osynthesis of photosynthetic pigments called thesis inhibition prevents spore germination
carotenoids, which protect chlorophyll from and germ tube growth. Benzimidazoles, for
destruction by light. Without carotenoids, example, suppress the reassembly of depol-
chlorophyll is destroyed and the plants are ymerized spindle microtubule division. Alt-
unable to carry out photosynthesis. hough these compounds exhibit specific effi-
ciency against fungal organisms, they also
target mammalian microtubule assembly dy-
1112
namics (Bolognesi and Merlo, 2011; Oruc, II. Carbamic acid derivates, namely di-
2010). thiocarbamates and ethylene(bis)-
3. Inhibitors of mitochondrial respi- dithiocarbamates.
ration. Azoxystrobin inhibits mitochondrial III. Halogenated substituted mono-
respiration and energy production by block- cyclic aromatics (substituted ben-
ing electron transfer at the quinone “outside” zenes) such as chlorothalonil.
site of the cytochrome bc1 complex between IV. Organomercury compounds. They
cytochrome b and cytochrome c1 referred to interact with sulfhydryl groups in
as the ubiquinol oxidizing or Qo site and proteins. In animals, they may block
thereby ultimately prevent the generation of transfer of amino acids across the
ATP (Figure 5) (Balba, 2007; Casida and blood-brain barrier and interfere
Durkin, 2017). with protein biosynthesis.
V. Phthalimides or chloroalkylthio-
dicarboximides are chemicals with
broad-spectrum fungicidal effects
(captan, folpet, captafol, etc.) used
as surface protectants and are usual-
ly believed to be nontoxic for
mammals.
Insecticides and their mode of action

Insecticides are any toxic substances
used to kill insects. They are used primarily
to control pests that infect cultivated plants
or to eliminate disease-carrying insects.
Based on their mechanisms of action, insec-
ticides can be grouped in few principal ways
(Figure 6) (Jayaraj et al., 2016; Liu et al.,
2007; Sparks and Nauen, 2015):
Figure 5: Quinone/quinol (Q) site of electron
transfer and azoxystrobin inhibition. Description Nerve and muscle targets
in the text (Modified from Casida and Durkin Cholinesterase inhibition. Carbamate and
(2017)). organophosphate insecticides are used to
control insects via inhibition of cholinester-
ase leading to overstimulation of insect
4. Multisite Fungicides. The wide- nervous system. Such inhibition of acetyl-
spread dithiocarbamate fungicides (man- choline esterase finally kills animals.
cozeb, zineb) are nonspecific and affect dif- Acetylcholine receptor stimulation. Ne-
ferent biochemical processes in target fungi. onicotinoid insecticides and spinosad mimic
These include inhibition of antioxidant en- the action of the neurotransmitter acetylcho-
zymes to disturb redox balance in cells line. They do not affect cholinesterase, but
(Lushchak et al., 2005), suppression of respi- rather bind to acetylcholine receptors result-
ration, and some of them also inhibit the nu- ing in prolonged stimulation leading to insect
clear factor-kB (NF-kB) signaling cascade death.
(Rath et al., 2011). Chloride channel regulation. There are
Chemical classes of fungicides include three mechanisms: activation of chloride
(Balba, 2007): channels (avermectins), inhibition of gam-
I. Benzimidazoles – benomyl, thio- ma-aminobutyric acid (GABA) receptor (or-
phanate-methyl. ganochlorine insecticides), and agonists of
1113
the GABA-gated chloride channel (bifena- mimic effects of juvenile hormone necessary
zate). to enter metamorphosis.
Sodium channel modulators. Pyrethrins Nonspecific growth regulators. The exact
and pyrethroids bind to sodium channels fix- mode of action of the growth regulators is
ing them in open state which leads to tremor, not well understood. For example, hexythi-
and eventually, to death. azox kills before mite eggs can hatch and al-
so kills some immature mites, but does not
Growth and development targets
kill adult forms.
Chitin synthesis inhibitors. There are
hormonal substances that inhibit the Energy production targets
synthesis of chitin in insects and therefore Electron transport inhibition. Aliphatic
result in death at early life stages during type of organochlorine insecticides interferes
embryonic development or molting. with electron transport. They corrupt the
Insect growth regulators. Insecticides of ability of target organism to supply energy.
this group disrupt endocrine system affecting Oxidative phosphorylation disruption.
in this manner production of hormones need- Organotin miticides directly inhibit mito-
ed for animal growth and development into chondrial electron transport chain, whereas
imago. Insects poisoned by insect growth pyrroles uncouple electron transport and ox-
regulators do not receive the signal to meta- idative phosphorylation. This results in disa-
morphose. Some of them were designed to bility to produce ATP.
Figure 6: Insecticide sites of action. Some general methods of insecticide action are shown. Insecti-
cides have many sites of action but most of those in common use affect the nervous system of the in-
sect (B.t., Bacillus thuringiensis; DDT, dichlorodiphenyltrichloroethane; CSIs, chitin synthesis inhibi-
tors; IGRs, interference growth regulators) (Modified from Schneider (2000)).
1114
COMMON INDICATORS OF Several hematological parameters, such

PESTICIDE TOXICITY as hematocrit or hemoglobin, protein or glu-
cose concentration, although mainly nonspe-
It is impossible to monitor all anthropo-
cific, may also be sufficiently sensitive indi-
genic influences that form potential threats to
cators of certain types of pollutants to be
the environment. Therefore, the most prom-
considered as potential biomarkers for pesti-
ising approach to assess the overall quality
cide toxicity (Husak et al., 2014; Husak,
of the environment is to examine biochemi-
2015; Maksymiv et al., 2015; Nieves-
cal responses that reflect the potential of con-
Puigdoller et al., 2007).
taminants impairing physiological processes
Furthermore, when a pesticide possesses
in the exposed organisms (McCarthy and
some genotoxic effect, it may induce a cas-
Shugart, 1990). When a pesticide enters a
cade of events such as formation of structur-
living organism, it may be involved in meta-
al alterations in DNA, DNA damage and
bolic processes due to which its toxic effects
subsequent expression of mutant gene prod-
may be modulated. From this point of view,
ucts, and diseases (e.g. cancer) resulting
a search for potential appropriate biomarkers
from damage to DNA, which also can be
for pesticide toxicity should include common
monitored for delineation of toxicity mecha-
indicators of overall health as well as specif-
nisms (Shugart et al., 1992). Detection and
ic indices selected according to the mode of
quantification of various events in this se-
action of the investigated pesticide. It should
quence also may be employed as biomarkers
be noted that selection of a reliable indicator
in organisms environmentally exposed to
for pesticide toxicity can be complicated if
genotoxic substances (van der Oost et al.,
the mode of action of a toxicant is not
2003).
known, or the presence of some other factors
obscure the investigation (Niimi, 1990).
Generally, it is believed that activities of Hematological and immunological
biotransformation enzymes, which may be parameters
either induced or inhibited upon exposure to Blood is a special organ which is quickly
pesticides and other xenobiotics, are among exposed to absorbed chemicals. Blood pa-
the most sensitive intoxication biomarkers rameters are known to be highly informative
(Bucheli and Fent, 1995). Many environ- indicators of organism status and have many
mental contaminants and/or their metabolites advantages over other tissue samples (Ewald,
have been shown to exert toxic effects such 1995). Samples of blood can be obtained
as inducing oxidative stress (Lushchak, regularly from test organisms, thus allowing
2011a, b; Winston and Di Giulio, 1991). the use of a non-destructive (vital) approach
Reactive oxygen species are well-known for effective assessment. In most cases,
side-products of certain metabolic pathways blood serves as a medium for signaling in
or the autoxidation of certain compounds and animals. Typically, hematological parame-
their concentrations may be acutely or ters are non-specific in their responses to-
chronically elevated under various condi- wards chemical stressors (van der Oost et al.,
tions and cause the development of oxidative 2003). Nevertheless, they may provide im-
stress (Lushchak, 2011a, 2014). The cytotox- portant information in effect-assessment
ic effects of ROS are of particular interest studies. Disturbances in integrated functions
since they may react with crucial cellular can be detected, or strongly indicated, with
macromolecules, usually leading to effects rather simple analysis of blood parameters
including enzyme inactivation, lipid peroxi- (Ewald, 1995).
dation, and DNA damage that, ultimately, Blood indices can be divided into prima-
can lead to cell death via necrosis or apopto- ry and secondary parameters. The primary
sis (Winston and Di Giulio, 1991). blood components include formed elements
(e.g. red and white blood cells) and plasma
1115
with diverse constituents. The latter include Decreases in lymphocyte numbers (lympho-
nutrients, ions, enzymes, and hormones penia) as a consequence of pesticide expo-
(Niimi, 1990). Hemoglobin content and sure have been reported for several fish spe-
hematocrit are common hematological indi- cies (Li et al., 2011; Pimpão et al., 2007;
ces that change in many model systems ex- Svoboda et al., 2001). Lymphopenia is often
posed to xenobiotics. Although their levels accompanied by concurrent increases in
can also be influenced by biological factors monocytes and neutrophils occurring in re-
like animal size, gender, and environmental sponse to stress exposure (Kubrak et al.,
factors like temperature and seasonality (Hu- 2012; Murad and Houston, 1988).
sak et al., 2014; Kennedy, 1995; Schlenk, Generally, immunological indices in the
2005), they are rather informative when deal- blood can supplement hematological pa-
ing with pesticide intoxication (Kubrak et al., rameters and help to clarify possible mecha-
2013). Under stress conditions (including nisms of toxic impacts (Kubrak et al., 2012;
pesticide-induced) these parameters can be Li et al., 2011).
elevated to increase oxygen carrying capaci-
ty and the supply of oxygen to the major or- Histological examinations
gans in response to higher metabolic de- Histological changes are associated with
mands (Rutten et al., 1992). However, most complex biochemical and physiological re-
investigators reported a decrease in hemo- sponses to any stressor. Despite histo-
globin and hematocrit in pesticide-treated an- pathological parameters are rather nonspecif-
imals indicating anemia, hemolysis and ic and do not provide quantitative infor-
erythropoiesis dysfunction (El-Sayed et al., mation, they are popular biomarkers for en-
2007; Kubrak et al., 2013; Saravanan et al., vironmental pollution (Hinton and Lauren,
2011; Svobodová et al., 2003; Vani et al., 1990). Being one of the most promising are-
2011). Hemolysis in human erythrocytes as for assessing animal health and response
caused by chlorophenoxy herbicides was re- to different chemical species, histological in-
ported by Duchnowicz et al. (2002) as a re- vestigations include a wide range of studies
sult of free radical production by phenols that have generally indicated cellular differ-
(probably, due to autoxidation) or/and their ences between control and pesticide-exposed
direct attack on cell structure. In 2005 Duch- animals (Niimi, 1990). It is generally as-
nowicz and colleagues (2005) found some sumed that histopathological biomarkers are
protein damage in erythrocyte membranes valuable indicators of overall health status
which might result from the direct interac- and that they reflect the total levels of pollu-
tion of the investigated herbicide or an indi- tion (van der Oost et al., 2003).
rect effect, for example, via ROS-mediated However, histological changes are not as
oxidation. easily and objectively assessed as are bio-
Several immunological parameters may chemical markers and may require substan-
also be potentially used as biomarkers of tial experience by the researcher (Ewald,
stress conditions, e.g. white blood cell (leu- 1995). The results of our studies, in particu-
kocyte) and lymphocyte status (measured as lar the histopathological changes, indicate
a blood cell or differential counts), non- that goldfish exposure to the triazine herbi-
specific defense factors (such as lysosomal cides, Sencor and Gesagard, over 96 h
activity and levels of acute phase proteins in caused severe deleterious effects which
body fluids), etc. Differential changes in leu- could be related to liver and kidney dysfunc-
kocyte counts may be a sensitive indicator of tion (Hodgson and Goldstein, 2001;
environmental stress. For example, differen- Maksymiv et al., 2015; Mosiichuk et al.,
tial changes in leukocyte counts were found 2015). The histological analysis of control
to be reliable markers of the stress caused by fish showed normal liver and kidney
environmental factors (Cole et al., 2001).
1116
Figure 7: Histopathological alterations of the kidney (A and B) and liver (C and D) tissues of goldfish
(Carassius auratus L.) is presented for exposure to control conditions (A and C) and 71.5 mg L-1 of
Sencor for 96 h (B and D). Samples were stained with hematoxylin-eosin and photomicrographs were
taken using 400× (for kidney) and 200× (for liver) magnification. RT – renal tubules; H – hematopoietic
tissue; N – necrotic cells and nuclei of tubular epithelium; MH – multiple hemorrhage; HT – hypertro-
phy of intertubular hematopoietic tissue; RC – red blood cells in necrotic tubules and Bowman’s cap-
sule; Fv – fatty vacuolization; Sy – sinusoids; Dh – detachment of endothelial cytoplasm with diffuse
hemorrhage; Dhs – dystrophy of hepatic cells; Dec – detachment of endothelial cytoplasm (modified
from Husak et al. (2014), Maksymiv et al. (2015)).
structures (Figure 7A and 7C). However, ex- Also, results from histological exam-
posure for 96 h to 71.5 mg L−1 of Sencor in- inations do not show a direct influence of the
creased the number of dilated sinusoids pollutant, so they should be considered to-
(Figure 7D). Dystrophy in hepatic cells and gether with other parameters. Moreover, they
detachment of endothelial cytoplasm was do not provide reliable quantitative parame-
observed along with an increased number of ters and researchers have to use them as
dilated sinusoids at this Sencor concentra- semi-quantitative data.
tion. The treatment induced various histo-
pathological changes in goldfish kidney, Biochemical indices
such as hypertrophy of intertubular hemato- In some cases, xenobiotic biotrans-
poietic tissue, small and multiple hemor- formation can result in the formation of
rhages, glomerular shrinkage, a decrease in compounds that may be more easily moni-
space between glomerulus and Bowman’s tored than the original chemical and thus
capsule, degeneration, and necrosis of the such products may be used as a biomarker of
tubular epithelium (Figure 7B). pesticide exposure. Biomonitoring using bio-
1117
transformation products of xenobiotics re- ed plasma LDH was reported by Li et al.

quires knowledge of the extent of metabolic (2011) in response to verapamil exposure of
conversion and the types of metabolic prod- juvenile rainbow trout (O. mykiss) and might
ucts formed for each particular compound/s be explained by the release of LDH from in-
produced by the organism (van der Oost et juried tissues (Mishra and Shukla, 2003). A
al., 2003). However, frequently we do not significant increase in LDH activity in the
know the nature of the compounds formed. serum of Cyprinus carpio exposed to 2,4-
In this case, a search for potential biochemi- diamin was also reported by Oruç and Ūner
cal markers of pesticide exposure should be (1999) along with increased serum glucose
focused on measurements of key metabolic and liver glycogen levels and decreased gly-
parameters of a particular pathway, because cogenolysis and glycolysis. Overall, this in-
many changes induced by pesticide exposure dicated significant effects of 2,4-diamin on
lead to metabolic disturbances, inhibition of carbohydrate metabolism.
important enzymes, growth retardation, etc. As described earlier, it is generally ac-
(Murty, 1986). From this point of view, main cepted that there are three phases in xenobi-
metabolic parameters, such as glucose con- otic detoxification. In phase I many xenobi-
centration or activities of serum enzymes, otics are enzymatically modified to hydro-
become of great interest. In some cases, so- lyze or introduce reactive and polar groups
matic (e.g. growth rate) and behavioral (such as hydroxyl) onto the molecule. In ma-
measures can also be effective. The tests of- jority cases, phase I involves transformation
ten require much work and take time to per- of xenobiotic compounds by microsomal
form, but can provide very valuable infor- monooxygenase enzymes, also known as the
mation (Ewald, 1995). mixed-function oxidase (MFO) system (i.e.
It has been suggested that, in general, cytochrome P450). The system facilitates the
stress induces elevation of the transamina- excretion of certain compounds by trans-
tion pathway (El-Sayed et al., 2007) and the forming lipophilic xenobiotics to more wa-
activities of plasma alanine aminotransferase ter-soluble compounds (Bucheli and Fent,
(ALT) and aspartate aminotransferase (AST) 1995). Since the mixed-function oxidase sys-
have been used as relevant stress indicators tem is sensitive to certain environmental pol-
(Ishikawa et al., 2007). Increases in ALT or lutants, its activity may serve as a marker for
AST activities in the extracellular fluid or exposure to certain classes of pesticides
plasma are sensitive indicators to minor cel- (Bucheli and Fent, 1995).
lular damage since the levels of these en- Phase II detoxification enzymes catalyze
zymes within healthy cells always substan- conjugation of xenobiotics (usually after hy-
tially exceed those in the extracellular fluids droxylation) with several endogenous com-
(Moss et al., 1986). Monosex tilapia acutely pounds (e.g. GSH, sulfate, glycine, or glucu-
exposed to a deltamethrin-based pesticide ronic acid), thus facilitating excretion of the
demonstrated significantly increased activi- chemicals by the addition of more polar
ties of these serum transaminases (El-Sayed groups to their structures (Commandeur et
et al., 2007). Also increased plasma ALT ac- al., 1995). Phase II enzymes can play an im-
tivity was found in our previous investiga- portant role in homeostasis as well as in de-
tion in goldfish exposed to 2,4-D herbicide toxification and clearance of many xenobiot-
(Kubrak et al., 2013) and interpreted as a ics (van der Oost et al., 2003). Conjugation
possible evidence of hepatotoxicity and with GSH is the major pathway for pro-
damage to other tissues investigated. cessing of electrophilic compounds and their
Lactate dehydrogenase (LDH) is a glyco- metabolites (George, 1994), due to which
lytic enzyme recognized as a potential bi- GSH levels can be used as another potential
omarker for assessing chemical toxicity biomarker for pesticide toxicity. As an im-
(Kubrak et al., 2013; Li et al., 2011). Elevat- portant antioxidant, GSH is involved in the
1118
enzymatic and non-enzymatic protection various environmental and chemical stresses

against ROS and detoxification of endoge- (Hermes-Lima, 2004; Lushchak, 2011a, b;
nous and exogenous toxicants (i.e. pesti- Storey, 1996; Tseng et al., 2011).
cides) via reaction with electrophilic com- Zhang and colleagues (2004, 2005) de-
pounds to replace hydrogen, chlorine, or ni- scribed the effects of 2,4-dichlorophenol
tro-groups (Lushchak, 2012; Stegeman et al., (2,4-DCP) on antioxidant indices in goldfish
1992). In this case, changes in the levels of liver after a 40-day exposure. The authors
different glutathione forms (either reduced found a significant increase of superoxide
GSH or oxidized GSSG) may indicate a shift dismutase activity at low/intermediate con-
in the prooxidant-antioxidant balance, which centrations of 2,4-DCP perhaps due to early
often takes place under pesticide-induced adaptation suggesting that this parameter
stress conditions (Atamaniuk et al., 2013; could be a potential biomarker of fish expo-
Lushchak, 2012; Maher, 2005). Hence, an sure to 2,4-DCP (Zhang et al., 2004, 2005).
increase in glutathione levels is likely to Goldfish exposure to mancozeb-containing
provide increased protection of cells from carbamate fungicide Tattoo for 96 h also en-
both ongoing stress and subsequent, more hanced liver and renal SOD activity
severe stress (Maher, 2005), whereas eleva- (Atamaniuk et al., 2013). Catalase activity is
tion of oxidized glutathione (GSSG) or the also an important indicator of pesticide-
ratio [GSSG]/[total GSH] is used as an evi- induced oxidative stress (Manda et al.,
dence of oxidative stress (Lushchak, 2012; 2009; Shi et al., 2005) particularly aminotri-
Zhang et al., 2004). A decrease in glutathi- azole inhibited catalase in goldfish tissues
one thiol status, i.e. the ratio of reduced to (Lushchak, 2011b; Vasylkiv et al., 2011),
oxidized glutathione, due to either direct whereas the activity was enhanced in liver of
ROS scavenging or increased glutathione pe- Tattoo-treated goldfish (Atamaniuk et al.,
roxidase/transferase activity is perhaps the 2013). The activity of Se-dependent gluta-
most obvious direct effect of certain pollu- thione peroxidase (Se-GPx) was also in-
tants (Otto and Moon, 1995; Stegeman et al., creased under fish exposure to 2,4-DCP and
1992). Alternatively, a normal ratio was proposed as a potential biomarker
[GSSG]/[total GSH] can be maintained due (Zhang et al., 2005).
to increased activities of glutathione reduc- Additionally, if pesticides are involved in
tase or increased glutathione synthesis (van oxidative stress development, they directly
der Oost et al., 2003). Conjugation of elec- or indirectly increase ROS steady-state level
trophilic compounds with GSH is substan- (Atamaniuk et al., 2013; Kubrak et al.,
tially accelerated by GSTs (Lushchak, 2012) 2013). Therefore, commonly used indices of
and the toxicity of many exogenous com- ROS damage to biomolecules may be im-
pounds can be modulated by induction of portant. Protein carbonyl groups are fre-
GSTs (van der Oost et al., 2003). quently quantified among such indices and
Animal treatment with pesticides is often indicate ROS-induced protein oxidation in
accompanied by the development of oxida- tissues (Dean et al., 1997; Lushchak, 2007).
tive stress (Atamaniuk et al., 2013; Kubrak Enhanced levels of protein carbonyls indi-
et al., 2013; Lushchak, 2011a, b; Matviishyn cate a potentially increased ROS steady-state
et al., 2014). Antioxidant enzymes play key concentration under pesticide influence
roles in ROS detoxification. Therefore their (Atamaniuk et al., 2013; Li et al., 2010b,
activities are believed to be good markers of 2011). Measurements of levels of lipid per-
perturbations in ROS homeostasis frequently oxides may be used similarly (Calabrese et
affected by environmental toxicants (van der al., 2000; Lushchak, 2012).
Oost et al., 2003; Lushchak, 2016). At the With respect to neuromuscular functions,
same time, these enzymes are sensitive to recent studies indicated that the “old” classic
many factors and show diverse responses to biomarker, AChE, that is sensitive to organ-
1119
ophosphate (OP) and carbamate pesticides, auratus L., showed a significant increase in
may respond to low levels of contaminants the frequencies of micronuclei and DNA
in the environment and be successfully used strand breaks in goldfish erythrocytes, indi-
in the toxicity monitoring (Liu et al., 2007; cating the genotoxic potential of this pesti-
Valbonesi et al., 2011; Vani et al., 2011). In- cide (Cavas, 2011). DNA damage under 2,4-
hibition of AChE results in a buildup of ace- D exposure of CHO (Chinese hamster ovary)
tylcholine levels, causing a continuous and cells also provided additional evidence for
excessive stimulation of the nerves and mus- the genotoxicity of pesticides (González et
cle fibers, which leads to tetany, paralysis, al., 2005). All methods applied to demon-
and eventual death (Liu et al., 2007). Meas- strate high efficiency and may be considered
urement of AChE inhibition is one of the as potential biomarkers of pesticide genotox-
most widely used biomarkers of environ- icity (Bolognesi, 2003; González et al.,
mental pollution with pesticides (Atamaniuk 2005; van der Oost et al., 2003).
et al., 2013; Edwards et al., 1991; Mat-
viishyn et al., 2014; Vani et al., 2011). PRINCIPAL MOLECULAR
All of the biochemical indices mentioned MECHANISMS OF PESTICIDE
above are very important in the investigation TOXICITY
of hazardous influences of pesticides, but the The problem of the toxicity of pesticides
relevant list of biomarkers may become wid- and other related chemicals to non-target or-
er or narrower in each particular study de- ganisms is still a major concern around the
pending on the mode of action and metabolic world. Since pesticides may produce many
processes of the chemicals under inspection. physiological and biochemical changes when
Therefore, these and many other biochemical they enter the body, a search for mechanisms
parameters help to clarify the possible mech- of their toxicity can be much more compli-
anisms of the toxic impacts of pesticides. cated than expected. Perhaps the pesticide
mode of action may be one of the most relia-
Genetic studies ble tools for searching the mechanisms of
Direct or indirect interaction of pesticides their toxicity.
with DNA leads to damage of the latter or Pesticides can cause adverse effects by
chromosomal aberrations are also effective interfering with the body’s hormones or
indicators of pesticide toxicity within the messengers (Khan and Law, 2005), affecting
context of carcinogenesis and teratogenesis the nervous system (e.g. organochlorine pes-
(Calviello et al., 2006; González et al., ticides) (Bolognesi and Merlo, 2011), or di-
2005). They are studied in the field of genet- rectly or indirectly inducing changes in the
ic toxicology and can be analyzed by distinc- activities of certain enzymes (Atamaniuk et
tive kinds of genotoxicity tests. Genetic toxi- al., 2013; Kubrak et al., 2012, 2013; Mat-
cology can be defined as the study of pollu- viishyn et al., 2014). A large group of pesti-
tant-induced changes to the genetic material cides may directly enhance ROS levels in the
of organisms and a growing body of data living organisms due to their autoxidation by
concerning the genetic toxicity of pesticides molecular oxygen (Bolognesi and Merlo,
has been collected from epidemiological and 2011; Lushchak, 2011b). Mostafalou and
experimental studies that examine parame- Abdollahi (2013) have conducted extensive
ters including chromosomal aberrations, work to systematically catalog the molecular
formation of micronuclei, cell-cycle progres- mechanisms of pesticide toxicity. Their
sion, sister chromatid exchanges and DNA study resulted in a theoretical interpretation
strand breaks (comet assay) (Bolognesi, of causal relationships between pesticide ex-
2003). For example, a recent study of the posure and human chronic diseases via DNA
pesticide genotoxic effects of an atrazine- damage (Mostafalou and Abdollahi, 2013).
based herbicide on a model fish, Carassius
1120
Molecular mechanisms of pesticide-induced decreasing its activity (Figure 8C). In result,

neurotoxicity acetylcholine accumulates in the central and
The nervous system is the main target of peripheral nervous systems. Such inhibition
acute toxic action by diverse organochlorine provokes an accumulation of acetylthio-
insecticides. These chemicals are the active choline in synapses with disruption of the
ingredients of various home and garden nerve function that can end in the death of
products as well as some agricultural and the organism (Peakall, 1992).
environmental pest control products; their Chlorpyrifos, an organophosphate insec-
high environmental persistence makes them ticide, is known to inhibit AChE by phos-
dangerous contaminants (Bolognesi and phorylating the enzyme in both neuron syn-
Merlo, 2011; Rizzati et al., 2016). Some of apse and plasma and it can cause symptoms
them, such as derivatives of the banned pes- such as nausea, dizziness, and confusion, and
ticide DDT have been shown to induce neu- even hyperactivity, paralysis, respiratory pa-
ral cell death by apoptosis through the acti- ralysis, and death at exposure to pesticide at
vation of mitogen-activated protein kinases high concentrations (John and Shaike, 2015).
(Shinomiya and Shinomiya, 2003). Toxicity Not like most organochlorine pesticides, it is
of DDT and pyrethroids was found to be as- relatively nonpersistent and its principal deg-
sociated with blocking of voltage-gated so- radation products are less toxic than the par-
dium channels (VGSCs) in plasmatic mem- ent chemical. Interestingly, aquatic and ter-
brane of neurons (Silver et al., 2017). The restrial microorganisms and plants are rather
neurotoxic effect of endosulfan is probably tolerant to chlorpyrifos, whereas aquatic in-
realized via its well-known ability to block vertebrates, particularly crustaceans and in-
neuronal GABAA-gated chloride channels sect larvae, are very sensitive to exposure
(Kamijima1 and Casida, 2000). (Barron and Woodburn, 1995). Diazinon,
Organophosphorus pesticides are also another organophosphate, also inhibits
potent neurotoxins since they are irreversible AChE (Bisson and Hontela, 2002).
inhibitors of acetylcholinesterase (Figure 8) A lot of studies verifying the neuro-
(Galloway and Handy, 2003). Most animals toxicity of 2,4-dichlorophenoxyacetic acid
also possess non-specific esterases or pseu- (2,4-D) have been focused on the central
docholinesterases with high affinity for bu- nervous system (Rosso et al., 2000). This
tyrylcholine. Fish brain, for example, con- toxicity is caused, in part, by the formation
tains AChE, but not BChE, whereas muscle of free radicals and leads to decreased GSH
tissues contain both AChE and BChE (Sturm levels and impaired action of antioxidant
et al., 2000). AChE is involved in the deacti- enzymes such as superoxide dismutase and
vation of acetylcholine (hydrolysis to choline catalase (Bukowska, 2003). Bernard et al.
and acetate) at nerve endings, preventing (1985) found decreased AChE specific activ-
continuous nerve firing, and is vital for nor- ity after 2,4-D injection in some rat muscles
mal functioning of sensory and neuromuscu- in vivo, but not in vitro indicating a nondirect
lar systems (van der Oost et al., 2003). The effect unlike that of OPs. Others found that
activity of AChE has been widely used in 2,4-D might also affect the enteric nervous
aquatic animals to diagnose exposure to or- system by documenting atrophy of the cellu-
ganophosphate or carbamate pesticides (Ful- lar body in a general population of rat myen-
ton and Key, 2001). In the synapse, acetyl- teric neurons and triggered by 2,4-D hyper-
cholinesterase catalyzes degradation of ace- trophy of the cell body of neurons positive to
tylcholine (Figure 8B). Organophosphate NADPH-diaphorase (Correa et al., 2011).
pesticides phosphorylate acetylcholinesterase
1121
Figure 8: Effect of organophosphorus insecticides in the transmission of nerve impulses: A – acetyl-

choline signaling at synapse; B – acetylcholinesterase stops signaling process; C – organophosphates
inhibit acetylcholinesterase.
Many dithiocarbamates are implicated in neurological disorder – Parkinson’s disease,

inducing peripheral Parkinson’s-like neuro- the occurrence of may be linked with influ-
pathy (Rath et al., 2011). These chemicals ence of pesticides as an environmental factor
induce intraneuronal oxidative stress leading (Bolognesi and Merlo, 2011). Indeed, Par-
to neuronal damage, since metal ions re- kinsonian symptoms occurred following ex-
leased during cell damage may promote lipid posure to the herbicide paraquat or the fungi-
peroxidation and enzyme inhibition resulting cide maneb. Paraquat is thought to be trans-
in neurotoxic effects (Fitsanakis et al., 2002; ported across the blood-brain barrier by the
Nobel et al., 1995). The fungicide, maneb, action of a neutral amino acid transporter
affects biological systems in numerous ways, such as the system L carrier (LAT-1), which
but its primary neurotoxic mechanism is still normally carries L-valine and L-phenyl-
under debate (Meco et al., 1994). The com- alanine; indeed, administration of high levels
pound impairs the operation of some recep- of these amino acids has been reported to
tors and ion channels of the plasma mem- prevent paraquat-induced neurotoxicity
brane, systems for signal transduction and (Chanyachukul et al., 2004). The mito-
second messenger synthesis, and some cellu- chondrial complex I inhibitor, rotenone, en-
lar enzymes and metalloproteins. The mech- hances mitochondrial ROS production result-
anisms that have been suggested to explain ing in dopamine redistribution to the cytosol
the maneb neurotoxicity include dopamine and may potentiate rotenone-induced apop-
autoxidation, stimulation of ROS generation, tosis of dopaminergic cells (Watabe and
a decrease in the levels of GSH and reduced Nakaki, 2007).
activities of glutathione peroxidase and cata-
lase (Meco et al., 1994). Degeneration of ni- ROS-mediated pesticide toxicity
grostriatal dopaminergic neurons is often as- Many pollutants including pesticides
sociated with a late onset of the progressive may exert toxicity related to induction of ox-
1122
idative stress (Lushchak, 2011a, b, 2016; van to proteasomal dysfunction, which was
der Oost et al., 2003; Wang et al., 2016). shown to be modulated by intracellular glu-
This induction can take place in several tathione (Barlow et al., 2005). Mancozeb,
ways: thiram, and disulfiram also caused mem-
1. Certain chemicals may increase ROS brane potential changes, impaired ATP-
production as byproducts of the op- dependent glutamate uptake into the synaptic
eration of detoxification pathways; vesicles, and prevented binding of glutamate
2. Some pesticides can alter the opera- to its receptors resulting in excitotoxic ef-
tion of the mitochondrial and endo- fects in the brain (Vaccari et al., 1999). Gen-
plasmic reticulum electron transport erally, the prooxidant properties of DTC
chains leading to ROS overprod- compounds cause imbalances between GSH
uction; and GSSG, typically raising levels of GSSG
3. Pesticides can also increase ROS (Burkitt et al., 1998). Increased levels of
production by entering redox cycles GSSG can lead to the activation of the tran-
(e.g. autoxidation), which has been scription factor nuclear factor kappa B (NF-
proposed as the central mechanism κB) that in turn stimulates a stress and in-
for the toxic effects of many envi- flammatory response and affects cell survival
ronmental toxicants including pesti- (Delhalle et al., 2004). On the other hand,
cides; reduction of GSSG to GSH catalyzed by glu-
4. Pesticide can also inhibit antioxidant tathione reductase was inhibited by DTC
and associated enzymes or the bio- which was found to inactivate several differ-
synthesis of antioxidants such as glu- ent transcription factors principally, the NF-
tathione. κB and hypoxia-inducible factor HIF-1
The ability to act as a prooxidant agent is (Haddad, 2003). A number of enzymes in-
one of the possible mechanisms to explain cluding heme oxygenase, cytochrome P450,
the toxicity of DTC fungicides and several superoxide dismutase, glutathione reductase,
reports have recently provided support to this caspase, etc. are inhibited by DTC (Dalvi et
hypothesis. In particular, maneb and zineb al., 2002; Seefeldt et al., 2009). On the other
were shown to catalyze cathecol autoxidation hand, DTC pesticides are also capable of act-
(Fitsanakis et al., 2002), and the mancozeb- ing as antioxidants. They react with hydroxyl
containing pesticide Tattoo induced oxida- radicals, peroxides, and superoxide ions to
tive stress in goldfish and frogs, altering ac- decrease their oxidative activity (Liu et al.,
tivities of primary antioxidant enzymes 1996; Nobel et al., 1995). Additionally, the
(Atamaniuk et al., 2013; Falfushinska et al., DTC compounds can form mixed disulfides
2008). The presence of metals in the chemi- with other molecules containing thiol func-
cal structure of these pesticides can catalyze tional groups such as proteins, peptides and
ROS formation via the Fenton reaction that enzymes modulating their biological activi-
could explain the observed prooxidant activities. Covalent modification of cysteine resi-
ty (Calviello et al., 2006; Lushchak, 2016). dues in the active sites can affect enzyme ac-
Interestingly, oxidative stress along with tox- tivities (Lushchak, 2012, 2016; Rath et al.,
ic effects was noted in various species of an- 2011).
imals, such as rats, mice, zebrafish, clams, The activities of antioxidant enzymes, in
and sea snail, Hexaplex trunculus, suggest- turn, can be affected by pesticides. Super-
ing that oxidative stress induced by perme- oxide dismutase (SOD) plays a pivotal anti-
thrin might be a common mechanism for its oxidant role as evidenced by its presence in
toxicology (Wang et al., 2016). Maneb can virtually all aerobic organisms examined to
also induce oxidative stress as evidenced by date (Lushchak, 2011a, b; Stegeman et al.,
the formation of additional carbonyl groups 1992). Catalases are known to facilitate the
in proteins and α-synuclein aggregation due removal of hydrogen peroxide, which is me-
1123
tabolized by them to molecular oxygen and as the result of ROS generation with exten-
water. Glutathione peroxidase (GPx), which sive oxidative damage represent the most le-
employs GSH as a cofactor, reduces many thal and least treatable manifestation of par-
organic peroxides; its operation plays an es- aquat toxicity in exposed animals (Bolognesi
pecially important role in protecting the in- and Merlo, 2011). Despite its structural simi-
tegrity of membranes under oxidative insults larity to paraquat, the mechanism of diquat
via prevention of lipid peroxidation toxicity was found to differ. It has been pro-
(Stegeman et al., 1992; van der Oost et al., posed that diquat stimulates ROS production
2003). Lipid peroxidation or oxidation of by inhibition of complexes I and III of the
polyunsaturated fatty acids is a very im- mitochondrial electron transport chain
portant consequence of ROS attack to living (Drechsel and Patel, 2009).
organisms since it demonstrates the ability of In redox cycles, the parent compound is
a single radical species to propagate a num- typically first reduced enzymatically by a
ber of deleterious biochemical reactions NADPH-dependent reductase to yield a xe-
(Stegeman et al., 1992; van der Oost et al., nobiotic radical (van der Oost et al., 2003).
2003). This radical donates its unshared electron to
It is known that some pesticides can molecular oxygen, yielding an O2•− radical
cause oxidative stress by stimulating ROS and the parent compound. Thus, at each turn
generation (Banerjee et al., 1999). Therefore, of the cycle, two potentially deleterious
they are suspected to induce alterations in events occur: reductant oxidation and ox-
antioxidant and ROS-scavenging enzymatic yradical formation (Goeptar et al., 1995).
systems. Pesticide-induced toxicity of many These processes induce either adaptive re-
pollutants may be realized via stimulation of sponses, such as increase in the activities of
peroxidation of lipids (Akhgari et al., 2003). antioxidant enzymes and concentrations of
For example, long-term exposure to pro- low molecular mass antioxidants like gluta-
piconazole was shown to cause ROS- thione, or manifestations of oxidant-
promoted stress in several tissues of rainbow mediated toxicity such as oxidations of pro-
trout, O. mykiss, reflected by significantly teins, lipids and nucleic acids, as well as per-
higher levels of lipid peroxides and protein turbing tissue redox status (Lushchak, 2011a,
carbonyl groups (Li et al., 2010b). b, 2016).
Production of ROS can also be stimulat-
ed by phenoxy herbicides perhaps due to Endocrine and reproductive disruptions
ROS formation by autoxidation, or a direct under pesticide influence
attack of the phenoxyl radicals on sensitive A number of pesticides, such as vinclo-
enzymes from a number of metabolic path- zolin, dicofol, atrazine, and others, belong to
ways (Selassie et al., 1998). Indeed, several the class of chemicals called endocrine dis-
studies demonstrated that 2,4-D induced oxi- ruptors (EDCs) that are known to interfere
dative stress and depleted antioxidants both with the production, release, transport, me-
in vitro and in vivo (Bukowska, 2003; Ku- tabolism, action, or elimination of hormones
brak et al., 2013; Matviishyn et al., 2014; responsible for maintenance of homeostasis
Wafa et al., 2012). and regulation of developmental processes
Herbicide paraquat can enter an autoxi- (Bolognesi and Merlo, 2011; Khan and Law,
dation process resulting in the production of 2005). In fish, EDCs can cause male fish to
superoxide anion radicals (Figure 9) transform into ones with female characteris-
(Bonneh-Barkay et al., 2005). As a free radi- tics. These outward symptoms of develop-
cal generator, paraquat has a redox potential mental disruption are accompanied by re-
of -446 mV. Formed superoxide anion may duced fertility or even sterility in adults, as
be converted to hydrogen peroxide and hy- well as lower hatching rates and viability of
droxyl radical (Figure 9). Pulmonary effects offsprings (Ewing, 1999; Goodbred et al.,
1124
Figure 9: Paraquat-induced oxidative stress. Description in the text. (Modified from Dinis-Oliveira et
al. (2008))
1997). Pesticides as the exogenous hormone mones (Tollefsen, 2002). Some toxicants al-
agonists/antagonists can disrupt the function so disrupt the synthesis of hormone receptors
of endogenous hormones. Agonists may in- (Scott and Sloman, 2004).
teract with hormone-binding proteins, and The ultimate aim of reproduction is birth
antagonists may displace endogenous hor- and its success depends upon both male and
1125
female reproductive systems (Gupta, 2011). sure to atrazine (Grasiela and Silva-Zacarin,
The decreased reproductive capability may 2012).
be considered as one of the most damaging It was observed that a single dose of ben-
effects of the persistent pollutants (e.g. pesti- zimidazole carbamates induced rapid testicu-
cides) released by humans (van der Oost et lar effects, detectable as an increase in testis
al., 2003). The presence of these chemicals weight, but having long-term effects leading
in the environment has become a global con- to testicular atrophy and infertility. The in-
cern. As blockers of sex hormone effects, flammatory response with occluded ductules
pesticides may cause abnormal sexual devel- caused subsequent damage to the ductal epi-
opment and other disturbances of other vital thelium. The rete testis was swollen with
processes (Ewing, 1999; Gupta, 2011). compacted sperm and the seminiferous tu-
Although dioxin is not used as pesticide, bules were atrophic with edematous intersti-
in some cases it can arise as a contaminant at tial space (Nakai and Hess, 1997).
production of herbicides (Manz et al., 1991). Dithiocarbamates are well-known endo-
Dioxin is the most toxic and best-studied crine disrupters that alter thyroid hormone
chemical that can lead to male reproductive levels and animal mass. The number of
toxicity (Gupta, 2011). It causes functional healthy follicles was a significantly de-
developmental toxicity with additional struc- creased, whereas thyroid gland weight was
tural abnormalities that are delayed in their increased (Baligar and Kaliwal, 2001). The
appearance in multiple species. The effects hypothyroid and antithyroid effects of the
of prenatal dioxin exposure on the reproduc- fungicides zineb and mancozeb are associat-
tive system of female rats and hamsters indi- ed with their metabolite ethinylthiourea
cated a delay in vaginal opening and clefting (Houeto et al., 1995). The action of ethinyl-
of the external genitalia (Cooper et al., 2000). thiourea on the thyroid gland with resultant
This may reflect a lack of appropriate differ- hyperplasia and a decrease in thyroid hor-
entiation. mone levels is the most prominent aspect of
The herbicide atrazine has been proposed its toxicity (Houeto et al., 1995).
to exert adverse effects on the reproductive Interestingly, ROS are not only associat-
system of animals including mammals, fish, ed with oxidative stress, but are also thought
and amphibians (Grasiela and Silva-Zacarin, to play significant roles in reproduction
2012). Indeed, it is reported to disrupt ovari- (Bongiovanni et al., 2012). Hence, induction
an function by altering hypothalamic control of oxidative stress by pesticides has also
of the pituitary and the release of luteinizing been pointed out as a possible mechanism of
hormone and prolactin in female rats some toxic effects on the reproductive sys-
(Cooper et al., 2000). Ovarian cycle irregu- tem (Abdollahi et al., 2004).
larities may be due to the ability of atrazine
to interfere with hormone synthesis, binding Carcinogenic, teratogenic, and genotoxic
to the estrogen receptor without activation effects of pesticide exposure
(Solomon et al., 2008). Similar effects were Animal studies remain a valuable tool for
observed when atrazine degradation products detecting of potential human cancer hazards.
were found to affect the onset of puberty and However, the evidence that a chemical caus-
thyroid function in male rats via actions on es tumors in experimental animals is consid-
the central nervous system and its subse- ered sufficient only when experimental data
quent control of the pituitary-gonadal axis show an increased incidence of malignant
(Stoker et al., 2002). There was also evi- tumors in multiple species and following
dence of reproductive function impairment multiple routes (Bolognesi and Merlo, 2011).
and depletion of the antioxidant defense sys- A few pesticides (e.g. dithiocarbamates)
tem in rat testis and epididymis after expo- have been demonstrated to be animal carcin-
ogens. The production of carcinogenic com-
1126
pounds such as N-nitrosocarbaryl, a deriva- damage, embryo loss during pregnancy, oxi-
tive of carbaryl which is a potent carcinogen dative DNA damage, and cancers of the kid-
in rats is the principal hazard of these toxins ney and forestomach (Oruc, 2010). Most of
(Bolognesi and Merlo, 2011). Ethylene thio- these effects have been observed in several
urea, a degradation product of ethylene bisdi- tested species. As a result, chlorothalonil is
thiocarbamate fungicides, is also reported to classified as a “probable human carcinogen”
be a teratogen, goitrogen, and carcinogen by the U.S. Environmental Protection Agen-
that can disrupt thyroid function and is caus- cy (Cox, 1997).
ally related to thyroid cancer in animals Pesticide-induced oxidative stress is
(Steenland et al., 1997). Thyroid-like effects well-known to cause genotoxicity (Franco et
of fungicides were observed in subchronic al., 2010). In general, pesticides have been
level studies of metiram-treated rats as evi- shown to alter cellular redox balance enhanc-
denced by increased thyroid mass, increased ing ROS levels, lipid peroxidation, and de-
levels of thyroid-stimulating hormone and pletion of antioxidant defenses (Abdollahi et
decreased levels of T4 (serum thyroxin) al., 2004; Banerjee et al., 2001; Lushchak,
(U.S. EPA, 2005). The ethylene-bis- 2016). Living organisms protect themselves
dithiocarbamates, in general, are considered from genotoxic and carcinogenic compounds
to be carcinogenic because of their metabo- in different ways. GSTs are an enzyme su-
lite ETU (Houeto et al., 1995; U.S.DA, perfamily responsible for GSH conjugation
1998). In vitro studies of zineb effects on with xenobiotics in their original or trans-
human lymphocytes and CHO cells showed formed forms and they might protect organ-
induction of DNA strand breaks suggesting isms against exogenous and endogenous tox-
its carcinogenic potential in the event that icants (Lushchak, 2012). The activity of
the affected cells survived and propagated these enzymes in many cases can be altered
(González et al., 2003; Soloneski et al., by pesticide exposure (Atamaniuk et al.,
2002). Calviello et al. (2006) demonstrated 2013; Kubrak et al., 2012).
DNA single-strand breaks in rat fibroblasts It is known that the herbicide 2,3,7,8-
exposed to mancozeb. tetrachlorodibenzodioxin is also an environ-
Atrazine is one of the most important tri- mental teratogen. It affects cellular immunity
azine herbicides used in large quantities in rodents and alters reproductive functions
worldwide. It has been identified as an endo- in the immature rat model through influences
crine disrupting chemical and a potential on the hypothalamic-pituitary axis as well by
carcinogen (Chelme-Ayala et al., 2005). The direct effects on the ovary (Li et al., 1995).
appearance of mammary tumors in atrazine- Teratology studies on 2,4-D indicated that
treated female rats has been documented malformations are likely to occur only at
(Eldridge et al., 1999). doses that are fetotoxic or maternally toxic
Genotoxic compounds are those that act (USDA, 1998).
through direct or indirect DNA damage (Bo-
lognesi and Merlo, 2011). Many pesticides
OVERALL CONCLUSIONS AND
tested induced diverse mutations via DNA
PERSPECTIVES
damage. The genotoxic potential of agro-
chemical ingredients is generally low, but There is no doubt that pesticides influ-
occupational exposure to mixtures of pesti- ence the host's energy metabolism, nervous,
cides has been associated with an increase in cardiovascular, and endocrine systems, either
genotoxic damage in a number of studies directly or indirectly. It is clear that they
(Calviello et al., 2006; González et al., cause many diseases, including metabolic
2005). syndrome, malnutrition, atherosclerosis, in-
In laboratory tests, chlorothalonil fungi- flammation, pathogen invasion, nerve injury,
cide caused kidney damage, anemia, liver and infectious disease susceptibility. Moreo-
1127
ver, the listed pathologies may be aggravated Conflict of interest

in animals after exposure to pesticides. In The authors declare that they have no
this review, we discussed the classification conflict of interest.
of pesticides and their possible effects on
non-target organisms. We further empha- REFERENCES
sized the importance and necessity of con- Abdollahi M, Ranjbar A, Shadnia S, Nikfar S, Rezaie
sidering non-target living organisms as toxi- A. Pesticides and oxidative stress: a review. Med Sci
cological indicators for environmental pollu- Monit. 2004;10:141-7.
tion by pesticides. In the future, more studies
Akhgari M, Abdollahi M, Kebryaeezadeh A, Hosseini
should focus on the mechanisms of pesticide R, Sabzevari O. Biochemical evidence for free radical
long-term influences on health. induced lipid peroxidation as a mechanism for sub-
Pesticides are known to exert specific ef- chronic toxicity of malathion in blood and liver of rats.
fects on some cellular processes and/or key Hum Exp Toxicol. 2003;22:205-11.
proteins involved in the regulation of general Atamaniuk TM, Kubrak OI, Storey KB, Lushchak VI.
metabolism, cell growth, differentiation, and Oxidative stress as a mechanism for toxicity of 2,4-
survival. Individual pesticides can influence dichlorophenoxyacetic acid (2,4-D): studies with
the mitochondrial respiratory chain, leading goldfish gills. Ecotoxicology. 2013;22:1498-508.
to apoptosis and/or increased ROS levels.
Balba H. Review of strobilurin fungicide chemicals. J
The latter, which is also part of the detoxify- Environ Sci Health. 2007;42:441-51.
ing process, may provoke inflammation
and/or alter cell signaling cascades involved Baligar PN, Kaliwal BB. Induction of gonadal toxici-
in the control of growth and survival or in- ty to female rats after chronic exposure to mancozeb.
Ind Health. 2001;39:235-43.
duce DNA damage. Moreover, the chronic
duration of exposure to most contaminants Banaszkiewicz T. Biomonitoring in the assessment of
may add another level of complexity that chemical threats to the environment. In: Skibniewska
must also be considered in risk evaluation. KA (ed): Contemporary problems of management and
environmental protection (pp 31-41). Olsztyn:
Future studies should be directed to mini- Univeristy of Warmia and Mazury, 2010.
mize or eliminate influence of pesticides on
non-target living organisms, produce more Banerjee B, Seth V, Bhattacharya A, Pasha S,
specific pesticides and using of modern Chakraborty A. Biochemical effects of some pesti-
technologies to decrease contamination of cides on lipid peroxidation and free radical scavengers.
Toxicol Lett. 1999;107:33-47.
food and other goods by pesticides.
Banerjee BD, Seth V, Ahmed RS. Pesticide-induced
Acknowledgments oxidative stress: perspectives and trends. Rev Environ
We thank the many members of the V. Health. 2001;16:1-40.
Lushchak’s laboratory who have contributed Barlow BK, Lee DW, Cory-Slechta DA, Opanashuk
over the years: Drs. T. Bagnyukova, O. Ku- LA. Modulation of antioxidant defense systems by the
brak, O. Lushchak, N. Semchuk (Mosi- environmental pesticide maneb in dopaminergic cells.
ichuk), H. Semchyshyn, O. Vasylkiv, and I. Neurotoxicology. 2005;26:63-75.
Maksymiv, the research reviewed in this ar- Baron JM, Wiederholt T, Heise R, Merk HF, Bickers
ticle. The works were partially supported by DR. Expression and function of cytochrome P450-
the grants from Ministry of Education and dependent enzymes in human skin cells. Curr Med
Science of Ukraine to VIL and a discovery Chem. 2008;15:2258–64.
grants from the Natural Sciences and Engi- Barron MG, Woodburn KB. Ecotoxicology of
neering Research Council of Canada to KBS. chlorpyrifos. Rev Environ Contam Toxicol. 1995;144:
1-93.
1128
Bernard PA, Toyoshima E, Eccles CU, Mayer RF, Calabrese V, Bates TE, Stella AMG. NO synthase and
Johnson KP, Max SR. 2,4-Dichlorophenoxyacetic ac- NO-dependent signal pathways in brain aging and
id (2,4-D) reduces acetylcholinesterase activity in rat neurodegenerative disorders; the role of oxidant/anti-
muscle. Exp Neurol. 1985;87:544-56. oxidant balance. Neurochem Res. 2000;25:1315-41.
Bisson M, Hontela A. Cytotoxic and endocrine- Calviello G, Piccioni E, Boninsegna A, Tedesco B,

disrupting potential of atrazine, diazinon, endosulfan Maggiano N, Serini S, et al. DNA damage and apop-
and mancozeb in adrenocortical steroidogenic cells of tosis induction by the pesticide Mancozeb in rat cells:
rainbow trout exposed in vitro. Toxicol Appl Pharma- Involvement of the oxidative mechanism. Toxicol
col. 2002;180:110-7. Appl Pharmacol. 2006;211:87-96.
Bolognesi C. Genotoxicity of pesticides: a review of Casida JE, Durkin KA. Pesticide chemical research in
human biomonitoring studies. Mutat Res. 2003;543: toxicology: lessons from nature. Chem Res Toxicol.
251-72. 2017;30:94-104.
Bolognesi C, Merlo FD. Pesticides: human health ef- Cavas T. In vivo genotoxicity evaluation of atrazine
fects. In: Nriagu JO (ed): Encyclopedia of environ- and atrazine-based herbicide on fish Carassius au-
mental health (pp 438-53). Burlington: Elsevier, 2011. ratus using the micronucleus test and the comet assay.
Food Chem Toxicol. 2011;49:1431-5.
Bongiovanni B, Konjuh C, Pochettino A, Ferri A. Ox-
idative stress as a possible mechanism of toxicity of Chanyachukul T, Yoovathaworn K, Thongsaard W,
the herbicide 2,4-dichlorophenoxyacetic acid (2,4-D). Chongthammakun S, Navasumrit P, Satayavivad J.
In: Hasaneen MNAE-G (ed): Herbicides – properties, Attenuation of paraquat-induced motor behavior and
synthesis and control of weeds (pp 315-34). Croatia: neurochemical disturbances by l-valine in vivo. Toxi-
InTech, 2012. col Lett. 2004;150:259-69.
Bonneh-Barkay D, Reaney SH, Langston WJ, Di Chelme-Ayala P, El-Din MG, Smith DW, Guest RK.
Monte DA. Redox cycling of the herbicide paraquat Pesticides and herbicides. Water Environ Res. 2005;
in microglial cultures. Brain Res Mol Brain Res. 77:2021-129.
2005;134:52-6.
Chovanec A, Hofer R, Schiemer F. Fish as bio-
Bounds SVJ, Hutson DH. The comparative metabo- indicators. In: Markert BA, Breure AM, Zechmeister
lism of agrochemicals in plants and mammals. In: HG (eds): Bioindicators and biomonitors (pp 639-76).
Roberts T (ed): Metabolism of agrochemicals in Burlington: Elsevier, 2003.
plants (pp 179-209). Chichester: Wiley, 2000.
Cole MB, Arnold DE, Watten BJ, Krise WF. Haema-
Bucheli TD, Fent K. Induction of cytochrome P450 as tological and physiological responses of brook charr
a biomarker for environmental contamination in to untreated and limestone neutralized acid mine
aquatic ecosystems. Crit Rev Environ Sci Technol. drainage. J Fish Biol. 2001;59:79-91.
1995;25:201-68.
Commandeur JNM, Stijntjes GJ, Vermeulen NPE.
Bukowska B. Effects of 2,4-D and its metabolite 2,4- Enzymes and transport systems involved in the for-
dichlorophenol on antioxidant enzymes and level of mation and disposition of glutathione S-conjugates.
glutathione in human erythrocytes. Comp Biochem Role in bioactivation and detoxification mechanisms
Physiol Part C. 2003;135:435-41. of xenobiotics. Pharmacol Rev. 1995;47:271-330.
Burda K, Kruk J, Schmid HG, Strzalka K. Inhibition Connell DW, Bowman M, Hawker DW. Bioconcen-
of oxygen evolution in photosystem II by Cu(II) ions tration of chlorinated hydrocarbons from sediment by
is associated with oxidation of cytochrome b559. Bio- oligochaetes. Ecotoxicol Environ Saf. 1988;16:293-
chem J. 2003;371:591-601. 302.
Burkitt MJ, Bishop HS, Milne L, Tsang SY, Provan Cooper RL, Stoker TE, Tyrey L, Goldman JM,
GJ, Nobel CS, et al. Dithiocarbamate toxicity toward McElroy WK. Atrazine disrupts the hypothalamic
thymocytes involves their copper-catalyzed conver- control of pituitary – ovarian function. Toxicol Sci.
sion to thiuram disulfides, which oxidize glutathione 2000; 53:297-307.
in a redox cycle without the release of reactive oxy-
gen species. Arch Biochem Biophys. 1998;353:73-84. Correa OP, Mari RB, Toledo EL, Guimarгes JP, Pe-
reira JNB, Germano RM, et al. Effects of the inges-
tion of 2,4 dichlorophenoxyacetic acid on jejunal
myenteric neurons in rats. J Morphol Sci. 2011;28:
104-112.
1129
Cox C. Chlorothalonil, Fungicide Factsheet. J Pestic Eldridge JC, Wetzel LT, Stevens JT, Simpkins JW.
Reform. 1997;17:14-20. The mammary tumor response in triazine-treated fe-
male rats: A threshold-mediated interaction with
Dalvi PS, Wilder-Ofie T, Mares B, Lane C, Dalvi RR, strain and species-specific reproductive senescence.
Billups LH. Effect of cytochrome P450 inducers on Steriods.1999;64:672-8.
the metabolism and toxicity of thiram in rats. Vet
Hum Toxicol. 2002;44:331-3. El-Sayed YS, Saad TT, El-Bahr SM. Acute intoxica-
tion of deltamethrin in monosex Nile tilapia, Oreo-
Dean RT, Fu S, Stocker R, Davies MJ. Biochemistry chromis niloticus, with special reference to the clini-
and pathology of radical-mediated protein oxidation. cal, biochemical and haematological effects. Environ
Biochem J. 1997;324:1-18. Toxicol Pharmacol. 2007;24:212-7.
Delhalle S, Blasius R, Dicato M, Diederich M. A be- Ewald G. Chronic measures of toxicant-induced ef-
ginner's guide to NF-kappaB signaling pathways. Ann fects on fish. Ann Zool Fennici. 1995;32:311-6.
N Y Acad Sci. 2004;1030:1-13.
Ewing RD. Diminishing returns: Salmon decline and
Devine M, Duke S, Fedtke C. Herbicide inhibition of pesticides. Funded by the Oregon pesticide education
photosynthetic electron transport. Physiology of herb- network, biotech research and consulting. Oregon:
icide action. Englewood Cliffs, NJ: Prentice Hall, Oregon Pesticide Education Network (OPEN), 1999.
1993.
Falfushinska HI, Romanchuk LD, Stolyar OB. Differ-
Ding X, Kaminsky LS. Human extrahepatic cyto- ent responses of biochemical markers in frogs (Rana
chromes P450: function in xenobiotic metabolism and ridibunda) from urban and rural wetlands to the effect
tissue-selective chemical toxicity in the respiratory of carbamate fungicide. Comp Biochem Physiol C
and gastrointestinal tracts. Ann Rev Pharmacol Toxi- Toxicol Pharmacol. 2008;148:223-9.
col. 2003;43:149-73.
Fitsanakis VA, Amarnath V, Moore JT, Montine KS,
Dinis-Oliveira RJ, Duarte JA, Sánchez-Navarro A, Zhang J, Montine TJ. Catalysis of catechol oxidation
Remião F, Bastos ML, Carvalho F. Paraquat poison- by metal-dithiocarbamate complexes in pesticides.
ings: mechanisms of lung toxicity, clinical features, Free Radic Biol Med. 2002;33:1714-23.
and treatment. Crit Rev Toxicol. 2008;38:13-71.
Franco R, Li S, Rodriguez-Rocha H, Burns M,
Drechsel DA, Patel M. Differential contribution of the Panayiotidis MI. Molecular mechanisms of pesticide-
mitochondrial respiratory chain complexes to reactive induced neurotoxicity: Relevance to Parkinson’s
oxygen species production by redox cycling agents disease. Chem Biol Interact. 2010;188:289-300.
implicated in Parkinsonism. Toxicol Sci. 2009;112:
427-34. Fukuto TR. Mechanism of action of organophospho-
rus and carbamate insecticides. Environ Health Per-
Dubus IG, Hollis JM, Brown CD. Pesticide in rainfall spect. 1990;87:245-54.
in Europe. Environ Pollut. 2000;110:331-44.
Fulton MN, Key PB. Acetylcholinesterase inhibition
Duchnowicz P, Koter M, Duda W. Damage of eryth- in estuarine fish and invertebrates as an indicator of
rocyte by phenoxyacetic herbicides and their metabo- organophosphorus insecticide exposure and effects.
lites. Pest Biochem Physiol. 2002;74:1-7. Environ Toxicol Chem. 2001;20:37-45.
Duchnowicz P, Szczepaniak P, Koter M. Erythrocyte Galloway T, Handy R. Immunotoxicity of organo-
membrane protein damage by phenoxyacetic herbi- phosphorous pesticides. Ecotoxicology. 2003;12:345-
cides and their metabolites. Pest Biochem Physiol. 63.
2005;82:59-65.
Galloway TS, Millward N, Browne MA, Depledge
Duggleby RG, McCourt JA, Guddat LW. Structure MH. Rapid assessment of organophosphorus/car-
and mechanism of inhibition of plant acetohydroxy- bamate exposure in the bivalve mollusc Mytilus edu-
acid synthase. Plant Physiol Biochem. 2008;46:309- lis using combined esterase activities as biomarkers.
24. Aquat Toxicol. 2002;61:169-80.
Edwards IR, Ferry DH, Temple WA. Fungicides and Garcia MD, Nouwens A, Lonhienne TG, Guddat LW.
related compounds. In: Hayes WJ, Laws ER (eds): Comprehensive understanding of acetohydroxyacid
Handbook of pesticide toxicology (pp 1409-70). San synthase inhibition by different herbicide families.
Diego, CA: Academic Press, 1991. Proc Natl Acad Sci U S A. 2017;114:E1091-100.
1130
George SG. Enzymology and molecular biology of Hemond HF, Fechner EJ. Chemical fate and transport
phase II xenobiotic-conjugating enzymes in fish. In: in the environment. San Diego, CA: Academic Press,
Malins DC, Ostrander GK (eds): Aquatic toxicology: 1994.
Molecular, biochemical and cellular perspectives (pp
37-85). Boca Raton, FL: CRC Press, 1994. Hermes-Lima M. Oxidative stress and medical sci-
ences. In: Storey KB (ed): Functional metabolism:
Giddings JM, Anderson TA, Hall LW, Kendall RJ, regulation and adaptation (pp 269-82). New York:
Richards RP, Solomon KR, et al. A probabilistic Wiley, 2004.
aquatic ecological risk assessment of atrazine in North
American surface waters. Pensacola, FL: SETAC Hinton DE, Lauren DJ. Liver structural alterations ac-
Press, 2005. companying chronic toxicity: potential biomarkers of
exposure. In: McCartney JF, Shugart LR (eds): Bi-
Gobas FAPC, Muir DCG, Mackay D. Dynamics of omarkers of environmental contamination (pp 15-57).
dietary bioaccumulation and fecal elimination of hy- Boca Raton, FL: Lewis Publ., 1990.
drophobic organic chemicals in fish. Chemosphere.
1988;17:943-62. Hodgson E. Metabolism of pesticides. In: Krieger R
(ed): Hayes’ handbook of pesticide toxicology, 3rd ed.
Goeptar AR, Scheerens H, Vermeulen NP. Oxygen (pp 893-921). New York: Academic Press, 2010.
reductase and substrate reductase activity of cyto-
chrome P450. Crit Rev Toxicol.1995;25:25-65. Hodgson E, Goldstein JA. Metabolism of toxicants:
phase I reactions and pharmacogenetics. In: Hodgson
González M, Soloneski S, Reigosa MA, Larramendy E, Smart RC (eds): Introduction to biochemical toxi-
ML. Effect of dithiocarbamate pesticide zineb and its cology (pp 67-113). New York: Wiley, 2001.
commercial formulation, azzurro. IV. DNA damage
and repair kinetics assessed by single cell gel electro- Homolya L, Váradi A, Sarkadi B. Multidrug re-
phoresis (SCGE) assay on Chinese hamster ovary sistance-associated proteins: Export pumps for conju-
(CHO) cells. Mutat Res. 2003;534:145-54. gates with glutathione, glucuronate or sulphate. Bio-
Factors. 2003;17:103-14.
González M, Soloneski S, Reigosa MA, Larramendy
ML. Genotoxicity of the herbicide 2,4-dichloro- Houeto P, Bindoula G, Hoffman JR. Ethylene-
phenoxyacetic and a commercial formulation, 2,4- bisdithiocarbamates and ethylenethiourea: Possible
dichlorophenoxyacetic acid dimethylamine salt. I. human health hazards. Environ Health Perspect.
Evaluation of DNA damage and cytogenetic end- 1995;103: 568-73.
points in Chinese Hamster ovary (CHO) cells. Toxi-
col In Vitro. 2005;19: 289-97. Huggenberger F, Letey J, Farmer WJ. Adsorption ad-
sorption and mobility of pesticides in soil. California
Goodbred SL, Gilliom RJ, Gross TS, Denslow NP, Agriculture. 1973;27:8-10.
Bryant WL, Schoeb TR. Reconnaissance of 17beta-
estradiol, 11-ketotestosterone, vitellogenin, and gonad Husak V. Copper and copper-containing pesticides:
histopathology in common carp of United States metabolism, toxicity and oxidative stress. J Vasyl
streams: Potential for contaminant-induced endocrine Stefanyk Precarpathian National Univ. 2015;2:38-50.
disruption. Sacramento, CA: U.S Geological Survey,
1997. (U.S. Geological Survey Open-File Report 96- Husak VV, Mosiichuk NM, Maksymiv IV, Sluchyk
627). IY, Storey JM, Storey KB, et al. Histopathological
and biochemical changes in goldfish kidney due to
Grasiela DCS-A, Silva-Zacarin ECM. Effects of herb- exposure to the herbicide Sencor may be related to in-
icide atrazine in experimental animal models. In: Ha- duction of oxidative stress. Aquat Toxicol. 2014;155:
saneen MNAE-G (ed): Herbicides – properties, syn- 181-9.
thesis and control of weeds (pp 285-96). Croatia:
InTech, 2012. Husak VV, Mosiichuk NM, Storey JM, Storey KB,
Lushchak VI. Acute exposure to the penconazole-
Gupta PK. Herbicides and fungicides. In: Gupta RC containing fungicide Topas partially augments antiox-
(ed): Reproductive and developmental toxicology (pp idant potential in goldfish tissues. Comp Biochem
503-21). Amsterdam: Academic Press/Elsevier, 2011. Physiol C Toxicol Pharmacol. 2017;193:1-8.
Haddad JJ. Science review: redox and oxygen- Ishikawa NM, Ranzani-Paiva MJT, Lombardi JV,
sensitive transcription factors in the regulation of oxi- Ferreira CM. Hematological parameters in Nile Tilap-
dant-mediated lung injury: role for hypoxia-inducible ia, Oreochromis niloticus exposed to sub-lethal con-
factor-1alpha. Crit Care. 2003;7:47-54. centrations of mercury. Braz Arch Biol Technol.
2007;50:619-26.
1131
Jablonkai I. Molecular mechanism of function of Kubrak OI, Atamaniuk TM, Storey KB, Lushchak VI.
herbicides. In: Hasaneen MNAE-G (ed): Herbicides – Goldfish can recover after short-term exposure to 2,4-
mechanisms and mode of action (pp 3-24). Croatia: dichlorophenoxyacetate: Use of blood parameters as
InTech, 2011. vital biomarkers. Comp Biochem Physiol C Toxicol
Pharmacol. 2013;157:259-65.
James MO. Pesticide metabolism in aquatic organ-
isms. Chem Plant Prot 1994;9:153-89. Küpper H, Küpper F, Spiller M. Environmental rele-
vance of heavy metal-substituted chlorophylls using
Jayaraj R, Megha P, Sreedev P. Organochlorine pesti- the example of water plants. J Exp Bot. 1996;47:259-
cides, their toxic effects on living organisms and their 66.
fate in the environment. Interdiscip Toxicol.
2016;9:90-100. Kulkarni AP. Lipoxygenase - a versatile biocatalyst
for biotransformation of endobiotics and xenobiotics.
Jegerschöld C, Arellano JB, Schröder WP, van Kan Cell Mol Life Sci. 2001;58:1805-25.
PJ, Barón M, Styring S. Copper(II) inhibition of elec-
tron transfer through photosystem II studied by EPR Landrum PF, Fisher SW. Influence of lipids on the bi-
spectroscopy. Biochemistry. 1995;34:12747-54. oaccumulation and trophic transfer of organic contam-
inants in aquatic organisms. In: Arts MT, Wainman
John EM, Shaike JM. Chlorpyrifos: pollution and re- BC (eds): Lipids in freshwater ecosystems (pp 203-
mediation. Environ Chem Lett. 2015;13:269-91. 34). New York: Springer, 1998.
Kamijima1 M, Casida JE. Regional modification of LeBlanc GA, Cochrane BJ. Identification of multiple
[3H]ethynylbicycloorthobenzoate binding in mouse glutathione-S-transferases from Daphnia magna.
brain GABAA receptor by endosulfan, fipronil, and Comp Biochem Physiol. 1987;88B:39-45.
avermectin B1a. Toxicol Appl Pharmacol. 2000;163:
188-94. Leighton T, Marks E, Leighton F. Pesticides: insecti-
cides and fungicides are chitin synthesis inhibitors.
Katagi T. Bioconcentration, bioaccumulation, and Science. 1981;213(4510):905-7.
metabolism of pesticides in aquatic organisms. Rev
Environ Contam Toxicol. 2010;204:1-132. Li X, Johnson DC, Rozman KK. Reproductive effects
of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in
Kawatski JA, Bittner MA. Uptake, elimination and female rats: ovulation, hormonal regulation, and pos-
biotransformation of the lampricide 3-trifluoromethyl- sible mechanism(s). Toxicol Appl Pharmcol. 1995;
4-nitrophenol (TFM) by larvae of the aquatic midge 133:321-7.
Chironomus tentans. Toxicology. 1975;4:183-94.
Li ZH, Velisek J, Zlabek V, Grabic R, Machova J,
Kennedy CJ. Xenobiotics. In: Hochachka PW, Kolarova J, et al. Hepatic antioxidant status and he-
Mommsen TP (eds): Biochemistry and molecular bi- matological parameters in rainbow trout, Oncorhyn-
ology of fishes (pp 281-312). New York: Elsevier chus mykiss, after chronic exposure to carbamazepine.
Science, 1995. Chem Biol Interact. 2010a;183:98-104.
Khan ZM, Law FCP. Adverse effects of pesticides Li ZH, Zlabek V, Grabic R, Li P, Randak T. Modula-
and related chemicals on enzyme and hormone sys- tion of glutathione-related antioxidant defense system
tems of fish, amphibians and reptiles: A review. Proc of fish chronically treated by the fungicide propicona-
Pakistan Acad Sci. 2005;42:315-23. zole. Comp Biochem Physiol C Toxicol Pharmacol.
2010b;152:392-8.
Kreuz K, Tommasini R, Martinoia E. Old enzymes
for a new job: herbicide detoxification in plants. Plant Li ZH, Velisek J, Zlabek V, Grabic R, Machova J,
Physiol. 1996;111:349-53. Kolarova J, et al. Chronic toxicity of verapamil on ju-
venile rainbow trout (Oncorhynchus mykiss): Effects
Kubrak OI, Atamaniuk TM, Husak VV, Drohomy- on morphological indices, hematological parameters
retska IZ, Storey JM, Storey KB, et al. Oxidative and antioxidant responses. J Hazard Mater. 2011;185:
stress responses in blood and gills of Carassius au- 870-80.
ratus exposed to the mancozeb-containing carbamate
fungicide Tattoo. Ecotoxicol Environ Saf. 2012;85: Liu H, Yi M, Shi X, Liang P, Gao X. Substrate
37-43. specificity of brain acetylcholinesterase and its sensi-
tivity to carbamate insecticides in Carassius auratus.
Fish Physiol Biochem 2007;33:29-34.
1132
Liu J, Shigenaga MK, Yan LJ, Mori A, Ames BN. Matviishyn TM, Kubrak OI, Husak VV, Storey KB,
Antioxidant activity of diethyldithiocarbamate. Free Lushchak VI. Tissue-specific induction of oxidative
Radic Res. 1996;24:461-72. stress in goldfish by 2,4-dichlorophenoxyacetic acid:
Mild in brain and moderate in liver and kidney. Envi-
Lushchak VI. Free radical oxidation of proteins and ron Toxicol Pharmacol. 2014;37:861-9.
its relationship with functional state of organisms. Bi-
ochemistry (Moscow). 2007;72:809-27. McCarthy JF, Shugart LR. Biological markers of en-
vironmental contamination. In: McCarthy JF, Shugart
Lushchak VI. Adaptive response to oxidative stress: LR (eds): Biomarkers of environmental contamination
Bacteria, fungi, plants and animals. Comp Biochem (pp 3-16). Boca Raton, FL: Lewis Publ., 1990.
Physiol Part C. 2011a;153:175-90.
Meco G, Bonifati V, Vanacore N, Fabrizio E. Parkin-
Lushchak VI. Environmentally induced oxidative sonism after chronic exposure to the fungicide maneb
stress in aquatic animals. Aquat Toxicol. 2011b;101: (manganese ethylene-bis-dithiocarbamate). Scand J
13-30. Work Environ Health. 1994;20:301-5.
Lushchak VI. Glutathione homeostasis and functions: Mishra R, Shukla SP. Endosulfan effects on muscle
potential targets for medical interventions. J Amino malate dehydrogenase of the freshwater catfish Clari-
Acids. 2012;2012:736837. as batrachus. Ecotoxicol Environ Saf. 2003;56:425-
33.
Lushchak VI. Free radicals, reactive oxygen species,
oxidative stress and its classification. Chem Biol In- Miyamoto J, Mikami N, Takimoto Y. The fate of pes-
teract. 2014;224C:164-75. ticides in aquatic ecosystems. In: Hutson DH, Roberts
TR (eds): Progress in pesticide biochemistry and toxi-
Lushchak VI. Contaminant-induced oxidative stress cology, environmental fate of pesticides (pp 123-47).
in fish: a mechanistic approach. Fish Physiol Biochem. New York: Wiley, 1990.
2016;42:711-47.
Mosiichuk NM, Husak VV, Maksymiv IV, Hlodan
Lushchak V, Semchyshyn H, Lushchak O, Mandryk OY, Storey JM, Storey KB, et al. Toxicity of envi-
S. Diethyldithiocarbamate inhibits in vivo Cu,Zn- ronmental Gesagard to goldfish may be connected
superoxide dismutase and perturbs free radical pro- with induction of low intensity oxidative stress in
cesses in the yeast Saccharomyces cerevisiae cells. concentration- andtissue-related manners. Aquat Tox-
Biochem Biophys Res Commun. 2005;338:1739-44. icol. 2015;165: 249-58.
Maher P. The effects of stress and aging on glutathi- Moss DW, Henderson AR, Kochmar JF. Enzymes;
one metabolism. Ageing Res Rev. 2005;4:288-314. principles of diagnostic enzymology and the ami-
notransferases. In: Tietz NW (ed): Textbook of clini-
Maksymiv IV, Husak VV, Mosiichuk NM, Mat- cal chemistry (pp 663-78). Philadelphia, PA: Saun-
viishyn TM, Sluchyk IY, Storey JM, et al. Hepatotox- ders, 1986.
icity of herbicide Sencor in goldfish may result from
induction of mild oxidative stress. Pestic Biochem Mostafalou S, Abdollahi M. Pesticides and human
Physiol. 2015; 122:67-75. chronic diseases: Evidences, mechanisms, and per-
spectives. Toxicol Appl Pharmacol. 2013;268:157-77.
Manda G, Nechifor MT, Neagu TM. Reactive oxygen
species, cancer and anti-cancer therapies. Curr Chem Murad A, Houston AH. Leukocytes and leukopoietic
Biol. 2009;3:342-66. capacity in goldfish, Carassius auratus, exposed to
sublethal levels of cadmium. Aquat Toxicol. 1988;13:
Mangas I, Estevez J, Vilanova E, França TC. New in- 141-54.
sights on molecular interactions of organophosphorus
pesticides with esterases. Toxicology. 2017;376: 30- Murty AS. Toxicity of pesticides to fish, Vols I and II.
43. Boca Raton, FL: CRC Press, 1986.
Manz A, Berger J, Dwyer JH, Flesch-Janys D, Nagel Nakai M, Hess RA. Effects of carbendazim (methyl
S, Waltsgott H. Cancer mortality among workers in 2-benzimidazole carbamate; mbc) on meiotic sper-
chemical plant contaminated with dioxin. Lancet. matocytes and subsequent spermatogenesis in the rat
1991;338:959-64. testis. Anat Rec. 1997;247:379-87.
Nies AT, Keppler D. The apical conjugate efflux

pump ABCC2 (MRP2). Pflugers Arch. 2007;453:643-
59.
1133
Nieves-Puigdoller K, Bjornsson BT, McCormick SD. Revitt D, Ellis JB, Llewellyn NR. Herbicide behav-
Effects of hexazinoneand atrazine on the physiology iour in the runoff from an urban catchment. In: 8th In-
and endocrinology of smolt development in Atlantic ternational Conference on Urban Storm Drainage (pp
salmon. Aquat Toxicol. 2007;84:27-37. 96-104). Sydney, 1999.
Niimi AJ. Review of biochemical methods and other Riechers DE, Kreuz K, Zhang Q. Detoxification with-
indicators to assess fish health in aquatic ecosystems out intoxication: herbicide safeners activate plant de-
containing toxic chemicals. J Great Lakes Res. 1990; fense gene expression. Plant Physiol. 2010;153:3-13.
16:529-41.
Rizzati V, Briand O, Guillou H, Gamet-Payrastre L.
Nobel CI, Kimland M, Lind B, Orrenius S, Slater AF. Effects of pesticide mixtures in human and animal
Dithiocarbamates induce apoptosis in thymocytes by models: An update of the recent literature. Chem Biol
raising the intracellular level of redox-active copper. J Interact. 2016;254:231-46.
Biol Chem. 1995;270:26202-8.
Rosso SB, Cáceres AO, Evangelista De Duffard AM,
Oruc HH. Fungicides and their effects on animals. In: Duffard R, Quiroga S. 2,4-Dichlorophenoxyacetic ac-
Carisse O (ed): Fungicides (pp 349-62). Rijeka: id disrupts the cytoskeleton and disorganizes the Gol-
InTech, 2010. gi apparatus of cultured neurons. Toxicol Sci.
2000;56: 133-40.
Oruç OE, Üner N. Effects of 2,4-Diamin on some pa-
rameters of protein and carbohydrate metabolisms in Rutten AA, Falke HE, Catsburg JF, Wortelboer HM,
the serum, muscle and liver of Cyprinus carpio. Envi- Blaauboer BJ, Doorn L, et al. Interlaboratory compar-
ron Pollut. 1999;105:267-72. ison of microsomal ethoxyresorufin and pentox-
yresorufin O-dealkylation determination. Standardiza-
Otto DM, Moon TW. 3,3',4,4'-tetrachlorobiphenyl ef- tion of assay conditions. Arch Toxicol. 1992;66:237-
fects on antioxidant enzymes and glutathione status in 44.
different tissues of rainbow trout. Pharmacol Toxicol.
1995;77:281-7. Saravanan M, Karthika S, Malarvizhi A, Ramesh M.
Ecotoxicological impacts of clofibric acid and diclo-
Peakall D. Animal biomarkers as pollution indicators. fenac in common carp (Cyprinus carpio) fingerlings:
London: Chapman & Hall, 1992. hematological, biochemical, ionoregulatory and en-
zymological responses. J Hazard Mater. 2011;195:
Peterson DE, Shoup DE, Thompson CR, Olson BL. 188-94.
Herbicide mode of action, cooperative extension ser-
vice. Kansas: Kansas State Univ., 2013. Sathiakumar N, MacLennan PA, Mandel J, Delzell E.
A review of epidemiologic studies of triazine herbi-
Pimpão CT, Zampronio AR, Silva de Assis HC. Ef- cides and cancer. Crit Rev Toxicol. 2011;41:1-34.
fects of deltamethrin on hematological parameters and
enzymatic activity in Ancistrus multispinis (Pisces, Schlenk D. Pesticide biotransformation in fish. In:
Teleostei). Pestic Biochem Physiol. 2007;88:122-7. Mommsen TP, Moon TW (eds): Biochemistry and
molecular biology of fishes, environmental toxicology
Prusty AK, Kohli MPS, Sahu NP, Pal AK, Saharan N, (pp 171-90). Amsterdam: Elsevier, 2005.
Mohapatra S, et al. Effect of short term exposure of
fenvalerate on biochemical and haematological re- Schneider D. Using Drosophila as a model insect. Nat
sponses in Labeo rohita (Hamilton) fingerlings. Pestic Rev Genet. 2000;1:218-26.
Biochem Physiol. 2011;100:124-9.
Scott GR, Sloman KA. The effects of environmental
Rand GM, Wells PG, McCarty LS. Introduction to pollutants on complex fish behaviour: integrating be-
aquatic toxicology. In: Rand GM (ed): Fundamentals havioural and physiological indicators of toxicity.
of aquatic toxicology: Effects, environmental fate, Aquat Toxicol. 2004;68:369-92.
and risk assessment (pp 3-67). North Palm Beach:
Taylor & Francis, 1995. Seefeldt T, Zhao Y, Chen W, Raza AS, Carlson L,
Herman J, et al. Characterization of a novel dithio-
Rath NC, Rasaputra KS, Liyanage R, Huff GR, Huff carbamate glutathione reductase inhibitor and its use
WE. Dithiocarbamate toxicity – an appraisal. In: as a tool to modulate intracellular glutathione. J Biol
Stoytcheva M (ed): Pesticides in the modern world – Chem. 2009;284:2729-37.
effects of pesticides exposure (pp 323-40). Rijeka:
InTech, 2011. Selassie C, De Soya T, Rosario M, Gao H, Hansch C.
Phenol toxicity in leukemia cells: a radical process?
Chem Biol Interact. 1998;113:175-90.
1134
Semple KT, Cain RB, Schmidt S. Biodegradation of Stegeman JJ, Broumer M, DiGiulio RT. Molecular re-
aromatic compounds by microalgae. FEMS Microbiol sponses to environmental contamination: Enzyme and
Lett. 1999;170:291-300. protein synthesis as indicators of chemical exposure
and effects. In: Huggett RA, Kimerle PM, Mehrle
Shi H, Sui Y, Wang X, Luo Y, Ji L. Hydroxyl radical PMJr, Bergman HL (eds): Biomarkers, biochemical,
production and oxidative damage induced by cadmi- physiological and histological markers of anthropo-
um and naphthalene in liver of Carassius auratus. genic stress (pp 235-335). Boca Raton, FL: Lewis
Comp Biochem Physiol C Toxicol Pharmacol. Publ., 1992.
2005;140:115-21.
Stoker TE, Guidici DL, Laws SC, Cooper RL. The ef-
Shinomiya N, Shinomiya M. Dichlorodiphenyltri- fects of atrazine metabolites on puberty and thyroid
chloroethane suppresses neurite outgrowth and induc- function in the male Wistar rat. Toxicol Sci. 2002;67:
es apoptosis in PC12 pheochromocytoma cells. Toxi- 198-206.
col Lett. 2003;137:175-83.
Storey KB. Oxidative stress: Animal adaptations in
Shugart LR, Bickham J, Jackim G, McMahon G, Rid- nature. Braz J Med Biol Res. 1996;29:1715-33.
ley W, Stein J, et al. DNA alterations. In: Huggett RJ,
Kimerly RA, Mehrle PM, Bergman HL (eds): Bi- Sturm A, Wogram J, Segner H, Liess M. Different
omarkers: biochemical, physiological and histological sensitivity to organophosphates of acetylcholinester-
markers of anthropogenic stress (pp 155-210). Boca ase and butyrylcholinesterase from three-spined stick-
Raton, FL: Lewis Publ., 1992. leback (Gasterosteus aculeatus): application in bio-
monitoring. Environ Toxicol Chem. 2000;19:1607-15.
Sijm DTHM, Seinen W, Opperhuizen A. Life-cycle
biomagnification study in fish. Environ Sci Technol. Svoboda M, Luskova V, Drastichova J, Ilabek V. The
1992;26:2162-74. effect of diazinon on hematological indices of com-
mon carp (Cyprinus carpio L.). Acta Vet Brno. 2001;
Silver K, Dong K, Zhorov BS. Molecular mechanism 70:457-65.
of action and selectivity of sodium channel blocker
insecticides. Curr Med Chem. 2017;24:2912-24. Svobodová Z, Lusková V, Drastichová J, Svoboda M,
Žlábek V. Effect of deltamethrin on haematological
Solomon KR, Carr JA, Du Preez LH, Giesy JP, Ken- indices of common carp (Cyprinus carpio L.). Acta
dall RJ, Smith EE, et al. Effects of atrazine on fish, Vet Brno. 2003;72:79-85.
amphibians, and aquatic reptiles: a critical review.
Crit Rev Toxicol. 2008;38:721-72. Tarazona JV, Court-Marques D, Tiramani M, Reich H,
Pfeil R, Istace F, et al. Glyphosate toxicity and car-
Soloneski S, Reigosa MA, Larramendy ML. Effect of cinogenicity: a review of the scientific basis of the
dithiocarbamate pesticide zineb and its commercial European Union assessment and its differences with
formulation, azzurro. II. micronucleus induction in IARC. Arch Toxicol. 2017;91:2723-43.
immunophenotyped human lymphocytes. Environ
Mol Mutagen. 2002;40:57-62. Thompson HM. Esterases as markers of exposure to
organophosphates and carbamates. Ecotoxicology.
Sparks TC, Nauen R. IRAC: Mode of action classifi- 1999;8:369-84.
cation and insecticide resistance management. Pestic
Biochem Physiol. 2015;121:122-8. Tollefsen KE. Interaction of estrogen mimics, singly
and in combination, with plasma sex steroid-binding
Speerschneider P, Dekant W. Renal tumorigenicity of proteins in rainbow trout (Oncorhynchus mykiss).
1,1-dichloroethene in mice: The role of male-specific Aquat Toxicol. 2002;56:215-25.
expression of cytochrome P450 2E1 in the renal bio-
activation of 1,1-dihloroethene. Toxicol Appl Phar- Tomlin CDS. The pesticide manual: a world compen-
macol. 1995;130:48-56. dium. 12th ed. Surrey, UK: British Crop Protection
Council, 2000.
Steenland K, Cedillo L, Tucker J, Hines C, Sorensen
K, Deddens J, et al. Thyroid hormones and cytogenet- Tseng YC, Chen RD, Lucassen M, Schmidt MM,
ic outcomes in backpack sprayers using eth- Dringen R, Abele D, et al. Exploring uncoupling pro-
ylenebis(dithiocarbamate) (EBDC) fungicides in teins and antioxidant mechanisms under acute cold
Mexico. Environ Health Perspect. 1997;105:1126-30. exposure in brains of fish. PLoS One. 2011;6:e18180.
U.S. EPA, United Stated Environmental Protection

Agency. Metiram Facts. Washington, DC: U.S. EPA,
2005. (EPA 738-F-05-XX).
1135
U.S. DA Forest Service, United States Department of Watabe M, Nakaki T. Mitochondrial complex I in-
Agriculture Forest service. 2,4-Dichlorophenoxy- hibitor rotenone-elicited dopamine redistribution from
acetic acid formulations-human health and ecological vesicles to cytosol in human dopaminergic SHSY5Y
risk assessment. New York: Syracuse Research Cor- cells. J Pharmacol Exp Ther. 2007;323:499-507.
poration, 1998.
Watanabe Y. High-valent intermediates. In: Kadish
Vaccari A, Saba P, Mocci I, Ruiu S. Dithiocarbamate KM, Smith KM, Guilard R (eds): The Porphyrin
pesticides affect glutamate transport in brain synaptic handbook, biochemistry and binding: activation of
vesicles. J Pharmacol Exp Ther. 1999;288:1-5. small molecules (pp 97-117). New York: Academic
Press, 2000.
Valbonesi P, Brunelli F, Mattioli M, Rossi T, Fabbri
E. Cholinesterase activities and sensitivity to pesti- Wheelock CE, Shan G, Ottea J. Overview of carboxy-
cides in different tissues of silver European eel, lesterases and their role in the metabolism of insecti-
Anguilla anguilla. Comp Biochem Physiol. 2011; cides. J Pestic Sci. 2005;30:75-83.
C154:353-9.
Wilkinson CF, Christoph GR, Julien E, Kelley JM,
van der Oost R, Beyer J, Vermeulen NP. Fish bioac- Kronenberg J, McCarthy J, et al. Assessing the risks
cumulation and biomarkers in environmental risk as- of exposures to multiple chemicals with a common
sessment: a review. Environ Toxicol Pharmacol. mechanism of toxicity: how to cumulate? Regul Toxi-
2003;13: 57-149. col Pharmacol. 2000;31:30-43.
Vani T, Saharan N, Mukherjee SC, Ranjan R, Kumar Williams TR. Detoxification mechanisms: the metab-
R, Brahmchari RK. Deltamethrin induced alterations olism and detoxification of drugs, toxic substances
of hematological and biochemical parameters in and other organic compounds. 2nd ed. London: Chap-
fingerlings of Catla catla (Ham.) and their ameliora- man and Hall, 1959.
tion by dietary supplement of vitamin C. Pestic Bio-
chem Physiol. 2011;101:16-20. Winston GW, Di Giulio RT. Prooxidant and antioxi-
dant mechanisms in aquatic organisms. Aquat Toxicol.
Vasylkiv OY, Kubrak OI, Storey KB, Lushchak VI. 1991;19:137-61.
Catalase activity as a potential vital biomarker of fish
intoxication by the herbicide aminotriazole. Pestic Bi- Zhang J, Shen H, Wang X, Wu J, Xue Y. Eﬀects of
ochem Physiol. 2011;101:1-5. chronic exposure of 2,4-dichlorophenol on the antiox-
idant system in liver of freshwater fish Carassius au-
Vermeulen NPE. Role of metabolism in chemical tox- ratus. Chemosphere. 2004;55:167-74.
icity. In: C. Ioannides (ed): Cytochromes P450: meta-
bolic and toxicological aspects (pp 29-53). Boca Ra- Zhang JF, Liu H, Sun YY, Wang XR, Wu JC, Xue
ton, FL: CRC Press, 1996. YQ. Responses of the antioxidant defenses of the
goldfish Carassius auratus, exposed to 2,4-
Wafa T, Amel N, Ikbal C, Mohamed H. Oxidative dichlorophenol. Environ Toxicol Pharmacol. 2005;19:
stress induced by the 2,4-dichlorophenoxyacetic herb- 185-90.
icide. In: Lushchak VI (ed): Oxidative stress – envi-
ronmental induction and dietary antioxidants (pp 115- Zhang Q, Xu FX, Lambert KN, Riechers DE. Safen-
30). Rijeka: InTech, 2012. ers coordinately induce the expression of multiple
proteins and MRP transcripts involved in herbicide
Wang X, Martínez MA, Dai M, Chen D, Ares I, metabolism and detoxification in Triticum tauschii
Romero A, et al. Permethrin-induced oxidative stress seedling tissues. Proteomics. 2007;7:1261-78.
and toxicity and metabolism: A review. Environ Res.
2016;149:86-104.
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EXCLI Journal 2018;17:1101-1136 – ISSN 1611-2156

PESTICIDE TOXICITY: A MECHANISTIC APPROACH

* Corresponding author: Department of Biochemistry and Biotechnology, Vasyl Stefanyk

Keywords: Bioaccumulation, biotransformation, pollutants, mechanisms, oxidative stress, xenobiotics

INTRODUCTION biotransformation, conjugation, isolation

cesses, or deplete antioxidant defenses that GENERAL APPRAISAL”). The ability of

verse chemicals in an aqueous environment Transfer and bioaccumulation of pesticides

state of organisms (Katagi, 2010). Finally, Concentration of DDT in living organ-

and dehydrohalogenation, typical reactions cretable products (Figure 3) (Lushchak, 2011

Figure 3: Biotransformation of pesticides. Description in the text. *glutathione, carbohydrates, amino

Organisms eliminate absorbed chemicals transporters providing release of pesticides

Fungicides and their mode of action

Insecticides and their mode of action

COMMON INDICATORS OF Several hematological parameters, such

transformation products of xenobiotics re- ed plasma LDH was reported by Li et al.

enzymatic and non-enzymatic protection various environmental and chemical stresses

Molecular mechanisms of pesticide-induced decreasing its activity (Figure 8C). In result,

Figure 8: Effect of organophosphorus insecticides in the transmission of nerve impulses: A – acetyl-

Many dithiocarbamates are implicated in neurological disorder – Parkinson’s disease,

ver, the listed pathologies may be aggravated Conflict of interest

Bisson M, Hontela A. Cytotoxic and endocrine- Calviello G, Piccioni E, Boninsegna A, Tedesco B,

Nies AT, Keppler D. The apical conjugate efflux

U.S. EPA, United Stated Environmental Protection

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