Administration of potentially antiandrogenic pesticides (procymidone, linuron, iprodione, chlozolinate, p,p'-DDE, and ketoconazole) and toxic substances (dibutyl- and diethylhexyl phthalate, PCB 169, and ethane dimethane sulphonate) during sexual differentiation produces diverse profiles of reproductive malformations in the male rat.
Antiandrogenic chemicals alter sexual differentiation by a variety of mechanisms, and as a consequence, they induce different profiles of effects. For example, in utero treatment with the androgen receptor (AR) antagonist, flutamide, produces ventral prostate agenesis and testicular nondescent, while in contrast, finasteride, an inhibitor of 5 alpha-dihydrotestosterone (DHT) synthesis, rarely, if ever, induces such malformations. In this regard, it was recently proposed that dibutyl phthalate (DBP) alters reproductive development by a different mechanism of action than flutamide or vinclozolin (V), which are AR antagonists, because the male offsprings display an unusually high incidence of testicular and epididymal alterations--effects rarely seen after in utero flutamide or V treatment. In this study, we present original data describing the reproductive effects of 10 known or suspected anti-androgens, including a Leydig cell toxicant ethane dimethane sulphonate (EDS, 50 mg kg-1 day-1), linuron (L, 100 mg kg-1 day-1), p,p'-DDE (100 mg kg-1 day-1), ketoconazole (12-50 mg kg-1 day-1), procymidone (P, 100 mg kg-1 day-1), chlozolinate (100 mg kg-1 day-1), iprodione (100 mg kg-1 day-1), DBP (500 mg kg-1 day-1), diethylhexyl phthalate (DEHP, 750 mg kg-1 day-1), and polychlorinated biphenyl (PCB) congener no. 169 (single dose of 1.8 mg kg-1). Our analysis indicates that the chemicals discussed here can be clustered into three or four separate groups, based on the resulting profiles of reproductive effects. Vinclozolin, P, and DDE, known AR ligands, produce similar profiles of toxicity. However, p,p'-DDE is less potent in this regard. DBP and DEHP produce a profile distinct from the above AR ligands. Male offsprings display a higher incidence of epididymal and testicular lesions than generally seen with flutamide, P, or V even at high dosage levels. Linuron treatment induced a level of external effects consistent with its low affinity for AR [reduced anogenital distance (AGD), retained nipples, and a low incidence of hypospadias]. However, L treatment also induced an unanticipated degree of malformed epididymides and testis atrophy. In fact, the profile of effects induced by L was similar to that seen with DBP. These results suggest that L may display several mechanisms of endocrine toxicity, one of which involves AR binding. Chlozolinate and iprodione did not produce any signs of maternal or fetal endocrine toxicity at 100 mg kg-1 day-1. EDS produced severe maternal toxicity and a 45% reduction in size at birth, which resulted in the death of all neonates by 5 days of age. However, EDS only reduced AGD in male pups by 15%. Ketoconazole did not demasculinize or feminize males but rather displayed anti-hormonal activities, apparently by inhibiting ovarian hormone synthesis, which resulted in delayed delivery and whole litter loss. In summary, the above in vivo data suggest that the chemicals we studied alter male sexual differentiation via different mechanisms. The anti-androgens V, P, and p,p'-DDE produce flutamide-like profiles that are distinct from those seen with DBP, DEHP, and L. The effects of PCB 169 bear little resemblance to those of any known anti-androgen. Only in depth in vitro studies will reveal the degree to which one can rely upon in vivo studies, like those presented here, to predict the cellular and molecular mechanisms of developmental toxicity.
Wolf
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Endocrinology Branch, National Health and Environmental Effects Research Laboratory, US Environmental Protection Agency, MD-72, Research Triangle Park, NC 27711, USA. gray.earl@epamail.epa.gov
Lambright
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Mann
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Price
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Cooper
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Ostby
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Gray
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D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000633:toxicity; D000726:Androgen Antagonists / Q000494:pharmacology / Q000633:toxicity*; D000818:Animals; D001643:Bridged Bicyclo Compounds / Q000633:toxicity; D003993:Dibutyl Phthalate / Q000633:toxicity; D003633:Dichlorodiphenyl Dichloroethylene / Q000633:toxicity; D004051:Diethylhexyl Phthalate / Q000633:toxicity; D005260:Female; D005837:Genitalia, Male / Q000002:abnormalities* / Q000187:drug effects / Q000254:growth & development; D012739:Gonadal Steroid Hormones / Q000378:metabolism; D006827:Hydantoins; D007654:Ketoconazole / Q000633:toxicity; D008044:Linuron / Q000633:toxicity; D008297:Male; D010080:Oxazoles; D010575:Pesticides / Q000494:pharmacology / Q000633:toxicity*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D051381:Rats; D020318:Rats, Long-Evans; D017207:Rats, Sprague-Dawley; D011944:Receptors, Androgen / Q000187:drug effects / Q000502:physiology; D012733:Sex Differentiation / Q000187:drug effects; D015262:Xenobiotics / Q000494:pharmacology / Q000633:toxicity*
D000726:Androgen Antagonists; D001643:Bridged Bicyclo Compounds; D012739:Gonadal Steroid Hormones; D006827:Hydantoins; D010080:Oxazoles; D010575:Pesticides; D011944:Receptors, Androgen; D015262:Xenobiotics; D008044:Linuron; D003993:Dibutyl Phthalate; D000620:Aminoimidazole Carboxamide; D003633:Dichlorodiphenyl Dichloroethylene; C037268:dichlozolinate; D004051:Diethylhexyl Phthalate; C035988:procymidone; D007654:Ketoconazole; C033148:iprodione