FUNGAL TOXINS (MYCOTOXINS

)
AND
BACTERIAL TOXINS
MYCOTOXINS
MYCOTOXINS
Secondary metabolites of toxigenic fungi on animal
feed and food ingredients which cause adverse
biological effects when consumed in sufficient
quantities.
 Toxigenic fungi produce their toxins when
temperature, moisture and aeration are favourable.
 Minimum 15% moisture (10-33 %)
 90-95% relative humidity (>70%)
 Ambient temperature of 24-25° C (4 - 35 °C).


Characteristics of Mycotoxins
• Not transmissible from one animal to other, so are
not infectious.
• Outbreaks are usually seasonal.
• Adverse effects on health & production in all species of
animals and birds.
• Growing, pregnant and lactating ones are worst affected
• Have specific association with a particular feed.
• Treatment with antibiotics has little effect on the
mycotoxins and the course of disease.
• Immunosupressive.
• Mould infested feed, poor nutrition, inadequate diet are
predisposing factors.
• Stress, insect damage and plant disease enhance toxin
production.
MYCOTOXIN TYPES/ CLASSIFICATION
HEPATOTOXINS
 Aflatoxins - Aspergillus flavus, A. parasiticus.
 Sporidesmin- Pithomyces chartanum
 Rubratoxins - Penicillium rubrum, P.purpurogenum.
 Other- sterigmatocystin, luteoskyrin, cyclochlorotine
NEPHROTOXINS
 Ochratoxins - Aspergillus ochraceus,
Pencillium viridicatum
 Citrinin- Pencillium citrinum, A.ochraceus

OESTROGENIC MYCOTOXINS
 Zeralenone(F2 toxin) – Fusarium roseum
CYTOTOXIC MYCOTOXINS
 Trichothecenes(T-2 toxins)- Fusarium sp. F.gramaenareum and
F. roseum.
NEUROTOXIC MYCOTOXINS
 Tremorgens- Patulin and Penitrem A- Penicillium Aspergillus and Claviceps
MISCELLANEOUS
 Ergotoxins – Claviceps purpurea and C. paspali.
 Fescue toxin- Neotyphoidium coenophialum
 Slaframine- Rhizoctonia leguminicola


Commonly encountered mycotoxins in various
contaminated food and feeds are

 Aflatoxins- in warm, humid regions
 Ocharotoxin-A
 Zearalenone in cold, temperate regions
 Trichothecenes
 Citrinin
CHARACTERESTICS OF MYCOTOXINS
• .
• Aflatoxins affect all domestic animals.
• Zearalenone and vomitoxin mainly affect swine and dairy
animals.
• Fumosins mainly affect swines and equines.
• T-2 toxin, ocharotoxin, diacetoxyscirpenol (DAS) affect
mainly swine and poultry.
AFLATOXINS
• Aflatoxins are the toxic metabolites of toxigenic fungi Aspergillus flavus
and A. parasiticus.
• First discovered in England in1960. called as Turkey X disease.
• Aflatoxins are a group of polycyclic, unsaturated, substituted coumarin
derivatives with highly reactive bifuran nucleus on one side and a
pentenone (B toxin) or a six membered lactone (G - toxin) ring on the
other side.
 Polycyclic furan compounds ; Coumarin Nucleus with reactive bifuran
system on one side and either a pentenone (B series) or lactone (G series)
• Commonly affect GNC, CSC, coconut cake, sunflower cake, wheat,
sorghum, millets, soybean, peas and almonds,barley,oats,rice,cornmeal
,etc.
 Contamination can occur during- harvest, STORAGE, processing
 Produce aflatoxins under favourable aerobic conditions- Moisture (>
15%) ; Relative humidity (90 - 95%) ; Ambient temperature (24 -25c)

CHEMISTRY
• Several aflatoxin fractions have been isolated and differentiated
from one another by

• Their fluorescence under ultraviolet ; RF values on thin layer
chromatography and Structural identification and synthesis
 Total 18 compounds in the aflatoxin family
Four important ones
 B1 & B2 (fluoresce blue under long wave UV light)
 G1 & G2 (fluoresce green under long wave UV light)
 Aflatoxins with blue fluorescence under ultraviolet light are B
1

(most toxic) and B
2
.

 Dihydroderivatives of B
1
and B
2
and fluoresce green are designated
as G
1
and G
2
.


• Hydroxylated metabolites of B
1
and B
2
aflatoxins are excreted in milk
and are termed as M
1
and M
2.




LETHAL DOSE 50
♣Horse,sheep,goat : 2 mg/Kg
♣poultry & swine : 2 mg/Kg
♣Cattle : 0.5-2 mg/kg
♣Dog : 0.5-1mg/kg
♣Ducks : 0.3-0.6mg/kg
♣Rabbits : 0.3-0.5mg/kg
♣Mice : 9mg/kg
Toxicity
• Aflatoxin B
1
(AFB
1
) is most important because of its toxicity
and high concentration in the contaminated feeds.
• The order of toxicity is : B
1
> G
1
>B
2
> G
2

• Relatively heat resistant and not soluble in water.
• The LD
50
of AFB
1
is 0.3 - 9 mg/kg for all species of animals,
birds and fishes tested.
• Cattle, sheep and other ruminants appear less
susceptible than the monogastric animals and poultry.
• Sheep and mice are comparatively most resistant.; Cats,
dogs and rabbits are most sensitive
• Even the toxigenic fungi or toxins are not destroyed by milling
of the grains.


Toxicity

• Presence of additional oxygen in the AFG compounds
results in reduction of their activity by a factor of 2 while
unsaturated compounds are 4-5 times more potent
compared to dihydro derivatives.
• The structure of B toxin resembles closely with the
structure of pyrrozolidone which has got basic
carcinogenic activity.
• Aflatoxins are potent mutagens, carcinogens, teratogens
and liver damaging agents.


Factors affecting toxicity of aflatoxins:
 Species variations-Ducks, rabbits, dogs, pigs, calves, chicken,
cows, quail and sheep are susceptible in the order of preference.
 Broilers are more susceptible than layers.
 Calves are more susceptible than adult dairy cattle.
 Maximum allowable conc. in dairy cattle is 20 ppb (0.02 ppm) for the
fear of M1 metabolite.
 In India limit is up to 50 ppb (0.05ppm) that can be fed to beef cattle,
poultry and swine
• Age- Young ones most susceptible
• Sex – Males more susc. Tha females( except in pregnancy)
• Nutritional deficiencies- protein, selenium, vitamin C- more
susceptible-
• Diet rich in riboflavin, low in proteins, cholines, vitamin B
12
-
enhance toxicity.
• High dietary proteins, lipids and carotenes lower the susceptibility to
aflatoxins-induced toxicity.

TOXICODYNAMICS
• Majority of the aflatoxins ingested in feed are physically
bound to ruminal contents and as little as 2-5% reach the
intestines.
• Aflatoxin B
1


in excess of 100 μg/kg of feed is considered to
be toxic to cattle.
• Aflatoxins are rapidly absorbed from the intestine and
bound to blood proteins.
• Liver removes most of the toxins from the blood stream.


• AFB
1
is primarily metabolized by a microsomal cytochrome P-450
dependent mixed function oxidase system in the liver and other
organs to AFB
1
-2, 3 epoxide mainly, which is a highly reactive
intermediate.

• Epoxides are chiefly detoxified by glutathione (GSH)-S-transferase
and epoxide hydratase to aflatoxicol to some extent which
subsequently are conjugated and excreted.
• Excess of reactive products of aflatoxin B
1
interact with N-guanyl
residue of nuclear DNA of hepatocytes to inhibit synthesis of DNA,
DNA-dependent RNA polymerase activity, messenger RNA synthesis
and protein synthesis by interfering with transcription.

• AFB
1
also binds to endoplasmic steroidal ribosome-binding site
causing disaggregation of ribosomes.


Cont…..
• Number of ribosomes decrease, there is reduced proliferation
of smooth endoplasmic reticulum, loss of glycogen and
degeneration of mitochondria.
• Impaired protein synthesis interferes with the formation of
certain enzymes required for energy metabolism and fat
mobilization. As a result, there is hepatic steatosis.
• Cytotoxicity and carcinogenicity are due to
macromolecular binding, not only of AFB
1


but also other
metabolites.
• Haemorrhages, fatty liver and immunosuppression are
due to inhibition of clotting proteins and protein synthesis.



Mechanism of action
AFB1
Acts as electrophile Binds to ER

Binds to N7 guanine Dissagregation of ribosomes

RNA poymerase

RNA

Enzyme : protein synthesis

glubulins

immunosuppresion

Energy metabolism effected
`
Mechanism of action
AFb1

Interact with donor groups of macromolecules of hepatocytes(free
radical induced damage)

Hepatocellular necrosis Muatgenicity
a) Apoptosis
Deficiency of clotting factors 2,7,9,10, b)Repair
Heamolytic syndrome c)Carcinogenicity

Production or activation

Coagulopathy
Interference with energy metabolsim
TOXICOKINETICS
Rapid absorption from GIT
Bound serum albumin
Metabolites – water soluble conjugates or Lipid
soluble – liver – excretion – urine & bile (
enterohepatic circulation)
B1 7metabolites (q1,p1,b2a,m1,aflatoxicol)
M1 is more toxic,carcinogenic & excreted in milk
M1,M2,p1,q1 & aflatoxicol

Clinical signs

• Aflatoxicosis may be 1. Acute
2. Subacute
3. Chronic
• Chronic is the most commonly observed syndrome
• Characterised by high incidence of hepatic tumours.


Acute toxicity :

• Occurs sporadically as a farm disaster when high to
moderate amount of the toxin is consumed.

• Sudden deaths wthin 72 hours without much symptoms of
toxicity like anorexia, depression, ataxia, dyspnoea,
anaemia, haemorrhages, bloody faeces, tremors,
convulsions and death.



• A dose rate of 4 mg/kg of aflatoxin causes death of sheep,
calves and pigs with in 15 -18 hours due to acute hepatic
insufficiency
• With 2 mg/kg, there is anorexia, increased respiration rate,
increase in body temperature and diarrhoea with blood and
mucus.
• The clinical signs in dogs appear in 2-14 days (average 5 days)
and are characterized by anorexia, icterus, bile stained urine,
prostration, occasionally blood in faeces, vomition
(sometimes bloody), epistaxis and rarely convulsions.




LD
50
values of AFB
1
in some species of animals
and birds

SPECIES LD
50
VALUE (mg/kg)
Rabbits 0.3-0.5
Ducklings 0.5
Cats 0.3-0.6
Dogs 0.5-1.0
Cattle 0.5-2.0
Horses >2.0
Chicken >2.0
Subacute toxicity:
• Consumption of sublethal concentrations of aflatoxins for
several days or weeks
• icterus, hypoprothrombinemia, haemorrhages and
haematomas.
Chronic toxicity
• However, 1 -2 months or more later, gradual decrease in feed
efficiency, weight gain, productivity, icterus, ascites, oedema of
lungs and abortion in pregnant animals may be observed.

• In cattle, there is blindness, twitching of ear, grinding of teeth,
circling movement, frothing in the mouth, photosensitive
dermatitis, keratoconjunctivitis, haematomas, ataxia, diarrhoea,
anal prolapse, recumbency and convulsions, followed by death
within 48 hours.
• Placental transfer of aflatoxins --- cause cirrhosis of liver in
calves.




Chronic toxicity …contd
• Pigs also exhibit similar signs; there are intermittent haemorrhages
and diarrhoea. exhibit seizures before death.
• Horses -typical signs of hepatic toxicity and gastrointestinal upset
• Sheep, however, are refractory to these effects as the ewes fed on
highly toxic groundnut meal for 5 years failed to exhibit any clinical
signs of aflatoxicosis except for reduced fertility.
• In poultry, aflatoxins interfere with absorption of lipids and
transportation of yolk. Egg production and egg size are reduced.
• Increases susceptibility of turkeys to coccidiosis, pasteurellosis
and salmonellosis and of chicken to coccidiosis and Marek's
disease.
Post mortem lesions:

(i) Liver is pale, firm and fibrosed.
(ii) Microscopically, centrilobular necrosis, bile duct proliferation and veno occlusion
are the main changes. Hepatocytes are swollen, there are multiple foci of
necrosis and fibrosis and hepatic carcinoma.
(iii) Kidneys are yellow and surrounded by wet fat in young calves.
(iv) Serous exudate in the body cavities.
(v) Oedema and ascites of mesentery.
vi) Catarrhal enteritis.
(vii) Eversion of rectum.
(viii) Haemorrhages in thoracic and peritoneal cavities. Liver is yellow and mottled in
dogs, however, it is off white to bright orange alongwith proliferation of bile duct,
subcutaneous haemorrhages, ascites and oedema of mesentery in pigs.
(ix) Diarrhoea and dysentery.



DIAGNOSIS
• History and clinical signs
• Necropsy findings
• Laboratory investigation of feed and other
samples- blood, milk, urine etc-TLC,HPLC,RIA,ELISA
DIFFERENTIAL DIAGNOSIS
• warfarin poisoning (coagulation defects)
• Coal tar poisoning (mottling of liver)
• copper poisoning (hemolysis)
• infectious hepatitis , other hepatotoxicity due to –
CCi4, pyrrolizidone alkaloids
• Other moulds toxins
Laboratory investigations
• Blood examination of aflatoxicosis affected animals
would reveal elevation in blood serum levels of
– AST, Alkaline phosphatase
– Isocitrate dehydrogenase, Lactate dehydrogenase
– Gamma-glutamyl transpeptidase , Glutamate dehydrogenase
– Bilirubin.
• Blood clotting defects and extensive haemorrhages are
observed in almost all species of animals due to impairment of
blood clotting factors - II, VII, IX and X.
• Haemolytic syndrome is very common in poultry.
• Decrease in serum total proteins and elevation in blood urea
nitrogen are also observed.
• Both the cell mediated and humoral immune response are
suppressed.


Prevention and treatment:

• Contaminated feed must be withdrawn immediately.
• Provide easily digestible low fat and high protein diet/feed.
• Supportive therapy with multivitamins.
• 0.5% hydrated sodium calcium aluminosilicate as feed additive in the
feed of pigs and lambs. It adsorbs aflatoxins thus reduces their absorption
from the GIT.
• Anabolic steroid stanozolol (2 mg/kg) by 1M injection at 4-5 days
interval to decrease hepatic damage.
• Activated charcoal @ 6.7 mg/kg intraruminally as 30% W/V slurry in
M/15 phosphate buffer of pH 7.
• Oxytetracycline (10 mg/kg, 1M once daily) decreases hepatic necrosis
 Never administer oxytetracycline and stanzolol combination, they are
mutually antagonistic.
.

Prevention and treatment …contd
• Supplement the diet with vitamin E and selenium to
ameliorate the effects of aflatoxins.
• Supplement the diet of affected animals with hepatotonics.
• Prevent undue stress to the affected animals.
• (FDA considers aflatoxins in milk and meat as a serious threat
to human health and a serious regulatory violation)
 Treatment of grains with anhydrous NH
3
,H
2
o
2
,Chlorine,O
3

but efficacy not been established

 Activated charcoal 6.7 mg / Kg I/R as 30% W/V slurry in
M/15, PH7 Phosphate buffer.
 Along with charcoal, stanzolol/oxytetracycline (any one may
be given)
• Intravenously administer sufficient quantities of 5% dextrose
• GSH Precursors Cysteine,methionine @2.2mg/kgi/p

MYCOTOXIN BINDERS
• Mycotoxin adsorbents offer an attractive short-term solution to the
challenge of mycotoxin-contaminated animal feeds.
The only complete solution to the mycotoxin challenge will be the long-term
goal of eliminating mycotoxins from the food and feed chains through
improved quality control based on better analytical techniques coupled
with genetic advances in plant resistance to fungal infestation.
Mycotoxin binding is achieved through both:
• Physical adsorption
– Relatively weak bonding involving van der Waals interactions and
hydrogen bonding
• Chemical Adsorption:
– (Chemisorption) is a stronger interaction which involves ionic or
covalent bonding.
• An effective binder or sequestering agent is one that prevents or limits
mycotoxin absorption from the gastro-intestinal tract of the animal. In
addition, they should be free from impurities and odours. Be aware that
not all are equally effective. Many can impair nutrient utilisation and are
mainly marketed, based on in-vitro data only.


• There are two types of mycotoxin adsorbent/binder:
INORGANIC BINDERS AND ORGANIC ADSORBENTS
• Inorganic mycotoxin binders are silica based polymers. Examples
could include:
• zeolites
• bentonites
• bleaching clays from the refining of canola oil
• hydrated sodium calcium aluminosilicates (HSCAS)
• diatomaceous earth
• numerous clays
 They can be grouped into two categories: Phyllosilicates and
Tectosilicates:
 Phyllosilicates: bentonites/montmorillonites-Phyllosilicates are
characterised by alternating layers of tetrahedral silicon and
octahedral aluminium coordinated with montmorillonite oxygen
atoms
 Tectosilicates: zeolites
 Tectoalumosilicates of alkali and alkaline earth cations that have an
infinite three-dimensional cage-like structure


Organic Adsorbents
Organic mycotoxin adsorbents are carbon based
polymers. Examples could include:

fibrous plant sources such as:
– oat hulls
– wheat bran
– alfalfa fibre
– extracts of yeast cell wall
– cellulose
– hemi-cellulose
– pectin
• Such materials are biodegradable but can, in some
cases, also be vectors of mycotoxin contamination.
Benefits of yeast cell wall are low inclusion, high
surface area and certainly no toxic contaminants.


RUBRATOXIN


SOURCE
contaminated feed
 co-exist with aflatoxins
 Produced by fungus - Penicillium rubrum,
P.purpurogenum
CHEMISTRY
Occurs in Two forms- Rubrotoxin A & B
RBTA : Pencillium rubrum
 RBTB : pencillium purpurogenum
Toxicity is due to presence of αβ unsaturated
lactone ring
 Haemorraghic syndrome in poultry- first
recognised

PROPERTIES
Insoluble in oil & water
Soluble in alchohol and esters
Stable at room temperature(Heating at 85-100oc
destroys)
Rubratoxin B is major hepatotoxin, mutagenic,
carcinogenic
 LD 50 Value 400-450mg/kg
Potentiates Aflatoxicosis in mouldy feeds
Dog,cat,goat & horse Susceptible

TOXICODYNAMICS
Action similar to aflatoxins
 bind to cell macromolecules- DNA,RNA alter
the function
Lethal effects on ATP ases and electron
transpsort system
Severe liver damage and Heamorrhagic
pnuemonia
Mechanism of action
RBt-B

Rbtb1 epoxide

Interacts with Macromolecules of Hepatocytes

DNA & RNA polymerase

Protein synthesis

Mechanism of action
RBT- B


ATP ases(mitochondrial) Distintegration
of
Ionic movement Across Mitochondrial membrane Ribosomes

Loss of structural & Functional Integrity of Mitochondria Protein
synthesis

Hepatotoxicity

TOXICOKINETICS
Liver metabolism
Glucoranide & sulphate conjugates
Excreted in bile,urine ,feaces
Enterohepatic cycle
symptoms
Signs related to hepatotoxicity
Anorexia
Dehydration
Depression
Jaundice
Diarrhoea
Weight loss
Swine : head pressing& colic
Horse : Incordination

PM LESIONS
Hemorrhages in various organs
Renal damage
Horse : brain hemorrhage
DIAGNOSIS
History
Symptoms
Lesions
Lab tests – detection of rubrotoxin in urine and
feed by chromotography
DD:- Aflatoxicosis
 No specific treatmnet
 Withdrawl of contaminate dfeed, supportive
treatment
TREATMENT
Symptomatic
Withdrawl of suspected feed
Anabolic Steroids
Activated charcoal
Fluid therapy
SPORIDESMINS
SPORIDESMINS
• are secondary metabolites of the saprophytic fungus Pithomyces chartarum,
(Sporidesmium bakeri)which grows on dead pasture litter.
• The warm ground temperatures and high humidity required for rapid growth
of this fungus restrict disease occurrence to hot summer and autumn periods
shortly after warm rains.
• The sporidesmins are excreted via the biliary system, in which they produce
severe cholangitis and pericholangitis as a result of tissue necrosis.
• Biliary obstruction may be seen, which restricts excretion of bile pigments and
results in jaundice.
• Similarly, failure to excrete phylloerythrin in bile leads to photosensitisation.
• Previous ingestion of toxic spores causes potentiation, thus a succession of
small intakes of the spores can lead to subsequent severe outbreaks
Clinical Findings, Lesions
• photosensitisation and jaundice appear -10-14 days after
intake of the toxins.
• Animals frantically seek shade.
• Even short exposure to the sun rapidly produces the typical
erythema and edema of photodermatitis in unpigmented skin.
The animals suffer considerably, and deaths occur from one to
several weeks after photodermatitis appears.
PM Lesions:
• Characteristic liver and bile duct lesions are seen in all affected
animals
• livers are initially enlarged, icteric, and have a marked lobular
pattern. Later, there is atrophy and marked fibrosis.
• Generally, these areas are associated with fibrosis and
thickening of corresponding bile ducts.
• The bladder mucosa commonly shows hemorrhagic or
bilepigment- stained ulcerative erosions with circumscribed
edema.
Treatment and Control
• To minimise intake of pasture litter and toxic spores,
short grazing should be avoided.
• Other feedstuffs should be fed during danger periods
• Treating for – hepatitis and photosenstization
• Antibacterails, antihistaminics
• zinc sulphte in water(6g/100l) hastens wound
recovery Zinc may be administered by drenching
with zinc oxide slurry, by spraying pastures with zinc
oxide, or by adding zinc sulfate to drinking water
• . A pasture area calculated at 1 acre (0. 45
hectare)/15 cows or 100 sheep should be sprayed in
midsummer with a suspension of thiabendazole.
• When danger periods of fungal activity - animals
should be allowed only on the sprayed areas.
OCHRATOXIN
Feeds affected- Wheat rye, Corn , Barley , Cereal grains
• Ochratoxins and citrinin are produced by several species of genera
Aspergillus and Penicillium.
• The two most common species that produce ochratoxin A (OTA)
are Aspergillus ochraceus and Penicillium verrucosum.
• These fungi are ubiquitous and the potential for contamination of
animal feed and human food is widespread.
• Aspergillus spp. appears to produce ochratoxins at conditions of
high humidity and temperature
• Citrinin was first isolated as a pure compound from a culture of P.
citrinum in 1931. Later, it was also isolated from A. ochraceus, P.
verrucosum, and related species that contaminate grain.
FACTORS AFFECTING TOXICITY
Mositure content >16%
RH > 85%
Temparature 12-25
0
c
Species : swine & poultry more susceptible
Swine Mould nephrosis or Mycotoxic
nephropathy
Ruminants least susceptible
CHEMISTRY
Isocoumarin compounds
Synthesized from phenyl alanine
Nine ochratoxins present; A is more toxic
 Oral toxic dose for swine & poultry 1-5p
TOXICOKINETICS
Acitve metabolites – ochratoxin q & phenyl
alanine by microsomal MFO
Residue in kidney ,Foetal lamb blood
Crosses placental barrier



TOXICODYNAMICS
Action on renal PCT
Decrease metabolite clearance and urine
concentration ability
Inhibit anion transport & release of renal brush
border enzymes
Interfere with protein synthesis protein,RNA
synthesis
Disruption of carbohydrate metabolsim
Increased free radical generation via Cyt p450
reductase mechanism
SYMPTOMS
Acute :
rare, Anroxia,
Dehydration,Depression,Diarrhoea
Sub acute or chronic : common
Weight loss
Polyuria
Polydipsia, dehydration, anemia
Reduced feed effeciency
 immunosuppression, teratogenecity,
carcinogenecity-
 Foetal detah, resorption, abortion


PM LESIONS
Pale & enlarged kidney
Renal cortex cut surface shows pale cortical
streakings and cystic areas
Microscopically:
• proximal tubule degeneration
• Renal tubular swelling
• Interstitial fibrosis
• Hyalinization of gromeruli
• Hepatic necrosis
• Lymphoid depletion
DIAGNOSIS
 History and Symptoms
 Lesions
 Lab analysis of grains & feeds using TLC or
HPLC
 Blood Analysis : increased BUN & serum
creatinine
TREATMENT
No specific treatment
Activated charcoal reduces absorption but
not useful in case of chronic exposure
Symptomatic therapy- Supportive therapy
Harvesting and properly drying the feed
before storage

OESTROGENIC MYCOTOXIN
ZERALENONE
ZERALENONE
• Fusarium spp molds often contaminate growing plants and
stored feeds. Corn (maize), wheat, and barley are commonly
contaminated.
• Under humid weather conditions, F graminearum (F. roseum)
may produce zearalenone, one of the resorcyclic acid lactones
(RAL).
• Zearalenone (formerly called F2 toxin) is a potent
nonsteroidal estrogen and is the only known mycotoxin with
primarily estrogenic effects.
• Often, zearalenone is produced concurrently with
deoxynivalenol.
• Depending on the ratio of these 2 mycotoxins, signs of
reduced feed intake or reproductive dysfunction may
predominate,
• but presence of deoxynivalenol may limit exposure to
zearalenone, thus reducing its practical effect.
• SWINE – most susceptible species(porcine vulvovaginitis)
TOXICODYNAMICS
• Zearalenone binds to receptors for estradiol-17-b, and this
complex binds to estradiol sites on DNA.
• Specific RNA synthesis leads to signs of estrogenism.
• Zearalenone is a weak estrogen with potency 2-4 times less
than estradiol.
• Estrogenism due to zearalenone was first clinically
recognised as vulvovaginitis in prepubertal gilts fed moldy
corn (maize)
• High dietary concentrations are required to produce
disease in cattle and sheep, and extremely high dosages are
required to affect poultry.
Clinical Findings
• Physical and behavioral signs of estrus are induced in young
gilts by as little as 1 ppm dietary zearalenone.
• In pigs, zearalenone primarily affects weaned and
prepubertal gilts, causing hyperemia and enlargement of the
vulva.
• There is hypertrophy of the mammary glands and uterus, with
occasional prolapse of the uterus in severe cases. In
multiparous sows, signs include diminished fertility, anestrus,
reduced litter size, smaller offspring, and probably fetal
resorption.
• Constant estrus or pseudopregnancy may be seen.
• Zearalenone causes reproductive toxicosis in sexually mature
sows by inhibiting secretion and release of follicle-
stimulating hormone (FSH) resulting in arrest of preovulatory
ovarian follicle maturation.
• Embryotoxicity
LESIONS
• Lesions in pigs include ovarian atrophy and follicular atresia, uterine edema, cellular
• hypertrophy in all layers of the uterus, and a cystic appearance in degenerative
endometrial glands. The mammary glands show ductal hyperplasia and epithelial
proliferation. squamous metaplasia is seen in the cervix and vagina.
DIAGNOSIS
• Reproductive performance in the herd or flock, clinical signs, and history of diet-
related occurrence.
• Chemical analysis of suspect feed for zearalenone and careful examination of
reproductive organs at necropsy are required..
DIFFERENTIAL DIAGNOSES:
Reproductive tract infections and other causes of impaired fertility such as
diethylstilbestrol in the diet of housed stock. In grazing herbivores, especially sheep,
the plant estrogens (eg, isoflavones associated with some varieties of subterranean
and red clovers, and coumestans in certain fodders [eg, alfalfa]) should be considered.
Treatment , Control and Management
• Unless stock are severely or chronically affected, usually
reproductive functions recover and signs regress 1-4 wk
after intake of zearalenone stops.
• Management of swine with hyperestrogenism should
include changing the grain immediately.
• Animals should be treated symptomatically for vaginal
or rectal prolapse and physical damage to external
genitalia.
• For sexually mature sows with anestrus, one lO-mg dose
of prostaglandin F2a, or two 5-mg doses on successive
days, has corrected anestrus caused by retained corpora.
• Alfalfa and alfalfa meal fed to swine at 25% of the ration
may reduce absorption and increase fecal excretion of
zearalenone, but this is often not considered practical.

TRICHOTHECENES
(FUSARIOTOXICOSIS)
Trichothecenes
• Are a group of closely related secondary metabolic products of
several families of imperfect, saprophytic, or plant pathogenic fungi
such as Fusarium, Trichothecium, Myrothecium, Cephalosporium,
Stachybotrys,
• Trichodesma, Cylindrocarpon, and Verticimonosporium spp.
• On the basis of molecular structure, the trichothecenes are
classified as
– Nonmacrocyclic (eg, deoxynivalenol [DON] or vomitoxin, T-2
toxin, diacetoxyscirpenol, (DAS) and others)
– Macrocyclic (satratoxin, roridin, verrucarin).
• Most commonly found and studied are
DON,or vomitoxin, T-2 toxin, (MOST CYTOTOXIC) and
diacetoxyscirpenol, (DAS)
• Highly toxic at the subcellular, cellular, and organic system level.
• They swiftly penetrate cell lipid bilayers, thus allowing access to
DNA, RNA, and cellular organelles.
• Inhibit protein synthesis by affecting polyribosomes to interfere
with the initiation phase of protein synthesis.
• At the subcellular level, these toxins inhibit protein synthesis and
covalently bond to sulfhydryl groups.
• Toxicity of the trichothecenes is based on direct cytotoxicity and is
often referred to as a radiomimetic effect (eg, bone marrow
hypoplasia, gastroenteritis, diarrhea, hemorrhages).
• The cutaneous cytotoxicity - acute, necrotising process with
minimal inflammation of both the epidermis and dermis.
• Stomatitis, hyperkeratosis with ulceration of the esophageal portion
of the gastric mucosa, and necrosis of the GI tract have been seen
after ingestion of trichothecenes.
• Immunosuppressive
 Poultry and cattle are more tolerant of trichothecenes
than are PIGS - most suceptible.
 Nonmacrocyclic (eg, deoxynivalenol [DON] or vomitoxin,
T-2 toxin, diacetoxyscirpenol, (DAS) - mainly produced by
 Fusarium sporotrichoides ( T2 and DAS)
 F. roseum (DON)
– Lipophilic agents, absorbed through skin gut, pulmonary
mucosa
– affect rapidly proliferating tissues. Do not require
metabolic conversion to act, unlike other mycotoxins

TOXICODYNAMICS
• Potent inhibitors of protein synthesis – 60S
ribosomal subunit
• inhibit DNA, RNA synthesis
• directly cytotoxic
• produce hemorrhags by depression of
clotting factors, platelet function
• Hemorrhagic diathesis may occur after
thrombocytopenia or defective intrinsic or
extrinsic coagulation pathways.
• Immunosuppressive- sec. bact. infections

• Refusal to consume contaminated feedstuff is the typical sign,
which limits development of other signs.
• Excessive salivation and vomiting may occur. In the past, the
ability to cause vomiting had been ascribed to DON only,
hence the common name, vomitoxin.
• Feed refusal caused by DON is a learned response known as
taste aversion.
• It may be related to neurochemical changes in serotonin,
dopamine, and 5-hydroxyindoleacetic acid.
• DON in swine causes conditioned taste aversion, and swine
would be expected to recognise new flavors (eg, flavoring
agents) added to DON-containing feed and thus develop
aversion to the new taste
• Provision of uncontaminated feed usually leads to
resumption of eating within 1-2 days.
Stachybotryotoxicosis:
horse, cattle, sheep, pigs-affected due to consumpation of hay contaminated
with Stachybotris atra.
Control of Trichothecens
• Symptomatic treatment and feeding of uncontaminated feed
are recommended.
• Steroidal anti-shock and anti-inflammatory agents, such as
methylprednisolone, prednisolone, and dexamethasone,
have been used successfully in experimental trials.
ERGOTISM

ERGOTISM

• Longest known mycotoxin
• This worldwide disease of farm animals results from continued
ingestion of sclerotia of the parasitic fungus Claviceps purpurea,
which replaces the grain or seed of rye and other small grains or
forage plants, such as the bromes, bluegrasses, and ryegrasses.
• The hard, black, elongated sclerotia may contain varying quantities
of ergot alkaloids, of which ergotamine and ergonovine
(ergometrine) are pharmacologically most important.
• Cattle, pigs, sheep, and poultry are involved in sporadic outbreaks,
and most species are susceptible
TOXICODYNAMICS
• partial agonist and antagonist at alpha
adrenergic receptors in vascular and other
smooth muscles
• ergotamine- serotenergic antagonist
• ergometrine- potent oxytocic action
• Dopaminergic agonist- inhibits prolactin
• Ergot causes vasoconstriction by direct action on the repeated
dosages injure the vascular endothelium.
• Initially reduce blood flow and eventually lead to complete
stasis with terminal necrosis of the extremities due to
thrombosis.
• A cold environment predisposes the extremities to gangrene.
• Ergot has a potent oxytocic action and also causes stimulation
of the CNS, followed by depression.
• Ergot alkaloids inhibit pituitary release of prolactin with failure
of both mammary development in late gestation and delayed
initiation of milk secretion, resulting in agalactia at parturition.
Clinical Findings and Lesions
• Cattle - . Lameness, the first sign, may appear 2-6 wk or more after initial
ingestion, depending on the concentration of alkaloids in the ergot and
the quantity of ergot in the feed.
• Hindlimbs are affected before forelimbs, but the extent of involvement
of a limb and the number of limbs affected depends on the daily intake
of ergot.
• Body temperature and pulse and respiration rates are increased.
• Epidemic hyperthermia and hypersalivation may also .
• Swelling and tenderness of the fetlock joint and pastern.
• Within -1 wk, sensation is lost in the affected part, an indented line
appears at the limit of normal tissue, and dry gangrene affects distal part.
• One or both claws or part of limbs up to hock or knee may be sloughed.
PM Lesions
• cyanotic and hardened skin in advanced
cases.
• Subcutaneous hemorrhage and some edema
occur proximal to the necrotic area.

Diagnosis
• History and Cl Sg
• Ergot alkaloids may be extracted and
detected in suspect ground grain meals.
DD:
• Identical signs and lesions of lameness, and
sloughing of the hooves and tips of ears and
tail, are seen in fescue foot in cattle grazing in
winter on tall fescue grass infected with an
endophyte fungus
Treatment and Control
• Immediate change to an ergot-free diet
• Under pasture feeding conditions, frequent grazing or
topping of pastures prone to ergot infestation during the
summer months reduces flower-head production and
helps control the disease.
• Grain that contains even small amounts of ergot should
not be fed to pregnant or lactating sows.
• Symptomatic, supportive- saline purgatives,
anticonvulsant, antibiotics, keeping animal warm
FESCUE POISONING
• Tall fescue (Festuca arundinacea)is the predominant pasture
grass - Fescue lameness has been reported
• The causative toxic substance has actions similar to those
produced by sclerotia of Claviceps purpurea.
• Ergovaline and peramine are the toxins
• The clavicipitaceous endophyte fungus Acremonium
coenophialum
• Fescue summer toxicosis in cattle- poor weight gain, decr.
milk prodn, rough hair coat, salivatn, poor reprod
performance, agalactia
• Fescue foot- in sheep , cattle- occurs in winter- lesions
similar to gangrenous ergotism

FUMONISINS


Fumonisin Toxicosis

• Equine leukoencephalomalacia is a mycotoxic disease of
the CNS that affects horses, mules, and donkeys.
• Associated with the feeding of moldy corn (maize), usually
over a period of several weeks.
• Fumonisins are produced primarily by Fusarium
moniliforme and F proliferatum.
• Conditions favoring fumonisin production appear to
include a period of drought during the growing season with
subsequent cool, moist conditions during pollination and
kernel formation.
• Three toxins produced by the fungi have been classified as
fumonisin B1 (FB1), B2 (FB2), and B3 (FB3). FB3 is relatively
nontoxic.
• Major health effects are observed in Equidae and swine
Clinial Signs
• apathy, drowsiness, pharyngeal paralysis, blindness,
circling, staggering, and recumbency.
• Icterus may be present if the liver is involved.
• The characteristic lesion -liquefactive necrosis of the
white matter of the cerebrum.
• Hepatic necrosis similar to that seen in aflatoxicosis.
• Fumonisins have also been reported to cause acute
epidemics of disease in weanling or adult pigs,
characterised by pulmonary edema and
hydrothorax.
• Porcine pulmonary edema (PPE) is usually an acute,
fatal disease and appears to be caused by
pulmonary hypertension with transudation of fluids
in the thorax resulting in interstitial pulmonary

TREMORGENS
• Tremorgen-producing fungi grow on a wide variety of foodstuffs, including dairy
or grain-containing products intended for human consumption (e.g. cheeses
and pastas), stored grains and nuts (e.g. peanuts and walnuts) and a number
of forages (e.g. legumes and grasses) consumed by livestock species,
• Even garbage and compost piles can be sources of tremorgenic mycotoxin
• Although a variety of different fungi synthesize indole– diterpene mycotoxins
having specific tremorgenic effects on the central nervous system (CNS)
• Tremorgens produced by Penicillium spp. (especially penitrem A and
roquefortine) - most commonly encountered of these mycotoxins.
• Penitrem A is a potent neurotoxin which causes a syndrome characterized by
sustained tremors and, at high doses, convulsions and death in laboratory and
farm animals
SLAFRAMINE
• Alkaloidal mycotoxin produced by the fungus Rhizoctonia
leguminicola that causes profuse salivation (slobbers) in
animals.
• A common fungal pathogen of red clover (Trifolium pratense)
and causes a syndrome known as black patch disease in the
plant.
• Ingestion of clover hay containing slaframine causes salivary
episodes that last from several hours to over 3 days in
ruminants and horses
• Disease is short term and animals generally recover without
treatment
BACTERIAL TOXINS

BACTERIAL TOXINS
• Adverse reactions seen in animals (primarily
dogs) ingesting foods containing preformed
toxins and/or grossly contaminated with
bacteria.
Bacterias of Concern
• Salmonella spp.; Clostridium spp. ;
Escherichia coli: and Staphylococcus spp.
(S. typhimurium. S. anatum, S. cholerasuis, S.
newport. S. entetiditis.)
(Clostridium botulinum, tetani)
Bacterial Toxins
• Enterotoxins- E.coli, Vibrio cholerae
• Hemolytic- Streptococcus, Staph.
• Neurotoxin- Cl. botulinum, Cl. tetani
• cytotoxins- Strepto, Staph, Cl. difficile
• Endotoxins- All gram negative bact
• Clostridium Spp.
Clostridium perfringens:
• Spore-forming anaerobic bacillus. Heat resistant strains B, C, D are
associated with acute enterotoxemia.
• Rapid drop in blood pressure, intravascular stasis and thrombosis,
elevated PCV, congested liver and kidneys, and hemorrhagic necrosis of
the intestines
C. botulinum:
• Found in any food source with a pH>4.5 Produces a neurotoxin, which
causes flaccid motor paralysis (respiratory difficulty, excess salivation,
and death).
• Neurotoxin adsorbs to nervous tissues, thereby preventing
acetylcholine release and or its inactivation at the synaptic sites.
Variable sensitivity among species:
• Guinea pigs Extremely sensitive
• Turkey Resistant ; Dogs, Cats, and Pigs Relatively resistant
• Horses, Minks, and Poultry Most commonly affected
Treatment
• Polyvalent antotoxin with antibacterials-
crystalline penicillin G sodium
• fluid and electrolyte
• dietary deficiency if any should be corrected
TETANUS
• Neurotoxin- by Cl. tetani under anaerobic condtions
• Horse, humans most susceptible
• cattle, pig, sheep-less susc.
• Bird are relatively resistant
• toxin possess protease activity
• bind to gangliosides at presynaptic inhibitory motor nerve
endings in brain stem or spinal cord
• selective clevage of protein component of synaptic vesicles,
synaptobrevin
• prevents releaseof inhibitroy neurotransmitter- Glycine and
GABA
• this results in excessive stimulation of spinal cord leading to
spasmodic tonic contractions of skeletal muscle- called tetany
• Muscular stiffness accompanied by muscular tremors- cl sg.
• Excited by ext. stimuli
Diagnosis
• History and Cl Sg
• Lab findings- serum toxin detection
DD
• Hypomagnesemia, encephalitis
• Eclampsia, strychnine poisoning
Treatment
• Tetanus antitoxin(toxoid)- 300000U Q12h, in
horse
• Penicillin in large doses
BLUE GREEN ALGAE
• Cyanobacterial proliferations in freshwater ecosystems, also known
as blooms, can have a significant impact on the health of animals
and humans living in or using these systems for drinking water
and/or recreational purposes.
• Among the 2000 species identified on morphological criteria, 40 of
them are known to be toxigenic.
• Cyanobacteria are oxygenic photosynthetic prokaryotes that are
probably among the oldest form of microorganisms found on
earth, some 3 billion years ago.
• They can be observed as isolated cells (e.g. Synechococcus),
organized in filaments (e.g. Planktothrix) or in colonies (e.g.
Microcystis).

MICROCYSTINS
• Produced by several cyanobacteria, including species within
the genera Microcystis, Anabaena, Planktothrix, Nostoc,
Oscillatoria and Anabaenopsis
• Cyclic heptapeptides that cause hepatotoxicosis
• Specifically toxic to liver, causing liver enlargement,
progressive centrilobular hepatocyte rounding, dissociation
and necrosis.

ANATOXINS
• Mainly produced by cyanobacteria in the
Anabaena genus
• Neurotoxins- divided into
• anatoxin-a, homoanatoxin-a and anatoxina(s).
• Anatoxin-a is potent cholinergic agonist at
nicotinic acetylcholine receptors in neurons
and at the neuromuscular junctions


Treatment
• There is no specific antidote for anatoxin-a.
• Administration of activated charcoal has been recommended.
• artificial respiration may be of benefit along withsupportive
care.
• Specific measures to control seizures include benzodiazepines,
phenobarbital or pentobarbital.
• In any seizuring animal, control of body temperature is an
important part of the symptomatic care.
• Pralidoxime (2-PAM) is not able to reactivate the inhibited
acetylcholinesterase and is therefore not recommended
• Atropine should be given at a test dose to determine its
efficacy in animals with life-threatening clinical signs. After
the test dose, atropine can be given repeatedly

• Saxitoxins and derived forms belong to the group of paralytic
shellfish toxins and have been produced by a number of
freshwater
• cyanobacteria, including Aphanizomenon flos-aquae,
Cylindrospermopsis raciborskii, Anabanea circinalis, Lyngbya
wollei and Planktothrix sp.
• In humans, saxitoxins are associated with the development of
a neurological disease after the ingestion of shellfish
contaminated with saxitoxins