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EFFECTS OF ENVIRONMENTAL ANTIANDROGENS ON REPRODUCTIVE DEVELOPMENT IN EXPERIMENTAL ANIMALS
Citation:
Gray Jr., L E., J S. Ostby, J. R. Furr, C J. Wolf, C R. Lambright, L G. Parks, D. Veeramachaneni, V S. Wilson, M. G. Price, A. Hotchkiss, E. Orlando, AND L. J. Guillette. EFFECTS OF ENVIRONMENTAL ANTIANDROGENS ON REPRODUCTIVE DEVELOPMENT IN EXPERIMENTAL ANIMALS. HUMAN REPRODUCTION 7(3):248-264, (2001).
Description:
In mammals, the androgens testosterone (T) and dihydrotestosterone (DHT) are critical for normal male reproductive development and function. In humans, drugs that act as androgen receptor (AR) agonists and antagonists or inhibit fetal steroidogenesis can cause pseudohermaphroditism. In experimental animals, environmental antiandrogens act via several distinct mechanisms. Vinclozolin, p,p' DDE and procymidone are AR antagonists. The phthalate esters (PE) DEHP, DBP and BBP inhibit T synthesis in the fetal rat. Other pesticides, like linuron, may disrupt development via multiple mechanisms of action. Prenatal administration of dioxin (2,3,7,8 TCDD) or TCDD-like PCBs also alter the differentiation of androgen-dependent tissues via mechanisms that likely involve AhR but not AR binding. AR antagonists reduce male rat anogenital distance and induce areolas at low dosage levels. Hypospadias, agenesis of the sex accessory tissues and retained nipples are seen in the middle dosage levels, while undescended testes and epididymal agenesis are only seen in the highest dose groups. With the PEs, the testis and epididymides often are malformed at dosage levels that have little effect on differentiation of the external genitalia or other DHT-dependent tissues. TCDD and PCBs affect sperm counts and androgen-dependent tissue weights. TCDD induces epididymal agenesis, but not hypospadias or retained nipples. In addition to effects in rats, p,p'DDT and -DDE, vinclozolin and DBP affect reproductive function in male rabbits when administered during prenatal and/or neonatal life. P,p' DDT or DDE treatment during gestation induces cryptorchidism and carcinoma in situ-like lesions in the testes. Recently, samples from several bodies of water which contain masculinized female fish have been shown to display androgenic activity in vitro. As all female vertebrates can be masculinized by androgen treatment it is important to determine the nature of the chemical(s) responsible for this novel endocrine activity. In summary, several classes of environmental chemicals have been shown to alter reproductive development in an antiandrogenic manner, some of which (TCDD and p,p' DDE) disrupt development in rats and/or rabbits at fetal concentrations at, or near exposure levels seen in some of the human population.