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A mechanistic overview of health associated effects of low levels of

organochlorine and organophosphorous pesticides
Vasilis P. Androutsopoulos a , Antonio F. Hernandez b , Jyrki Liesivuori c , Aristidis M. Tsatsakis a,

Laboratory of Forensic Sciences and Toxicology, University of Crete, Voutes, 71003 Crete, Greece
University of Granada School of Medicine, Avda Madrid 11, 18071 Granada, Spain
Department of Pharmacology, Drug Development and Therapeutics, University of Turku, Turku, Finland

a r t i c l e

i n f o

Article history:
Received 25 May 2012
Received in revised form
19 September 2012
Accepted 25 September 2012
Available online xxx
Glucose homeostasis
Lipid metabolism
Oxidative stress
Endocrine disrupting chemicals

a b s t r a c t
Organochlorine and organophosphate pesticides are compounds that can be detected in human populations as a result of occupational or residential exposure. Despite their occurrence in considerably
low levels in humans, their biological effects are hazardous since they interact with a plethora of
enzymes, proteins, receptors and transcription factors. In this review we summarize the cell and molecular effects of organochlorine and organophosphate pesticides with respect to their toxicity, with particular
emphasis on glucose and lipid metabolism, their interaction with some members of the nuclear receptor family of ligand-activated transcription factors, including the steroid and peroxisome proliferator
activated receptors that changes the expression of genes involved in lipid metabolism and xenobiotic detoxication. More importantly, evidence regarding the metabolic degradation of pesticides and
their accumulation in tissues is presented. Potential non-cholinergic mechanisms after long-term lowdose organophosphate exposure resulting in neurodevelopmental outcomes and neurodegeneration are
also addressed. We conclude that the mechanism of pesticide-mediated toxicity is a combination of
various enzyme-inhibitory, metabolic and transcriptional events acting at the cellular and molecular
2012 Published by Elsevier Ireland Ltd.

1. Introduction
Pesticides constitute a diverse class of chemicals extensively
used for prevention of harmful effects caused by pests. Among
the large number of different pesticides those that are of particular concern are organophosphate (OPs) and organochlorines
(OCs). Despite their structural dissimilarities, these two classes
of pesticides result in neurological adverse effects through different mechanisms of toxicity. OPs mechanism of action involves
mainly inhibition of acetylcholinesterase (AChE) resulting in synaptic accumulation of acetylcholine and excessive stimulation of
cholinergic neurons. Nevertheless this mechanism cannot alone
account for some other effects such as neurodevelopmental alterations following low-dose chronic exposure by pregnant women. In
turn, OCs have afnity for the -subunit of the voltage-dependent
sodium channels in neurons, preventing their closing and resulting in repetitive ring of action potentials (Karami-Mohajeri and
Abdollahi, 2011). Primary adverse neurological effects of OC insecticides also result from inhibition of GABAA and glycine receptors
(Heusinkveld and Westerink, 2012).

The major part of OPs used contain the P = S moiety (Chambers,

1992) and includes compounds such as parathion, diazinon,
malathion and chlorpyrifos. Among the most commonly encountered classes of OC insecticides are chlorinated derivatives
of dichloro-diphenyl-ethane, such as DDT (dichloro-diphenyltrichloroethane). Detection of such compounds may occur in a wide
range of biological matrices, including blood and hair (Tsatsakis
et al., 2008a,b). OPs are subject to several biotransformation reactions following their entry to the body, whereas OCs accumulate in
organ tissues, without essentially undergoing metabolic degradation, thus showing long half-lives. Due to their potential for short
and long term hazardous effects, continuous biomonitoring of the
levels of pesticides and their metabolites in humans is an essential
step towards the evaluation of risk assessment and the prediction
of adverse health effects in populations with either occupational
or background environmental exposure to pesticides (Kavallakis
and Tsatsakis, 2012; Tsatsakis et al., 2012). In this review we will
summarize the major long-term biological effects of OP and OC pesticides that contribute to their toxicity, focusing on the mechanisms
of action at a molecular and cellular level.
2. Effects of OP and OC pesticides on glucose and lipid

Corresponding author. Tel.: +30 2810 394678; fax: +30 2810 542098.
E-mail address: (A.M. Tsatsakis).

OPs and OCs affect cellular metabolism of carbohydrate and

lipids and may lead to insulin resistance and impaired glucose

0300-483X/$ see front matter 2012 Published by Elsevier Ireland Ltd.

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homeostasis (Karami-Mohajeri and Abdollahi, 2011). Regarding

possible mechanisms of action, it is well documented that
exposure to OPs disrupts glucose homeostasis leading to elevated serum glucose levels (Amanvermez et al., 2010; Everett and
Matheson, 2010). The underlying mechanism is thought to involve
increased exocytosis of insulin and glucagon granules mediated
by enhanced free cytosolic calcium levels as a result of continuous activation of protein kinase C signaling following acetylcholine
binding to M3 muscarinic receptors in pancreatic cells (Gilon
and Henquin, 2001; Persaud et al., 1989). Tolerance to this effect
may develop due to down-regulation of these receptors or reduction in cell sensitivity to glucose following prolonged stimulation
by acetylcholine (Montgomery et al., 2008). On the other hand,
induction of oxidative stress by OPs via imbalance of the oxidative
status of cells can reduce glucose-stimulated insulin secretion (Karami-Mohajeri and Abdollahi, 2011), resulting in increased
serum glucose levels. However, this mechanism has been challenged by a few animal studies.
OCs do not follow the same metabolic pathways than OPs. Compounds such as DDE are persistent and remain in the body for
a long time period. The presence of multiple chlorine atoms in
their structure increases their lipophilicity and results in accumulation in adipose tissue. Several studies have explored the possible
relationship between OCs concentration and obesity (Jung et al.,
1997; Lee et al., 2011; Pelletier et al., 2002, 2003). p,p-DDE levels have been reported to increase the proliferative capacity of
preadipocytes, whose replication is needed for the development
of adipose tissue (Chapados et al., 2012). Mechanistically, estrogens receptors (ERs) and estrogens contribute to the development
of obesity as they regulate some aspects of metabolism, such as
glucose transport, glycolysis, mitochondrial activity and fatty acid
oxidation. Thus, ligands for the ER (such as OC compounds) may
play a role in the control of adipogenesis, weight gain and insulin
levels. As ERs are expressed in preadipocytes, estrogens and other
chemicals binding to ERs may contribute to an increased number
of adipocytes during development (Casals-Casas and Desvergne,
DDE has been also associated with increased body mass index
(BMI), increased triglycerides and decreased high density lipoprotein (HDL)-cholesterol levels (Lee et al., 2011). A signicant positive
relationship has been observed between OC concentration and
BMI in athletes suggesting that the adipose tissue level inuences the storage of OCs in the body (Pelletier et al., 2002).
Jung et al. (1997) found a positive relationship between the
percentage of body fat in workers occupationally exposed to hexachlorocyclohexane and the half life of this compound. There
is evidence to suggest that lipid mobilization that occurs during
weight loss of obese subjects on a hypocaloric diet may have an
impact on health mediated by the release of OCs accumulated in
adipose tissue as a result of adipocyte lipolysis associated with
reduced fasting insulin levels (Chevrier et al., 2000; Imbeault et al.,
Exposure to low concentrations of some OC pesticides has been
associated with metabolic dysregulation (excess adiposity and dyslipidemia) leading to prediabetes conditions. Furthermore, insulin
resistance associated with obesity and exhaustion of pancreatic
cells from overproduction of insulin may progress to diabetes (Lee
et al., 2007a,b, 2011).
Consistent with these observations is evidence suggesting the
direct interaction of pesticides with peroxisome proliferator activated receptors (PPARs), which are ligand-activated transcription
factors belonging to the nuclear receptor superfamily. OCs tend to
bind strongly to PPAR and thus activate a large battery of genes
involved in lipid metabolism, leading to an increased lipid oxidation, decreased tryglycerides accumulation and changes in glucose
metabolism. Mechanistically, once PPARs are activated by lipid

ligands, they bind to RXR (Retinoid X Receptor) and then the

heterodimeric transcription factor complex binds to specic DNA
sequence response elements located in promoter regions of target genes involved in the regulation of adipogenesis (adipocyte
proliferation and differentiation), intracellular lipid metabolism
and storage, glucose homeostasis, insulin sensitivity and embryonic and fetal development (Casals-Casas and Desvergne, 2011;
Lau et al., 2010). Thus, PPARs act as lipid sensors that play a role
in organs with a high rate of fatty acid metabolism in order to
adapt gene expression to a given metabolic status (Casals-Casas
and Desvergne, 2011). In addition to PPAR, estrogen receptors
(ERs) are also involved in the regulation of adiposity and obesity, so
that OC, as ER ligands, might be mechanistically associated to obesity. Interestingly, PPAR/RXR heterodimers are capable of binding
to estrogen response elements in target genes, suggesting that signal cross-talk between these two nuclear receptors may participate
in the control of obesity (Lau et al., 2010).

3. Interaction with endocrine system

Several pesticides have been documented to affect the
endocrine system in any stage of hormonal regulation, from synthesis to hormone receptor binding (Bretveld et al., 2007), resulting
in reproductive and developmental adverse effects. The OP insecticide dichlorvos increases the apoptosis of Leydig cells in the
offspring of pregnant rats (Zeng et al., 2009) and methoxychlor,
an OC compound, also induces testicular apoptosis (Vaithinathan
et al., 2010). Exposure to very low biologically relevant concentrations of dieldrin, an environmental OC, may affect the
fetal Leydig cells reducing testosterone synthesis, which may
have an effect on reproductive development and adult fecundity (Fowler et al., 2007). Decreased testosterone levels following
pesticide exposure results in a reduction of inhibin B concentration, which further induces FSH and LH secretion (Damstra et al.,
High concentrations of p,p-DDE functions as an inhibitor of
5-reductase, the enzyme that converts testosterone to dihydrotestosterone (DHT) (Frye et al., 2011; Hodgson and Rose, 2006;
Luccio-Camelo and Prins, 2011). DDE has also shown to enhance
basal and FSH-stimulated aromatase activity in ovarian granulosa cells (Younglai et al., 2004). As pesticides are small lipophillic
compounds, they can bind nuclear receptors causing perturbation
or modulation of downstream gene expression. For example, OC
pesticides such as lindane may act as androgens antagonist due
to inhibition of DHT binding to the AR. The resulting antiandrogenic effects involve impaired development of testes, changes in
testes histology, cryptorchidism and decreased fertility (LuccioCamelo and Prins, 2011). Similarly, DDT isomers also exhibit
antiandrogenic effects by reducing the binding of DHT to the AR
in vivo.
Mechanistically unrelated OPs, on their own, are capable of
interfering with the endocrine function by inhibiting the binding
of thyroid hormones to their corresponding receptors. OPs also
reduce the metabolism of oestradiol and perturb its normal function by potent inhibition of cytochrome P450 (CYP450) enzymes
(Symonds et al., 2006; Trankina et al., 1985), as a result of the binding of the active sulfur atom that arises from desulfuration in phase
I metabolism (Hodgson and Rose, 2006). OPs such as chlorpyrifos
are also able to inhibit adrenal steroidogenesis, thus affecting the
hormonal status (Civen et al., 1977; Walsh et al., 2000).
Inhibition of AChE in the hypothalamus after OP exposure alters
the rate of gonadotrophin releasing hormone (GnRH) secretion,
ultimately affecting secretion of pituitary hormones that stimulate
the gonads (gonadotrophic hormones), such as follicle stimulating
hormone (FSH) and leutinizing hormone (LH) (Krsmanovic et al.,

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1998). Brain cholinergic activity also increases pituitary secretion

of prolactin (Findling and Tyrrel, 1991).

4. Pesticide metabolism and induction of phases I and II

OP pesticides such as diazinon and chlorpyrifos are metabolized initially by CYP450 enzymes to yield oxidative desulfuration
products, where the sulfur atom in the P = S moiety is replaced by
oxygen (Hodgson and Rose, 2006). The so called oxon metabolites are then hydrolyzed by phosphotriesterases among which
the most commonly encountered is the paraoxonase-1 (PON1).
The main CYP450s involved in the oxidation reaction of OP compounds are CYP2B6, CYP2C19 and CYP3A4 (Flaskos, 2012). The
oxon forms are responsible for the acute neurotoxic effects that
occur following high exposure to OP compounds. It is evident that
genetic variations in the above mentioned xenobiotic-metabolizing
enzymes may alter their catalytic activity and the concentration of
oxon metabolites in either serum or target tissues. PON1 is one of
the most extensively studied xenobiotic metabolizing enzymes, as
two frequently encountered genetic polymorphisms in the coding
region (PON1Q192R and PON1L55M ) result in lower catalytic activity and reduced protein levels, respectively (Tsatsakis et al., 2009,
The notion that OP levels in biological uids are associated with
PON1 status has been adopted by various studies (Lopez-Flores
et al., 2009; Tsatsakis et al., 2011; Singh et al., 2011). Signicant
interactions have been reported between OP exposure and thyroid
et al.,
function in individuals with lower PON1 activity (Lacasana
2010). However other studies have found no association between
PON1Q192R polymorphism and poor general or mental health in the
general population (Rice et al., 2009).
Induction of several phase I and II xenobiotic-metabolizing
enzymes occurs as a result of xenobiotic entrance in the body.
Given that OC pesticides are small molecular weight compounds
with lipophillic nature, they may activate either the aryl hydrocarbon receptor (AhR) or the pregnane X receptor (PXR) and
consequently facilitate the expression of genes encoding for phase
I and II enzymes. Agonistic and antagonistic effects of pesticides
towards AhR and PXR have been reported, as well as inhibitory and
increased metabolic activities for detoxication enzymes, particularly hepatic CYP450 isoforms (Abass and Pelkonen, 2012; Chan
et al., 2009; Han et al., 2007; Das et al., 2008; Scollon et al.,
2009). OC pesticides bind strongly to the AhR and induce transcription of CYP1 family enzymes and glutathione-S-transferases
(GSTs) (Karami-Mohajeri and Abdollahi, 2011). Endosulfan, an OC
insecticide, has the ability to stimulate the PXR and/or the constitutive androstane receptor (CAR) resulting in activation of the
expression of CYP2B6 and CYP3A4 (Casabar et al., 2010). OC pesticides such as dicofol induce expression of hepatic and extrahepatic
CYP450s in vivo and in vitro, notably CYP1A1, CYP2B, CYP2E1
and CYP3A, whereas methoxychlor possesses antagonistic activity towards AhR and downregulates CYP1A1 levels (Abass and
Pelkonen, 2012; Chan et al., 2009; Das et al., 2008; Han et al.,
2007; Scollon et al., 2009). Increased levels of CYP450 enzymes may
further metabolize and bioactivate other xenobiotic substances,
such as nitrosamines and polycyclic aromatic hydrocarbons, leading to the formation of toxic metabolites (Androutsopoulos et al.,
Increased oxidative stress, as a result of an enhanced generation of highly reactive molecules and/or reduced capacity of the
antioxidant system of the body, is a second biological effect caused
by OP and OC insult. This leads to DNA damage and changes
in the expression of genes encoding for CYP450s, such as UDPglucuronosyl transferases and GSTs, as a feedback mechanism for

immediate detoxication of potentially harmful pesticide metabolites (Karami-Mohajeri and Abdollahi, 2011).

5. Non-cholinergic effects and developmental

It is well established that acute cholinergic neurotoxicity caused
by OPs is mediated by the inhibition of AChE by their corresponding oxon products, resulting in accumulation of acetylcholine,
which in turn causes overstimulation of muscarinic and nicotinic receptors. Recent reports suggest an additional mechanism
of neurotoxicity due to OP interference with normal neurodevelopment that appears to be independent of the cholinergic effects
since they occur at concentrations below those affecting cholinergic transmission (Pope et al., 2005). Chlorpyrifos and diazinon
elicit adverse effects on brain development at exposures lower than
those required to inhibit AChE, with the adverse effects involving
the parent compounds and not their oxon metabolites, which are
responsible for AChE inhibition (Jameson et al., 2007).
Evidence from in vitro studies indicates that diazinon-oxon is
capable of reducing the number of neurites, whereas chlorpyrifosoxon inhibits DNA synthesis in glioma cell lines and disrupts glial
cell differentiation by affecting the integrity of the microtubule
network (Flaskos, 2012). Chlorpyrifos-oxon and diazinon-oxon are
clearly more potent than their parent compounds in inhibiting neuronal and glial cell differentiation. However, such effects are not
related to AChE inhibition, as the concentration of chlorpyrifosoxon needed to activate CREB, (Ca2+ /cAMP response element
binding protein), a transcription factor involved in brain development, is lower than the concentration required to inhibit
AChE (Schuh et al., 2002). More specically, chlorpyrifos and
chlorpyrifos-oxon increase the phosphorylation of CREB, without affecting total CREB protein levels, and thus stimulate diverse
signaling pathways within neurons that are critical for neurodevelopment and cognitive function (Schuh et al., 2002). This effect was
demonstrated at nanomolar concentrations, which are much lower
than those required to inhibit AChE, suggesting that it occurs in an
AChE-independent fashion (Schuh et al., 2002).
On the other hand, the expression pattern of AChE variants plays
a role in the developmental neurotoxicity of OPs. It has been proposed that non-enzymatic functions of AChE splice variants may be
involved in the mechanisms underlying the developmental neurotoxicity of OPs (Jameson et al., 2007). AChE occurs in neuronal
and non-neuronal tissues where it exerts non-canonical functions
independent of the acetylcholine-hydrolyzing capacity, such as
neuritogenesis, synaptogenesis, proliferation, cell adhesion, apoptosis, hematopoiesis, and osteogenesis (Xie et al., 2011). These
non-catalytic functions have been ascribed to two AChE variants:
the more abundant synaptic isoform (AChE-S, a membrane multimeric enzyme) and the soluble monomeric readthrough isoform
(AChE-R). Although both isoforms are induced by neural injury or
cholinesterase inhibitors, overexpression of AChE-S is associated
with injury and enhances neurotoxicity, whereas AChE-R appears
to promote repair and protect against neurodegeneration (Jameson
et al., 2007; Xie et al., 2011).
In summary, the various OP pesticides differ in key mechanistic aspects involved in their neurodevelopmental toxicity. These
compounds affect brain development after fetal and childhood
exposures through mechanisms other than cholinergic overstimulation, particularly by targeting pathways involved in normal cell
development and alterations in the expression and function of
nuclear transcription factors that control cells replications, differentiation and apoptosis (Dam et al., 2003; Slotkin and Seidler,

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6. OP and OC pesticide exposure and neurodegeneration

Exposure to OPs can produce some long-term neurotoxic consequences as a result of acute poisoning and after long-term
exposure to subclinical doses of OPs. Irreversible AChE inhibition
after acute OP exposure may produce brain damage due to cholinergic neuronal dysfunction and excitotoxicity. Cholinergic neurons
damaged by high OPs doses might be responsible for persistent profound neuropsychiatric and neurobehavioral impairments,
including memory, cognitive, mental, emotional, motor and sensory decits (Chen, 2012; Kanavouras et al., 2011; Androutsopoulos
et al., 2011).
Different studies have pointed out mitochondria as a likely
target for neural degeneration caused by chronic low-level OP
exposure. Alterations of ATP concentrations and changes in mitochondrial transmembrane potential have been observed following
exposure to neuropathic OP compounds, suggesting mitochondrial dysfunction (Carlson and Ehrich, 1999). Mechanistically, OPs
might result in elevated mitochondrial calcium uptake that impair
complex I and complex II function and decrease electron transfer activities of cytochrome oxidase (complex IV). Collectively,
these events adversely affect ATP synthesis. As a result of disruption of mitochondrial transmembrane potential, cytochrome
c is released from mitochondria to cytosol and several caspases
are activated, leading to apoptotic cell death (Binukumar et al.,
2010; Kaur et al., 2007). The alteration in the mitochondrial calcium uptake and mitochondrial electron transfer enzyme activities
may cause lipid peroxidation, an increase in protein carbonyl,
enhanced 8-hydroxydeoxyguanosine formation, and protein and
mtDNA oxidation. Moreover, chronic OP exposure has the potential
of generating reactive oxygen species and/or impairing cellular antioxidant defense system, leading to oxidative stress. In
summary, chronic low-level exposure to OPs impairs mitochondrial bioenergetics resulting in apoptotic neuronal degeneration
(Binukumar et al., 2010; Kaur et al., 2007; Wani et al., 2011). This
common mechanism may underlie the development of many neurodegenerative diseases.
Increasing evidence suggests that in addition to excessive
cholinergic stimulation, OP compounds are also capable of inducing
activation of glutamatergic neurons and generation of reactive oxygen and nitrogen species, leading to lipid peroxidation
with dendritic degeneration of pyramidal neurons and ultimately neurodegeneration (Zaja-Milatovic et al., 2009). Although
chlorpyrifos-oxon is about three orders of magnitude more potent
than chlorpyrifos in inhibition of brain AChE activity, chlorpyrifosoxon is only slightly more potent in inducing apoptosis. Thus,
apoptosis may play a mechanistic role in chlorpyrifos neurotoxicity that may be independent of AChE inhibition (Caughlan et al.,
Another neurodegenerative disorder is organophosphateinduced delayed polyneuropathy (OPIDP), a rare toxicity that
typically occurs only after very large exposures to OP compounds causing severe cholinergic toxicity. The molecular target
for OPIDP is considered to be an enzyme in the nervous system
known as neuropathy target esterase (NTE) (Lotti and Moretto,
2005). This enzyme is localized to the cytoplasmic face of the
endoplasmic reticulum, the starting point for the constitutive
secretory pathway and transport of neuronal materials into axons
(Read et al., 2009). NTE catalyses the deacylation of endoplasmic
reticulum-membrane phosphatidylcholine to soluble products,
glycerophosphocholine and fatty acids. In the nervous system of
susceptible vertebrates, neuropathic OPs will cause a transient loss
of NTEs phospholipase activity, which in turn causes endoplasmic reticulum malfunction and perturbation of axonal transport
and glialaxonal interactions; with the distal parts of long axons
being particularly vulnerable to loss of these support functions

(Glynn, 2007). Proteins involved in axonal transport, especially

those whose function depends on reversible phosphorylation, may
have also a role in OP-induced neurodegeneration (Lockridge and
Schopfer, 2010).
Long-term environmental exposure to certain OC insecticides
(i.e., lindane and dieldrin) has been associated to the development of neurodegenerative disorders, such as Parkinsons disease
(Heusinkveld and Westerink, 2012). A combination of lindane and
dieldrin can induce a rapid increase in the levels of intracellular
reactive oxygen species, a decrease in mitochondrial membrane
potential and activation of caspases. Both oxidative stress and
mitochondrial dysfunction may result in dopamine neurotoxicity,
suggesting that those pesticides may play a role in the multifactorial etiology of Parkinsons disease (Sharma et al., 2010).
Oxidative stress induced by endosulfan has also been implicated in the neurotoxicity of this OC insecticide. Mechanistically,
endosulfan can modulate the activities of stress-responsive signal transduction pathways including extracellular signal regulated
kinases (ERK). These kinases can further activate mitogen-activated
protein kinases (MAPKs) and then enhance c-Jun phosphorylation,
which in turn increases activating protein-1 (AP-1) activity resulting in activation of antioxidant response element (ARE)-mediated
transcription (Song et al., 2012). DDT also exerts toxic effects
on neuronal cells by the stimulation of MAPKs (Shinomiya and
Shinomiya, 2003).
7. Conclusion
Pesticides are chemicals with diverse biological toxic effects
that act on multiple cellular targets. OP pesticides are metabolized
by CYP450s to their active oxons that are further hydrolyzed by
PON1 whereas OCs tend to accumulate in adipose fatty tissues
for a long time period, before being release to the blood. There
is evidence that substantiates the effect of pesticides on glucose
and lipid metabolism as well as their effect on normal endocrine
and hormonal function, via antagonism with hormonal-binding.
In addition, binding of organochlorine pesticides to nuclear and
cytoplasmic receptors affects the expression of an array of genes
encoding for xenobiotic-metabolizing enzymes as well as for cell
growth and differentiation. Due to their potential for short and long
term hazardous effects, continuous biomonitoring of the levels of
pesticides in humans is an essential step towards the evaluation
of risk assessment and the prediction of pathology in populations
either occupationally exposed to pesticides or with background
environmental exposure.
Conict of interest
There are none conict of interest to declare with respect to this
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