Vol.5 No.4 April-June 2018 ISSN: 2321-6387

Toxic Effects of Citrinin in Animals and Poultry

D.Basheer Ahamad Department of Veterinary Pathology, Veterinary College and Research Institute, Tamil Nadu Veterinary and Animal Sciences University, Tirunelveli, Tamil Nadu, India

Article Received on 20.03.2018 Article Published on 19.04.2018

Introduction and Aspergillus oryzae, the latter being Citrinin (CTN) is a secondary used to produce sake, miso, and soy sauce product of fungal metabolism, first isolated (Manabe, 2001). by Hetherington and Raistrick from a Citrinin is nephrotoxic and culture of Penicillium citrinum Thom implicated in disease outbreaks in both (Hetherington and Raistrick, 1931). animals and humans. Acutely lethal doses Meanwhile, several other fungal species administered to rabbits, guinea pigs, rats, within the three genera, Penicillium (P. swine, or mice caused swelling of the expansum, P. verrucosum), Aspergillus (A. kidneys with eventual necrosis (Friss et al., terreus), and Monascus (M. ruber) were 1969; Jordan et al., 1978; Krogh, 1978, also found to produce this mycotoxin Krogh et al., 1974). In mice, citrinin is (Ciegler et al., 1977, Bragulat et al., 1977). also embryocidal and fetotoxic (Hood et CTN contaminates maize (Nelson et al., al., 1976). In rats, citrinin has similar 1985), wheat, rye, barley, oats (Scott et effects and high doses are teratogenic al.,1972), and rice (Tanaka et al., 2007). (Reddy et al., 1982a,b). Citrinin has been Citrinin was considered as a potential implicated in porcine and avian antibiotic (IARC, 1986), but its toxic nephropathies and possibly in the fatal properties prevented its therapeutic use. renal disease in humans, causing endemic Citrinin (CTN), a low molecular weight Balkan nephropathy (Friss et al., 1969;, compound, that melts at 172oC and is Krogh et al., 1970 Witlock, et al., 1977). soluble in dilute sodium hydroxide, The nephropathy of citrinin in rats was sodium carbonate, methanol, ethanol and characterized by an enhanced excretion of other polar solvents (Leatherhead Food dilute urine glucosuria, proteinuria, and Research, 2000) was first isolated as a reduced glomerular filtration rate and renal pure compound from a culture of blood flow (Petkova-Bocharova et al., Penicillium citrinum in 1931. Later, 1991). yellowish coloured rice imported from The kidney is the major target Thailand to Japan in 1951 was found to be organ of CTN toxicity, but other target contaminated with citrinin. Subsequently, organs such as liver and bone marrow it was identified in over a dozen species of (Gupta et al., 1983). CTN could be Penicillium including certain strains of implicated in porcine nephropathy (Krogh Penicillium camemberti (used to produce et al., 1973). It is frequently found in food cheese) and several species of Aspergillus and feed in combination with ochratoxin A ( Aspergillus terreus, Aspergillus niveus) (OTA), and these two nephrotoxic

Shanlax International Journal of Veterinary Science 12 Vol.5 No.4 April-June 2018 ISSN: 2321-6387 mycotoxins are suspected to be involved in positive for CTN in the range of 3-70 ppb. the aetiology of a human kidney disease An outbreak of pruritis, pyrexia and called Balkan endemic nephropathy. In the haemorrhagic syndrome in cattle was endemic area in Bulgaria, CTN had higher attributed to feeding of citrus pulp concentrations in maize and beans containing citrinin 30 - 40 ppb (Griffiths intended for human consumption than in and Done, 1991). the non-endemic area (Petkova-Bocharova In India, Pande et al. (1990) et al., 1991). CTN is also found to increase reported the occurrence of CTN in feed. the toxicity of OTA either additively Manickam et al. (1985) encountered (Ahamad et al., 2006) or synergistically mycotoxicosis in buffaloes due to (Speijers and Speijers, 2004). The ingestion of mouldy fodder contaminated International Agency for Cancer Research with AFB1, CTN, ochratoxin and (IARC) classified CTN in Group 3 of penicillic acid of which CTN alone was carcinogens because of the limited present in around 18 per cent of samples. evidence of its carcinogenicity to Sundaram et al. (1999) recorded the co- experimental animals and no evidence for occurrence of CTN and AFB1 in maize. humans (IARC, 1986). Citrinin affects the Out of 229 samples of maize tested, 45 animals in a number of ways i.e. it leads to were positive for CTN, of which 23 decreased body weight, immunotoxicity, samples also contained AFB1. Natural nephrotoxicity, hepatotoxicity, occurrence of citrinin has been reported in teratogeniccity. Oxidative stress, apoptosis various agricultural products like coconut were found to be the important mechanism (Kumari and Nusrath, 1987), rice (Reddy for causing these effects and Reddy., 1983;, cereals (Pande et al., 1990), some herbal medicinal plants (0.01 Incidence of Citrinin - 0.76mg/ g) (Roy and Kumari, 1991; Krogh et al. (1973) reported Chourasia, 1995), groundnut ochratoxin A and CTN in cereals with an (Subrahmanyam and Rao, 1974; Mehan incidence of 58 and 9 per cent, and McDonald, 1984), sesame (Reddy and respectively, and these mycotoxins were Reddy, 1983), bakery bread (Sinha et al., also implicated in porcine nephropathy in 1994), poultry feeds (Rajeswari and Char, Denmark. Reiss (1977) considered CTN 1991), milk and milk products (Singh et responsible for “yellowed rice syndrome”, al., 1992), cattle feed (Jeswal and Jeswal, an animal mycotoxicosis in Japan. 1990; Ranjan and Sinha, 1991), root drugs Yoshisawa (1991) observed natural (Roy and chourasia, 1990) and dry fruits ( contamination of CTN in corn, rice, rye, Saxena et al., 1988). Ahamad and wheat, barley, oats and decaying tomato Vairamuthu (2000) recorded up to 400 ppb fruits. Abdelhamid (1990) reported the of CTN when singly or combination with occurrence of various mycotoxins in aflatoxin B1 (AFB1); up to 4800 ppb of Egyptian feeds in which 44.2 per cent of CTN in combination with ochratoxin A feed samples tested were positive for (OTA) up to 320 ppb of CTN in aflatoxin (AF) containing less than 100 combination with CTN- AFB1- OTA in ppb, and 15.4 per cent of samples were poultry feed where as CTN alone up to

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1800 ppb; CTN with AFB1 up to 400 ppb, effect has been reported from pigs given CTN with OTA up to 600 ppb and up to 20 µg/kg b.w. per day (Sándor et al., 1200 of CTN when combination of CTN, 1991).

AFB1-OTA in feed ingredients such as maize, sorghum, jowar, soya meal, sun Dogs flower oil cake and groundnut oil cake. In an early study, dogs were given citrinin with 5 mg/kg b.w. i.p. survived the Toxic Effects of Citrinin in Animals entire study, but severe proximal tubule Pigs damage was observed during the post- A case study by Friis et al. (1969) mortem examination. (Kitchen et al., reported the results from pigs administered 1977a, b, c). Anorexia, emaciation, citrinin in feed at 20, 40 or 100 mg/kg b.w. vomiting and polydipsia/polyuria and per day. At the highest dose level, the pigs consumption of the feed was reported to be died in a coma with renal insufficiency and „over one month‟. The dogs had high a decrease in appetite was observed in all blood urea nitrogen and creatinine. Two animals. At 20 and 40 mg/kg b.w. per day severely affected dogs died, while the growth depression, loss of weight and others recovered gradually. Renal failure, glucosuria were observed. The data are with renal atrophy, congestion of the poorly reported and as such were not used glomerula capillary, and diffuse for risk assessment. Sándor et al. (1991) degeneration, necrosis, dystrophic described a subacute toxicity study with calcification and regeneration of the ochratoxin A and citrinin in swine. Pigs tubular epithelium were seen @citrinin at are able to tolerate citrinin concentrations 8.3 µg/kg feed (Ahn et al., 2007) and in feed resulting in doses of up to 0.02 severe scrotal dermatitis 150 µg citrinin/kg mg/kg b.w. per day for a longer period feed (Little et al., 1991). without any signs of toxicity. Szczech et al. (1974) reported increased Toxic Effects of Citrinin in concentrations of glutamic oxalacetic Experimental Animals transaminase, isocitric dehydrogenase and Lethal Dose lactic dehydrogenase in serum and urine Acute LD50 of CTN varies with before clinical signs of renal disease were the route of administration, physiological evident in pigs given oral doses of 1.0 and conditions, and animal species Oral LD50 20.0 mg citrinin/kg b.w. per day. The for rats is 50 mg kg-1 b.w. while activities of the enzymes were elevated in subcutaneous LD50 is 67 mg kg-1 b.w. urine, whilst no other signs of renal (Ambrose and DeEds, 1945). In the Dutch disease were observable, and there was no Belted rabbit, oral LD50 is 134 mg kg-1, alteration in blood urea nitrogen. An early and in the New Zealand White rabbit it is elevation in these serum activities is about 120 mg kg-1 (Hanika et al., 1983, acknowledged to be a sensitive indicator Hanika et al., 1984). The LD50 of CTN for of renal damage. In conclusion, only few ducks is 57 mg/kg, for a rat 60mg/kg, for studies on adverse effects of citrinin in chickens 95 mg/kg, and for rabbits 134 pigs could be identified. At present, no mg/kg (Hanika et al., 1983). In a LD50

Shanlax International Journal of Veterinary Science 14 Vol.5 No.4 April-June 2018 ISSN: 2321-6387 study with hamsters, citrinin caused slight aminotransferase (AST) and Lactate to mild necrosis of scattered individual dehydrogenase (LDH) in rats (Beasley et lymphocytes in the spleen and the al., 1986; Singh et al., 2006). Increased intestinal submucosa (Jordan et al., level of total plasma protein in guinea Pig 1978a). The acute s.c. LD50 for citrinin in (Thacker et al., 1977)increased cholesterol rabbits is 20 mg/kg b.w. (Ambrose and esters, increased BUN and serum DeEds, 1946), with lacrymation and creatinine in rabbit (Ramadoss and salivation, and mild histopathological Shanmugasundaram, 1973; Hanika et al. changes in the kidneys. At higher s.c. 1983). Carlton et al. (1974) found in a doses (50-75 mg/kg b.w.) given for up to study on beagle dogs inconsistent changes 14 days, citrinin caused marked renal in leukocyte counts which were probably lesions, confirming rabbits as sensitive to more related to dehydration of citrinin citrinin much like guinea pigs (Ambrose treated animals than to any direct effect of and DeEds, 1946). Hanika et al. (1983) citrinin (20 and 40 mg/kg b.w. for 2 days determined intraperitoneal (i.p.) and oral administered in gelatine capsules and after 72-hr LD50 values of 50 mg/kg b.w. and that i.p. because of profound emetic 134 mg/kg b.w., respectively in rabbits. effects). Citrinin treated mice (20 mg/kg The LD50 of a single s.c. citrinin dose to b.w.; i.p. injections once a week for 6 rats was 67 mg/kg b.w. (Ambrose and weeks) shows a decrease in the total count DeEds, 1946). of bone marrow cells (precursors of erythrocytes, leucocytes and Clinical Pathology megakaryocytes) (Gupta et al., 1983). The CTN causes anaemia along with leucopenia due to lymphopenia,in Pathomorphology increase in platelet count, mean Dietary exposure to citrinin at 250 corpuscular volume (MCV) in rats (Gupta and 500 mg/kg feed for two weeks was et al., 1983;Singh et al., 2006) decrease in well tolerated by hamsters, with no clinical PCV, haemoglobin (Hb) and total signs of toxicity, no gross lesions at erythrocyte count (TEC) in guinea Pig necropsy and no histopathological changes (Thacker et al., 1977). Anorexia, were observed (Carlton and Szczech, decreased body weight gain in rats Beagle dogs (Carlton et al., 1974) (Lockard et al., 1980; Jordan et al., 1978a; commenced with dry feed containing 50 % Singh et al., 2006); anorexia, dullness, of rice moulded by Penicillium citrinum lethargy, loose faeces, polydypsia and and containing 100 mg citrinin/kg. showed dehydration in young growing New poor feed consumption and inappetance. In Zealand White rabbits (Kumar et al., rats, kidney shows necrosis in kidneys, 2007). vacuolar degeneration of renal tubular Biochemical alterations with epithelium, tubular degeneration with decreased BUN and creatinine levels, presence of proteinaceous casts in the decrease in total protein, albumin and lumen of renal tubules (Lockard et al., globulin, increase in activity of Alanine 1980, Jordan et al., 1978a, Singh et al., aminotransferase (ALT), Aspartate 2007b) The other lesions include

Shanlax International Journal of Veterinary Science 15 Vol.5 No.4 April-June 2018 ISSN: 2321-6387 hepatocytic degeneration with engorged weight, and decrease in the total spleen sinusoids, karyomegaly in liver, dilated cell count. cystic spaces with haemosiderosis in uterus, lymphoid depletion, Utrastructural Pathology Haemosiderosis in spleen,villous Kumar et al. (2007) investigated sloughing with lymphoid depletion in the utrastructural lesions in kidney of peyer’s patches in intestines (Singh et al., citrinin-treated animals focused on 2007b) are seen. In rabbit severe renal proximal convoluted tubules (PCT) and tubular degeneration with presence of interstitial cells, while epithelial cells of proteinous casts in tubular lumen. (Kumar, distal convoluted tubules had almost 2005) In hamster, necrosis of renal cortical normal appearance. In epithelial cells of tubular epithelium, tubular calcification, the PCT citrinin caused loss of nucleoli, presence of proteinaceous casts and depletion of cytoplasmic organelles, tubular dilations (Jordan et al., 1978b). peripheral condensation of pleomorphic mitochondria and cytoplasmic vacuolation. Histopathology Degenerative and necrotic changes were Degenerative changes in renal mild to moderate. The basement proximal tubule epithelium were reported membrane of PCT epithelial cells and in rats given citrinin contaminated feed, glomerulai were unaffected. Mitochondrial but no dose was specified (Friis et al., swelling and misshapen appearance are 1969; Krogh et al., 1970). In contrast, no consistent with the theory that the lesions clinical or renal histopathological changes of this organelle are crucial in the occurred in a rat given dietary citrinin for mechanism of citrinin toxicity. 5 days (~18 mg/kg b.w. per day) (Mantle and McHugh, 1993). Acute lethal doses Toxic Effects of Citrinin in Poultry administered to rabbits, guinea pigs, rats, Lethal Dose and swine caused swelling of the kidneys Mehdi et al. (1983) reported LD50 and acute tubular necrosis ((Friis et al., values of 56 and 57 mg/kg b.w. for turkey 1969; Ambrose and DeEds, 1946). poults and ducklings, respectively Subchronical oral treatment of rats with water suspension isolated from a strain of Clinical Pathology Penicillium viridicatum Westling caused Clinical Signs CTN-induced kidney damage Citrinin fed to mature laying hens characterised by enlarged kidney, hydropic at concentrations of 0, 50 or 250 mg/kg degeneration, loss of brush border, and diet for three weeks had no effect on body pyknotic nuclei in the proximal tubules weight, feed consumption, egg production, (Friis et al, 1969). Treatment of mice with egg weight, or quality of eggshell. weekly injections of CTN (20 mg kg-1) for Moderate diarrhoea, which subsided once six weeks resulted in a significant decrease the birds returned to their normal diet, was in total bone marrow cells, red blood cell observed after approximately three weeks precursors, white blood cell precursors, at the highest dose level (Ames et al., megakaryocytes, decrease in spleen 1976).The important clinical signs

Shanlax International Journal of Veterinary Science 16 Vol.5 No.4 April-June 2018 ISSN: 2321-6387 includes stunted growth, decreased body gizzards in broiler chicks fed with P. weight gain, watery droppings in poultry, lanosum contaminated feed. Uma and (Campbell et al., 1981, Mehdi et al., 1984; Vikram Reddy (1995) noticed Uma and Vikram Reddy, 1995; Ahamad, enlargement, congestion and mottling of and Vairamuthu,2001; Ahamad et al., kidneys; enlargement, congestion and 2009). fragility of liver; petechiae in fascia and thigh muscles and dilatation of heart in Haemato-Biochemical Changes broiler chicken fed 125 and 250 ppm CTN In haematological study, increased for 6 weeks. PCV, reported no significant change in CTN treated with 150 and 300 ppm PCV, Hb and TEC in poultry (Campbell et revealed moderate to severe enlargement, al,. 1981;Uma and Vikram Reddy, 1995; moderate congestion and petechiae in Manning et al., 1985; Ahamad et al., kidneys. Bursa of fabricius revealed 2006). Citrinin was fed to broiler chickens enlargement and congestion during 1st and at concentrations of 300 mg /kg feed 2nd wk and atrophy during 3rd wk of showed lower body weight and an sacrifice. The liver was swollen with increased water consumption. At the last paleness and moderate yellowish day of the study, serum protein, albumin discolouration with distended gallbladder. and globulin were significantly higher in (Ahamad and Vairamuthu, 2001; Ahamad the birds fed citrinin than in controls et al., 2009).The intestine revealed mild to (Manning et al., 1985). but no significant moderate mucosal congestion with mucous alteration was recorded in chicken when exudation . The caecum showed severe fed 150 and 300 ppm of CTN (Ahamad, dilatation. Multifocal peticheal and Vairamuthu,2001; Ahamad et al., haemorrhages were recorded in 2006; Ahamad, 2000). epicardium and endocardium of the heart and thigh muscles. (Ahamad and Gross Pathology Vairamuthu, 2001; Ahamad et al., 2009). Ames et al. (1976) observed enlargement of liver and kidneys in Histopathology broilers fed with 62.5, 125, 250 and 500 In chicken, hyperplastic glomeruli, ppm CTN for 3 weeks. Roberts and Mora atrophy of tubules, hydropic degeneration (1978) fed 130 and 260 ppm of CTN in of epithelial cells of the proximal and broilers and noticed haemorrhagic collecting tubules, glomerular atrophy and jejunum, mottled liver and enlarged hyalinisation, coagulative necrosis and kidneys. When broilers were fed with 62 hydropic degeneration of tubular epithelial per cent of mouldy ration for 6 weeks, cells of kidney (Roberts and Mora 1978, there was atrophy of spleen, bursa of Mehdi et al. 1983; Ahamad and Fabricius, thymus and testes. Heart was Vairamuthu, 2001; Ahamad et al., 2009) oedematous, congested and necrotic. The Toxic effects are not described in gall bladder was distended and bone broiler chicks fed a diet containing 65 mg marrow was pale. Beasley et al. (1980) citrinin/kg feed (Carlton, 1980). Up to 260 reported swollen kidneys and discoloured mg citrinin/kg feed to broiler chicks

Shanlax International Journal of Veterinary Science 17 Vol.5 No.4 April-June 2018 ISSN: 2321-6387 diarrhoea was observed at the two highest or mixed with diet (Mehdi et al., 1981) , concentrations. At necropsy these chicks 125 and 250 ppm of CTN in feed for 6 had haemorrhages in the jejunum as well wks (Uma and Reddy,1995) and 150 and as enlarged livers and kidneys. All dietary 300 ppm fed in broiler chicks for 4 wks levels resulted in lymphocyte and Severe degeneration with detachment of eosinophil infiltrations of the liver, lining epithelium of proximal convoluted kidneys and pancreas. Anaplastic areas of tubules might contribute to watery the kidney and pancreas, is observed at the droppings in poultry. (Ahamad and highest concentration of 260 mg/kg Vairamuthu, 2001; Ahamad et al., 2009). citrinin in chickens (Roberts and Mora, In liver, CTN treated chicks 1978). Citrinin was fed to broiler chickens revealed moderate toxic hepatitis at concentrations of 300 mg /kg feed charecterised by diffuse mild sinusoidal showed proximal tubular intra-nuclear dilatation, engorgement of blood vessels membrane-bound inclusions, misshaped with vacuolar degeneration with multifocal mitochondria, as well as an increase in size necrosis of hepatocytes with infiltration of and number of peroxisomes and secondary lymphocyte and heterophils, moderate to lysosomes(Manning et al., 1985). At severe diffuse Kuffer cell hypertrophy, autopsy the kidneys were observed to be bile duct hyperplasia, formation of acinar swollen, pale and friable‟ with the tubular pattern of hepatocytes were observed. epithelial cells noted to be necrotic. ,These similar findings were recorded by Kidneys of CTN group birds revealed earlier workers in broiler chicks when fed severe toxic tubular nephrosis with 130 and 260 ppm CTN in feed for 6 chareccterised with mild to moderate wks and 47.5 to 500 ppm CTN in multiple vascular changes with congestion and inter dose , 90.100.and 110 mg CTN/kg BW in tubular haemorrhages, moderate single oral dose (Mehdi et al., 1983); 125 hypertrophy of tubular epithelium with and 250 ppm CTN in feed for 6 wks in narrowing of proximal convoluted tubules, broiler chicken. (Uma and Reddy,1995) moderate to severe hydropic degeneration and 150 ppm fed in broiler chicks for 4 with multifocal necrosis of proximal wks. (Ahamad and Vairamuthu, 2001). In convoluted tubular epithelium, multifocal addition to above lesions, there was mild mononuclear cell (MNC) infiltration with to moderate periductular and perivenous a few heterophils and diffuse mild to fibrosis and capsular thickening of liver moderate intertubular fibroblast was also observed. These changes might proliferation and cellular debris in be due to CTN which pass through central collecting ducts were observed. The PCT vein and bile duct for such a long period revealed detachment of tubular lining for detoxification or excretion which acts epithelium from basal layer. The lumen as irritant which leads to proliferation of contained desquamated epithelial cells. fibroblast around perivenous and These similar findings were reported by periductular areas (Ahamad et al., 2009) Roberts and Mora (1978) when broiler In bursa of fabricius, mild chicks were fed with 33 to 260 ppm CTN congestion and generalized mild lymphoid for 6 weeks, 95 mg/kg BW by crop gavage

Shanlax International Journal of Veterinary Science 18 Vol.5 No.4 April-June 2018 ISSN: 2321-6387 depletion, mild to moderate broiler chickens when fed with 125 and lymphocytolysis was marked in cortex and 250 ppm CTN in feed for 6 wks (Roberts medulla of follicles degeneration and and Mora,1978; Uma and Reddy, 1995) necrosis of follicular epithelium with a few and 150 and 300 ppm fed in broiler chicks mitotic figures, glandular or cystic for 4 wks. (Ahamad and Vairamuthu, transformation of follicles and moderate to 2001;Ahamad et al ., 2009). Pancreas severe interfollicular fibrosis were showed mild to moderate congestion and reported by when the broiler chickens focal haemorrhages, mild diffuse vacuolar were fed with 47.5 to 500 mg CTN /kg changes,Perivascular cellular infiltration of BW in multiple dose (Mehdi et al, 1983); lymphocytes, eosinophils, reduced CTN.150 and 300 ppm fed in broiler zymogen granules and multifocal necrosis chicks for 4 wks. (Ahamad and of pancreatic acinar epithelium with MNC Vairamuthu, 2001;Ahamad et al ., 2009). infiltration (Roberts and Mora, 1978; These findings might incriminate the Maryamma et al., 1990; Ahamad and hypothesis of immunotoxic effect of CTN. Vairamuthu, 2001; Ahamad et al., 2009). In spleen, CTN group birds showed Lungs of CTN fed group birds showed mild to moderate diffuse lymphoid mild congestion and haemorrhages, depletion with reticular cell hyperplasia in multifocal MNC and heterophilic broiler chicks for 4 wks @150 and 300 infiltrationwith mild bronchiectasis in ppm CTN fed in broiler chicks for 4 wks. broiler chickens when fed with 125 and (Ahamad and Vairamuthu, 2001;Ahamad 250 ppm CTN in feed for 6 wks (Uma and et al ., 2009Mehdi et al. (1981) in broiler Reddy, 1995) and 150 and 300 ppm fed in chicks when fed with single oral dose of broiler chicks for 4 wks. (Ahamad and 90,100 and 110 mg CTN /kg BW and). In Vairamuthu, 2001; Ahamad et al ., 2009). thymus , mild lymphoid depletion was Intestine of CTN treated chicks showed observed from from 2nd to 4th wks of mild congestion in mucosl and submucosal sacrifice . Similar findings were reported layer of intestine increased goblet cell by Mehdi et al. (1981) studied in another activity, focal necrosis of enterocytes and experiment in broiler chicks when fed with mild desquamation of intestinal mucosa, single oral dose of 47.5,71,100,250 and catarrhal changes with infiltration of 500 mg CTN /kg BW and 150 and 300 mononuclear cells in the lamina propria, ppm fed in broiler chicks for 4 wks. mucosa and hyperplasia of the glandular (Ahamad and Vairamuthu, 2001;Ahamad epithelium in small intestine in broiler et al ., 2009).In heart, Loss of cross- chickens when fed with 125 and 250 ppm striations, enucleation, sarcolysis and CTN in feed for 6 wks (Uma and Reddy hyalinization of fibres with mononuclear (1995) ; 150 and 300 ppm fed in broiler cell infiltration Mild congestion and chicks for 4 wks (Ahamad and multifocal haemorrhages mild to moderate Vairamuthu, 2001; Ahamad et al., 2009).The gross and histopathological myocardial degeneration with multifocal mononuclear cell infiltration in changes in CTN fed birds were severe intermyofibrils were also recorded in toxic nephrosis in kidneys, severe atrophy of bursa of fabricius, moderate toxic

Shanlax International Journal of Veterinary Science 19 Vol.5 No.4 April-June 2018 ISSN: 2321-6387 hepatitis, moderate acute myocarditis, effectively suppress CTN-induced moderate acute pancreatitis, mild cytotoxicity and caspase-3 activity. These lymphoid depletion in spleen and thymus findings suggest that CTN induces and catarrhal enteritis are observed. Since, apoptosis in HL-60 cells by stimulating the proximal convoluted tubules of cytochrome c release followed by kidneys were severely damaged, there activation of multiple caspases, but might be the possibilities of hindrance in oxidative stress may not play a role in the resorption of large quantities of sodium apoptotic process by CTN in HL-60 (Yu et and chloride, water , required al., 2006). concentration of glucose , amino acid, calcium, phosphates uric acids, proteins Immunotoxicity and potassium and leads to watery In thymus mild to marked necrosis droppings and mild depression in CTN fed of lymphocytes occurred mostly in the chicks. The immunotoxic effects could cortex, in contrast to the cloacal bursa also be observed severely in bursa of where the necrosis and lymphoid depletion fabricius (Ahamad and Vairamuthu, 2001; was more prominent in the medulla in 7- Ahamad et al ., 2009). day old ducklings treated orally with a single dose (30, 40 and 50 mg/kg b.w.) of

citrinin and this study confirmed the Apoptosis and Oxidative Stress There are scarce reports on cytotoxicity of citrinin to splenic apoptosis caused by citrinin. Multiple lymphocytes in vitro (Mehdi et al., 1983). effects on mitochondrial function in renal Splenic cells from male CD1 mice, receiving 0.0,0 .12,0 .60 and 3 mg citrinin proximal tubules (RPT) and renal cortical mitochondria which might have / kg i/p daily for 2-4 weeks, when cultured contributed to the development of cell with or without mitogens, death in rat renal proximal tubule in rats phytohaemagglutinin (PHA), pokeweed treated with 250 mg of CTN. Aloe et al. mitogens (PWM), and lipopolysaccharide (1991). Number of apoptotic cells in dam exhibited splenic lymphocyte proliferation. (kidney, liver, spleen) as well as foetuses However, delayed type hypersensitivity, (kidney and liver) on analysed by FACS measured as footpad swelling in response When citrinin was fed @ 10ppm in to sRBC, was not affected (Reddy et al., pregnant wistar rats (Singh, 2005). Martin 1988). Similarly, De Souza et al. (1999) et al. (1986) reported that CTN induced also observed stimulation of lymphocyte single and double strand breaks in the proliferation when lymphocytes from DNA of intact E. coli and this activity was spleen and thymus of sensitised white prevented by NADPH, catalase and mice were cultured in presence of 4 superoxide dismutase, suggesting the different concentrations of CTN (0, 5, 10 involvement of free radicals in the and 20 mg/kg). Lymphoid depletion and mechanism of citrinin-induced damage. necrosis in both cortex and medulla in the The cytochrome c release from bursa of Fabricius and pronounced mitochondria to cytoplasm. The presence lymphoid necrosis in the medulla and of antioxidants in cultures did not cortex, lymphoid atrophy in thymic cortex

Shanlax International Journal of Veterinary Science 20 Vol.5 No.4 April-June 2018 ISSN: 2321-6387 were noticed in chicks fed with single oral complex cellular biotransformation to dose of 47.5, 71, 100, 250 and 500 mg become mutagenic.CTN have shown CTN per kg bw (Mehdi and Carlton, clastogenic activity in vitro and in vivo, 1981). Campbell et al. (1981), however, including a variety of chromosomal did not observe any effect on humoral and aberrations, save for sister chromatid cell mediated immunity when day- old exchange (SCE). In a study of Chinese broiler chickens were fed a starter mash hamster ovary cells and HEK293, CTN did with 0, 125, 250 or 500 ppm CTN for 3 not produce any significant difference in weeks. Significant decrease in both cell either SCE frequency or DNA gaps and mediated and humoral immune response breaks (Liu et al., 2003). CTN-induced was seen when citrinin was fed @ 10ppm/ SCEs in Chinese hamster V79-E cells in kg feed to pregnant rats and the effect the presence of S9-mix (Thust and Kneist, beibg additive with endosulfan fed @ 1 1979). CTN was found to be aneugenic mg/kg body weight (Singh, 2005). because it caused concentration-dependent mitotic arrest, regardless of incubation Genotoxicity time. This effect was reversible after the Genotoxicity of CTN has not been removal of CTN (Thust and Kneist , unequivocally established because various 1979). has found CTN induces test systems gave both positive and chromosome abnormalities and breaks in negative results. CTN-induced oxidative bone marrow cells in young weanling mice stress did not affect DNA (Liu et al.,2003). (Jeswal, 1996) and in adult mice included In contrast to negative results, various cell breaks, centric fusions, rings, and gaps cultures exposed to CTN showed a (Bouslimi et al., 2008). significant increase in micronucleus (MN) frequency (Šegvić Klarić et al., 2007). Developmental and Reproductive This increase was also noticed in HEPG2 Toxicity cells, human lymphocytes, and Chinese Citrinin is an embryocidal and hamster V79 cells, but CTN foetotoxic agent (Hood et al., 1976). In concentrations showing genotoxicity rats which received a single s.c. dose of 35 differed between cell cultures (Knasmüller mg citrinin/kg b.w. on days 3-15 of et al., 2004; Dömnez-Altuntas et al., 2007; gestation, no skeletal malformations of the Pfeiffer et al., 1998) foetuses were observed. However, enlarged kidneys, internal hydrocephalus Mutagenicity and cleft palates were found. As in this CTN was not mutagenic to S. experiment 30-50% of the pregnant dams typhymurium (Knasmüller et al., 2004; died and the resorption rate of foetuses in Sabater-Vilar et al., 1999). However, when the treated group was higher than in a primary hepatocyte culture was added, controls, it needs to be considered that strain TA98 showed a significant dose- maternal toxicity has influenced the dependent mutagenic response, and strain outcome of this study. (Reddy et al., TA-100 a slight positive response. These 1988). Citrinin was administered in the results indicate that CTN requires a feed at a concentration of 10 mg/kg feed

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(equivalent to approximately 1 mg/kg observed in mouse embryoblasts following b.w.) at GD (6 - 20 days post coitum), ex vivo treatment with citrinin at a foetal resorption rate was increased and concentration of 30 µg/ml (Chan, 2007). In 6.8 % of the examined foetuses showed further in vitro experiments, Chan (2008) severe malformations, including internal observed a significant reduction in the rate hydrocephalus and notched and contracted of oocyte maturation, fertilization and kidneys (Singh et al., 2007b). About 10 % embryonic development. Qingqing et al. of all foetuses were retarded with (2010) investigated the effects of citrinin incomplete ossification of the skull bones. on the reproductive organs of male mice. Histological investigations of the foetal Sperm counts were decreased and the kidneys showed tubular degeneration, number of abnormal spermatozoa was medullar tubular necrosis and interstitial increased. Histological examination fibrosation (Singh et al., 2008). The revealed an increased diameter of the embryotoxic potential of citrinin citrinin testicular seminiferus tubule. Serum tested 1 - 10 µg, injected subgerminally or testosterone concentrations were decreased intra-amniotically at different days of the and a significantly lower pregnancy rate egg incubation period) alone and together was observed when females were mated with ochratoxin A. The most pronounced with the citrinin-exposed males and no alterations in the early embryonic embryos occurred in the females mated development were observed following an with males given the highest dose of 6.25 exposure on day three, including mg/kg b.w. In vitro and in vivo studies embryonic death (up to 60 %), and provided clear evidence for reproductive embryos showed morphological alteration toxicity and, teratogenic and embryotoxic on their heads (exencephaly, effects of citrinin. The doses tested in the microophthalmia and cleft beak) (Vesela et in vivo experiments exerted, however, al., 1983). These data are in line with clear signs of maternal toxicity, including earlier studies by Ciegler et al. (1977) nephrotoxicity, indicating that these effects describing also exencephaly, exopthalmia, might be secondary to maternal toxicity. crossed beaks and occasional crooked necks. CTN (30 mg/kg) were Carcinogenicity subcutaneously injected in pregnant IARC (1986) concluded that there Sprague-Dawley rats, foetal resorptions was limited evidence for the and the foetal body weights were not carcinogenicity of citrinin to experimental significantly different except on day 8 of animals and that no evaluation could be gestation following CTN treatment. made of the carcinogenicity of citrinin to (Mayura et al.,1984).Recent in vitro humans. Citrinin is classified in group 3 studies with mouse embryonic cells (not classifiable as to its carcinogenicity to confirmed the previous in vivo data as humans). In an 80-week chronic toxicity blastocysts treated with citrinin showed study, all treated rats showed, starting apoptosis and significant decreased from week 40, focal hyperplasia of the implantation rates (Chan and Shiao, 2007). tubular epithelium and small renal An increased rate of apoptosis was adenomas were observed (Arai and

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Hibino, 1983). No evidence for Muralimanohar, B and carcinogenicity was found in a model fish Balachandran,C. (2006). Individual species (Oryzias latipes) which was and combined effects of citrinin exposed to citrinin for 24 weeks (Hatanaka and aflatoxin B1 in broiler chicken: et al., 1982). In an earlier study, Shinohara A clinicopathological study Indian et al. (1976) considered whether dietary Journal of Veterinary Pathology, citrinin could act as a tumour promoter in 30(1):32-35. male Sprague-Dawley rats. Arai and Hibino (1983) reported that the long term Ahamad, D. B. and Vairamuthu S. (2000). feeding, with a high dietary exposure to Occurrence of citrinin mycotoxin citrinin (initially ~70 mg/kg b.w. per day) in compounded feed and feed showed high incidences of adenomas in ingredients in and around rats. Namakkal area (Tamil Nadu) Indian Journal of Environment and Conclusions Toxicology, 10 (2):84-86. It is concluded that citrinin is a nephrotoxic mycotoxin. Studies on Ahamad, D. B. and Vairamuthu, S. (2001). immunotoxicity of citrinin do not allow a Individual and combined effects of conclusive evaluation. Citrinin and citrinin and aflatoxin B1 in broiler aflatoxin B1 has additive effect where as chicken : A pathomorphological CTN and Ochratoxin A has synergistic study Indian Journal of Veterinary effects. In vitro and in vivo studies Pathology 25(1&2) :32-34 provided clear evidence for reproductive toxicity and, teratogenic and embryotoxic Ahamad, D. B., Vairamuthu, S., Titus effects of citrinin. The doses tested in the George, Balachandran, C.V., in vivo experiments exerted clear signs of Muralimanohar, B and maternal toxicity, including Balasubramaniam, G.A., (2009). nephrotoxicity, indicating that the Pathological features of citrinin teratogenic effects might be secondary to toxicosis in broiler chicks. Indian maternal toxicity. Citrinin is not Veterinary Journal, 86(10):1014- mutagenic, but induces micronuclei, 1016 aneuploidy, and chromosomal aberrations Aloe, M.D., Wyatt, R.D. and Schnellmann, in vitro in mammalian cells. In vivo it R.G. (1991). Mitochondrial induced chromosome abnormalities and dysfunction is an early event in hypodiploidy in the bone marrow of mice. ochratoxin A but not oosporin This carcinogenicity effect of citrinin in toxicity to rat renal proximal rats, showing high incidences of adenomas tubules. Toxicol. Appl. Pharmacol., in the kidneys. 107: 73-75.

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