Ochratoxin A: developmental and reproductive toxicity-an overview.

Ochratoxin A (OTA) is nephrotoxic, hepatotoxic, reprotoxic, embryotoxic, teratogenic, neurotoxic, immunotoxic, and carcinogenic for laboratory and farm animals. Male and female reproductive health has deteriorated in many countries during the last few decades. A number of toxins in environment are suspected to affect reproductive system in male and female. OTA is one of them. OTA has been found to be teratogenic in several animal models including rat, mouse, hamster, quail, and chick, with reduced birth weight and craniofacial abnormalities being the most common signs. The presence of OTA also results in congenital defects in the fetus. Neither the potential of OTA to cause malformations in human nor its teratogenic mode of action is known. Exposure to OTA leads to increased embryo lethality manifested as resorptions or dead fetuses. The mechanism of OTA transfer across human placenta (e.g., which transporters are involved in the transfer mechanism) is not fully understood. Some of the toxic effects of OTA are potentiated by other mycotoxins or other contaminants. Therefore, OTA exposure of pregnant women should be minimized. OTA has been shown to be an endocrine disruptor and a reproductive toxicant, with abilities of altering sperm quality. Other studies have shown that OTA is a testicular toxin in animals. Thus, OTA is a biologically plausible cause of testicular cancer in man.

[1]  V. Dohnal,et al.  Ochratoxin A levels in blood serum of Czech women in the first trimester of pregnancy and its correspondence with dietary intake of the mycotoxin contaminant , 2013, Biomarkers : biochemical indicators of exposure, response, and susceptibility to chemicals.

[2]  Jiri Ruprich,et al.  Producers and Important Dietary Sources of Ochratoxin A and Citrinin , 2013, Toxins.

[3]  H. El‐Nezami,et al.  Potential endocrine disrupting effect of ochratoxin A on human placental 3β-hydroxysteroid dehydrogenase/isomerase in JEG-3 cells at levels relevant to human exposure. , 2013, Reproductive toxicology.

[4]  E. Novotná,et al.  Toxicity of the mycotoxin ochratoxin A in the light of recent data , 2013 .

[5]  L. Piterman,et al.  The male reproductive system - An overview of common problems. , 2013, Australian family physician.

[6]  E. Ropstad,et al.  Endocrine disrupting effects of ochratoxin A at the level of nuclear receptor activation and steroidogenesis. , 2013, Toxicology letters.

[7]  P. Myllynen,et al.  Placental transfer and metabolism: an overview of the experimental models utilizing human placental tissue. , 2013, Toxicology in vitro : an international journal published in association with BIBRA.

[8]  G. Lacalandra,et al.  First Evidence of Placental Transfer of Ochratoxin A in Horses , 2013, Toxins.

[9]  Jau-Song Yu,et al.  Ochratoxin A Inhibits Mouse Embryonic Development by Activating a Mitochondrion-Dependent Apoptotic Signaling Pathway , 2013, International journal of molecular sciences.

[10]  R. Manderville,et al.  Glutathione Conjugates of Ochratoxin a as Biomarkers of Exposure / Glutationski Konjugati Okratoksina A Kao Biomarkeri Izloženosti , 2012, Arhiv za higijenu rada i toksikologiju.

[11]  B. Šarkanj,et al.  Urinary ochratoxin A and ochratoxin alpha in pregnant women. , 2012, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[12]  V. Ostry,et al.  Ochratoxin A exposure biomarkers in the Czech Republic and comparison with foreign countries , 2012, Biomarkers : biochemical indicators of exposure, response, and susceptibility to chemicals.

[13]  R. Raz,et al.  Response to Comments on , 2012, Journal of child neurology.

[14]  R. Manderville,et al.  An update on direct genotoxicity as a molecular mechanism of ochratoxin a carcinogenicity. , 2012, Chemical research in toxicology.

[15]  P. Myllynen,et al.  Fate of the teratogenic and carcinogenic ochratoxin A in human perfused placenta. , 2012, Toxicology letters.

[16]  S. Bhatti,et al.  Toxico-Pathological Effects of In Ovo Inoculation of Ochratoxin A (OTA) in Chick Embryos and Subsequently in Hatched Chicks , 2012, Toxicologic pathology.

[17]  C. Lino,et al.  Ochratoxin A in feed of food-producing animals: an undesirable mycotoxin with health and performance effects. , 2011, Veterinary microbiology.

[18]  A. Jain,et al.  Experimentally Induced Toxicity of Ochratoxin A and Endosulfan in Male Wistar Rats: A Hormonal Disorder , 2011 .

[19]  C. Lemaire,et al.  Molecular events involved in ochratoxin A induced mitochondrial pathway of apoptosis, modulation by Bcl‐2 family members , 2011, Environmental toxicology.

[20]  B. Mandelli,et al.  The presence of ochratoxin A in cord serum and in human milk and its correspondence with maternal dietary habits , 2011, European journal of nutrition.

[21]  P. Mantle Comments on “Ochratoxin A: In utero Exposure in Mice Induces Adducts in Testicular DNA. Toxins 2010, 2, 1428–1444”—Mis-Citation of Rat Literature to Justify a Hypothetical Role for Ochratoxin A in Testicular Cancer , 2010, Toxins.

[22]  R. Manderville,et al.  Response to Comments of Peter G. Mantle , 2010, Toxins.

[23]  N. Sinha,et al.  TERATOGENIC EFFECTS OF OCHRATOXIN A IN RABBITS , 2010 .

[24]  Kenny Q. Ye,et al.  Genome-wide analysis of DNA binding and transcriptional regulation by the mammalian Doublesex homolog DMRT1 in the juvenile testis , 2010, Proceedings of the National Academy of Sciences.

[25]  Deborah Hughes,et al.  Variants near DMRT1, TERT and ATF7IP are associated with testicular germ cell cancer , 2010, Nature Genetics.

[26]  M. S. Miller,et al.  Ochratoxin A: In Utero Exposure in Mice Induces Adducts in Testicular DNA , 2010, Toxins.

[27]  P. Mantle,et al.  Pathological Outcomes in Kidney and Brain in Male Fischer Rats Given Dietary Ochratoxin A, Commencing at One Year of Age , 2010, Toxins.

[28]  Ryu-ichi Katagiri,et al.  Gender‐dependent differences in the incidence of ochratoxin A‐induced neural tube defects in the Pdn/Pdn mouse , 2010, Congenital anomalies.

[29]  M. Blaszkewicz,et al.  Exposure of neonates to ochratoxin A: first biomonitoring results in human milk (colostrum) from Chile , 2010, Mycotoxin Research.

[30]  M. Klein,et al.  Teratogens inducing congenital abdominal wall defects in animal models , 2010, Pediatric Surgery International.

[31]  Matthew S. Cook,et al.  The DM domain protein DMRT1 is a dose-sensitive regulator of fetal germ cell proliferation and pluripotency , 2009, Proceedings of the National Academy of Sciences.

[32]  C. Hilts,et al.  Health risk assessment of ochratoxin A for all age-sex strata in a market economy , 2009, Food additives & contaminants. Part A, Chemistry, analysis, control, exposure & risk assessment.

[33]  A. Pfohl-Leszkowicz,et al.  Ochratoxin A and Aristolochic Acid Involvement in Nephropathies and Associated Urothelial Tract Tumours , 2009, Arhiv za higijenu rada i toksikologiju.

[34]  R. Verma,et al.  Spermatotoxic effect of ochratoxin and its amelioration by Emblica officinalis aqueous extract. , 2009, Acta poloniae pharmaceutica.

[35]  M. Minta,et al.  Developmental Toxicity of Ochratoxin A in Rat Embryo Midbrain Micromass Cultures , 2008, International journal of molecular sciences.

[36]  R. Verma,et al.  Emblica officinalis aqueous extract ameliorates ochratoxin-induced lipid peroxidation in the testis of mice. , 2008, Acta poloniae pharmaceutica.

[37]  S. Wright,et al.  Influence of Estrogen and Xenoestrogens on Basolateral Uptake of Tetraethylammonium by Opossum Kidney Cells in Culture , 2007, Journal of Pharmacology and Experimental Therapeutics.

[38]  R. Manderville,et al.  New molecular and field evidences for the implication of mycotoxins but not aristolochic acid in human nephropathy and urinary tract tumor. , 2007, Molecular nutrition & food research.

[39]  Ryu-ichi Katagiri,et al.  Prevention of ochratoxin A‐induced neural tube defects by folic acid in the genetic polydactyly/arhinencephaly mouse, Pdn/Pdn , 2007, Congenital anomalies.

[40]  M. Blaszkewicz,et al.  Biomonitoring of ochratoxin A in grain workers , 2007, Mycotoxin Research.

[41]  L. Knudsen,et al.  Biomarkers of intermediate endpoints in environmental and occupational health. , 2007, International journal of hygiene and environmental health.

[42]  É. Huyghe,et al.  Testicular cancer variations in time and space in Europe. , 2007, European urology.

[43]  A. Sharma,et al.  Critical period and minimum single oral dose of ochratoxin A for inducing developmental toxicity in pregnant Wistar rats. , 2006, Reproductive toxicology.

[44]  R. Manderville,et al.  Genotoxicity of the hydroquinone metabolite of ochratoxin A: structure-activity relationships for covalent DNA adduction. , 2006, Chemical research in toxicology.

[45]  T. Vrabcheva,et al.  Balkan endemic nephropathy: role of ochratoxins A through biomarkers. , 2006, Molecular nutrition & food research.

[46]  F. Pont,et al.  Evidence of a new dechlorinated ochratoxin A derivative formed in opossum kidney cell cultures after pretreatment by modulators of glutathione pathways: correlation with DNA-adduct formation. , 2006, Molecular nutrition & food research.

[47]  A. Sharma,et al.  Teratogenic effects in rabbits of simultaneous exposure to ochratoxin A and aflatoxin B1 with special reference to microscopic effects. , 2005, Toxicology.

[48]  D. Dietrich,et al.  Investigation of the teratogenic potential of ochratoxin A and B using the FETAX system. , 2005, Birth defects research. Part B, Developmental and reproductive toxicology.

[49]  P. Scott Biomarkers of human exposure to ochratoxin A , 2005, Food additives and contaminants.

[50]  A. Sharma,et al.  Effect in rats of simultaneous prenatal exposure to ochratoxin A and aflatoxin B1. II. Histopathological features of teratological anomalies induced in fetuses. , 2004, Birth defects research. Part B, Developmental and reproductive toxicology.

[51]  N. Sinha,et al.  Effect in rats of simultaneous prenatal exposure to ochratoxin A and aflatoxin B1. I. Maternal toxicity and fetal malformations. , 2004, Birth defects research. Part B, Developmental and reproductive toxicology.

[52]  J. Simon,et al.  Molecular aspects of the transport and toxicity of ochratoxin a. , 2004, Accounts of chemical research.

[53]  A. Horvath,et al.  Balkan endemic nephropathy and genetic variants of glutathione S-transferases. , 2004, Journal of nephrology.

[54]  J. Fink-Gremmels,et al.  Evaluation of spermatological parameters in ochratoxin A--challenged boars. , 2003, Theriogenology.

[55]  J. Rubenstein,et al.  Molecular regionalization of the neocortex is disrupted in Fgf8 hypomorphic mutants , 2003, Development.

[56]  J. Rubenstein,et al.  Dosage of Fgf8 determines whether cell survival is positively or negatively regulated in the developing forebrain , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[57]  G. Koren,et al.  Clinical Relevance of Therapeutic Drug Monitoring During Pregnancy , 2002, Therapeutic drug monitoring.

[58]  J. Gilbert,et al.  Assessment of dietary exposure to ochratoxin A in the UK using a duplicate diet approach and analysis of urine and plasma samples , 2001, Food additives and contaminants.

[59]  S. Bonassi,et al.  Validation of biomarkers as early predictors of disease. , 2001, Mutation research.

[60]  S. Aizawa,et al.  Emx2 directs the development of diencephalon in cooperation with Otx2. , 2001, Development.

[61]  A. Pittet,et al.  Production of ochratoxin A by Aspergillus carbonarius on coffee cherries. , 2001, International journal of food microbiology.

[62]  C. S. Raymond,et al.  Dmrt1, a gene related to worm and fly sexual regulators, is required for mammalian testis differentiation. , 2000, Genes & development.

[63]  H. Blom,et al.  Polymorphisms in biotransformation enzymes and the risk for recurrent early pregnancy loss. , 2000, Molecular human reproduction.

[64]  S. Li,et al.  Identification of ochratoxins and some of their metabolites in bile and urine of rats. , 2000, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[65]  L. Solti,et al.  Analysis of serum and seminal plasma after feeding ochratoxin A with breeding boars. , 1999, Animal reproduction science.

[66]  O. Saugstad,et al.  Ochratoxin A: a naturally occurring mycotoxin found in human milk samples from Norway , 1998, Acta paediatrica.

[67]  H. Bartsch,et al.  Sex‐ and strain‐specific expression of cytochrome P450s in Ochratoxin A‐induced genotoxicity and carcinogenicity in rats , 1998, Molecular carcinogenesis.

[68]  T. Niu,et al.  Microsomal Epoxide Hydrolase Polymorphism and Risk of Spontaneous Abortion , 1998, Epidemiology.

[69]  H. Bartsch,et al.  Sex‐ and strain‐specific induction of renal tumors by ochratoxin A in rats correlates with DNA adduction , 1998 .

[70]  K. Hult,et al.  Placental and lactational transfer of ochratoxin A in rats. , 1998, Natural toxins.

[71]  A. Simeone,et al.  Genetic control of brain morphogenesis through Otx gene dosage requirement. , 1997, Development.

[72]  S. Aizawa,et al.  Otx1 function overlaps with Otx2 in development of mouse forebrain and midbrain , 1996, Genes to cells : devoted to molecular & cellular mechanisms.

[73]  K. Sulik,et al.  Pathogenesis of caudal dysgenesis/sirenomelia induced by ochratoxin A in chick embryos. , 1996, Teratology.

[74]  R. R. Marquardt,et al.  Toxicity of ochratoxin A, its opened lactone form and several of its analogs: structure-activity relationships. , 1996, Toxicology and applied pharmacology.

[75]  B Zimmerli,et al.  Determination of ochratoxin A at the ppt level in human blood, serum, milk and some foodstuffs by high-performance liquid chromatography with enhanced fluorescence detection and immunoaffinity column cleanup: methodology and Swiss data. , 1995, Journal of chromatography. B, Biomedical applications.

[76]  R. R. Marquardt,et al.  Synthesis and structural elucidation of analogs of ochratoxin A , 1995 .

[77]  S. P. Sinha,et al.  Modulation of ochratoxin-produced genotoxicity in mice by vitamin C. , 1994, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[78]  K. Sulik,et al.  Pathogenesis of craniofacial and body wall malformations induced by ochratoxin A in mice. , 1993, American journal of medical genetics.

[79]  A. Gharbi,et al.  Some effects of ochratoxin A, a mycotoxin contaminating feeds and food, on rat testis. , 1993, Toxicology.

[80]  K. Hult,et al.  Ochratoxin A in cow's milk and in human milk with corresponding human blood samples. , 1993, Journal of AOAC International.

[81]  M. Gulisano,et al.  Two vertebrate homeobox genes related to the Drosophila empty spiracles gene are expressed in the embryonic cerebral cortex. , 1992, The EMBO journal.

[82]  S. Hayasaka,et al.  Development of neurons and synapses in ochratoxin A-induced microcephalic mice: a quantitative assessment of somatosensory cortex. , 1992, Neurotoxicology and teratology.

[83]  R. Wiger,et al.  Effects of ochratoxins A and B on prechondrogenic mesenchymal cells from chick embryo limb buds. , 1990, Toxicology letters.

[84]  C. Ewald,et al.  [The sperm quality of 4 boars during the assimilation of mycotoxin-containing feed (ochratoxin A) amd after changing the feed--a case study]. , 1989, Berliner und Munchener tierarztliche Wochenschrift.

[85]  R. P. Myers,et al.  Human placental 3 beta-hydroxy-5-ene-steroid dehydrogenase and steroid 5----4-ene-isomerase: purification from mitochondria and kinetic profiles, biophysical characterization of the purified mitochondrial and microsomal enzymes. , 1989, Journal of steroid biochemistry.

[86]  T. Phillips,et al.  The effects of ochratoxin A on postimplantation rat embryos in culture , 1989, Archives of environmental contamination and toxicology.

[87]  J. Bauer,et al.  Bestimmung von Ochratoxin A in Muttermilch , 1988 .

[88]  E. Märtlbauer,et al.  Determination of ochratoxin A in human milk , 1988 .

[89]  P. Scott,et al.  Risk assessment of the mycotoxin zearalenone. , 1987, Regulatory toxicology and pharmacology : RTP.

[90]  L. Kubena,et al.  ASSESSMENT OF THE DISTRIBUTION AND ELIMINATION OF OCHRATOXIN A IN THE PREGNANT RAT , 1986 .

[91]  W. Berndt,et al.  Teratogenic effects of Ochratoxin A in rats with impaired renal function. , 1984, Toxicology.

[92]  L. Appelgren,et al.  Distribution studies of14C-labelled aflatoxin B1 and ochratoxin A in pregnant mice , 1983, Veterinary Research Communications.

[93]  H. Fellner-Feldegg,et al.  Inhibition of ochratoxin A teratogenesis by zearalenone and diethylstilboestrol. , 1983, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[94]  L. Appelgren,et al.  Distribution of 14C-labelled ochratoxin A in pregnant mice. , 1983, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[95]  W. Berndt,et al.  Effects of dietary protein on teratogenicity of ochratoxin A in rats. , 1983, Toxicology.

[96]  M. Gupta,et al.  Ovarian steroidogenesis in rats following ochratoxin A treatment. , 1980, Toxicology and applied pharmacology.

[97]  J. Moré,et al.  Effects of low doses of ochratoxin A after intratesticular injection in the rat , 1979, Experientia.

[98]  S H Gilani,et al.  Teratogenicity of ochratoxin A in chick embryos. , 1978, Toxicology and applied pharmacology.

[99]  R. Hood,et al.  Effects in mice of simultaneous prenatal exposure to ochratoxin A and T-2 toxin. , 1978, Teratology.

[100]  A. Wrathall,et al.  Effect of feeding ochratoxin to pigs during early pregnancy. , 1977, The British veterinary journal.

[101]  G. Szczech,et al.  Teratogenic and toxic effects of ochratoxin A in rats. , 1976, Toxicology and applied pharmacology.

[102]  A. Hayes,et al.  Prenatal effects of Ochratoxin A in hamsters. , 1976, Teratology.

[103]  F. Chu A comparative study of the interaction of ochratoxins with bovine serum albumin. , 1974, Biochemical pharmacology.

[104]  A. Hayes,et al.  Teratogenic effects of ochratoxin A in mice. , 1974, Teratology.

[105]  T. Shepard Catalog of Teratogenic Agents , 1973 .

[106]  W. E. Ribelin,et al.  Relationship of Ochratoxin A to Foetal Death in Laboratory and Domestic Animals , 1971, Nature.

[107]  F. Chu Interaction of ochratoxin A with bovine serum albumin. , 1971, Archives of biochemistry and biophysics.

[108]  A. Birtoiu,et al.  The presence of mycotoxins (OTA and ZEA) in feed for pigs and their influence on reproduction. , 2012 .

[109]  V. Dohnal,et al.  Metabolic pathways of ochratoxin A. , 2011, Current drug metabolism.

[110]  J. Srinivasa Does ochratoxin A (OTA) cause testicular cancer in humans , 2011 .

[111]  A. Hassan,et al.  Effect Of Aflatoxin B1, Zearalenone And Ochratoxin A On Some Hormones Related To Fertility In Male Rats , 2010 .

[112]  A. Pfohl‐Leszkowicz,et al.  Chapter 7 Formation, Persistence and Significance of DNA Adduct Formation in Relation to Some Pollutants from a Broad Perspective , 2008 .

[113]  N. Sinha,et al.  Teratogenic Effects of Ochratoxin A and Aflatoxin B1 Alone and in Combination on Post-Implantation Rat Embryos in Culture , 2007 .

[114]  R. Manderville,et al.  Ochratoxin A: An overview on toxicity and carcinogenicity in animals and humans. , 2007, Molecular nutrition & food research.

[115]  Juan Carlos Moltó,et al.  Review on the toxicity, occurrence, metabolism, detoxification, regulations and intake of zearalenone: an oestrogenic mycotoxin. , 2007, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[116]  M. Grigorov,et al.  A toxicogenomics approach to identify new plausible epigenetic mechanisms of ochratoxin a carcinogenicity in rat. , 2006, Toxicological sciences : an official journal of the Society of Toxicology.

[117]  J. Fink-Gremmels,et al.  Effects of fungal metabolites on testosterone secretion in vitro , 2005, Archives of Toxicology.

[118]  Ljubica Djukanović,et al.  Balkan endemic nephropathy , 2003 .

[119]  H. Bartsch,et al.  MESNA PROTECTS RATS AGAINST NEPHROTOXICITY BUT NOT CARCINOGENICITY INDUCED BY OCHRATOXIN A, IMPLICATING TWO SEPARATE PATHWAYS , 2002 .

[120]  P. Beaune,et al.  Phenobarbital increases DNA adduct and metabolites formed by ochratoxin A: Role of CYP 2C9 and microsomal glutathione‐S‐transferase , 2000, Environmental and molecular mutagenesis.

[121]  H. Rosner,et al.  Ochratoxin A in human serum , 2000 .

[122]  S. Nada,et al.  Ochratoxicosis: prevention of developmental toxicity by L‐methionine in rats , 1999, Journal of applied toxicology : JAT.

[123]  D. Hadjiolov,et al.  Investigation on the genotoxicity of ochratoxin A by measurement of DNA-adducts in different organs of Syrian hamsters after chronic intoxication , 1998 .

[124]  M. Castegnaro,et al.  Formation of DNA adducts in tissues of mouse progeny through transplacental contamination and/or lactation after administration of a single dose of ochratoxin A to the pregnant mother , 1998, Environmental and molecular mutagenesis.

[125]  R. Kavlock,et al.  Drug Toxicity in Embryonic Development I , 1997, Handbook of Experimental Pharmacology.

[126]  C. R. Lalithakunjamma,et al.  PATHOMORPHOLOGY OF THE COMBINE EFFECT OF OCHRATOXIN A AND CITRININ IN CHICKEN EMBRYOS , 1997 .

[127]  A. Huggett,et al.  Effects of the naturally occurring food mycotoxin ochratoxin A on brain cells in culture. , 1997, Neurotoxicology.

[128]  S. Aizawa,et al.  Emx1 and Emx2 functions in development of dorsal telencephalon. , 1997, Development.

[129]  F. Kovács,et al.  Detection of ochratoxin a in human blood and colostrum. , 1995, Acta veterinaria Hungarica.

[130]  F. Jonsyn,et al.  Human fetal exposure to ochratoxin A and aflatoxins. , 1995, Annals of tropical paediatrics.

[131]  R. Onori,et al.  Contamination of human milk with ochratoxin A. , 1991, IARC scientific publications.

[132]  O. Flint,et al.  Midbrain micromass cultures: a model for studies of teratogenic and sub-teratogenic effects on CNS development. , 1990, Acta physiologica Scandinavica. Supplementum.

[133]  Y. Fukui,et al.  Placental transfer of ochratoxin A and its cytotoxic effect on the mouse embryonic brain. , 1987, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[134]  P. Dwivedi The immunological and pathological changes in poultry induced by ochratoxin A , 1984 .

[135]  W. Berndt,et al.  Effect of simultaneous prenatal exposure to ochratoxin A and citrinin in the rat. , 1984, Journal of toxicology and environmental health.

[136]  W. Berndt,et al.  Embryocidal, fetotoxic and teratogenic effects of ochratoxin A in rats. , 1982, Toxicology.