Tcdd A Putative Antiandrogen

Exposure to aromatic hydrocarbon (Ah) receptor agonists such as TCDD, PCBs, and PCDFs is causally linked to developmental/reproductive toxicity in humans, nonhuman primates, rodents, mink, fish, and other wildlife species [171]. Effects are expressed in vertebrates at ppt concentrations. TCDD and other agonists bind a cellular steroid hormone-like receptor, termed the Ah receptor, forming a complex that acts as a transcriptional factor by binding to specific dioxin response elements (DREs) on specific genes. Some, if not all, of the tox-icity of TCDD appears to result from activation of the Ah receptor. TCDD is an "endocrine disruptor" that acts on multiple components of the endocrine axis. TCDD exposure alters the levels of many hormones, growth factors, and their receptors.

In addition to the effects of these chemicals seen in humans (discussed earlier), exposure to very low doses of TCDD produces infertility in rodent progeny [172-180]. Exposure to a single low dose of TCDD ranging from 50 ng to

2 |g/kg during sex differentiation of the rat or Syrian hamster results in a number of unusual reproductive alterations in male and female progeny [181-184]. In the female rat, oral treatment with 0.2-1 |g TCDD/kg on GD 15 induced clefting of the phallus with a mild degree of hypospadias in females and a permanent "thread" of tissue across the opening of the vagina of the progeny [184]. Female progeny treated earlier in gestation with 1 |g TCDD/kg displayed reduced fecundity, a high incidence of constant estrus, and cystic endometrial hy-perplasia at middle age. Female hamsters, treated by gavage on GD 11 with 2 |g TCDD/kg, also display clitoral clefting, reduced fertility as a result of several functional reproductive problems, but they did not display the vaginal thread. In TCDD-treated male rat and hamster offspring (dosing as per female offspring above), puberty was delayed, ejaculated and epididymal sperm numbers are reduced, while the reductions in ventral prostate, seminal vesicle, and testis size, displayed during peripubertal life (49-63 days of age), are attenuated with age. Mating behavior was normal in male hamsters, while male rats had some difficulty achieving intromissions. No malformations were noted in male rat or hamster offspring at these dosage levels, although epididymal agenesis has been reported in males exposed orally to doses above 1 |g TCDD/kg on GD 15 [185].

Studies indicate that development of the reproductive system is seriously altered when fetal TCDD concentrations reach 50 ppt, produced by dosing the dam with 1 |g TCDD/kg on GD 15 [186]. Our two lowest dosage levels (0.2 and 0.05 |g/kg on GD 15), which lower sperm counts and induce anomalies in female offspring, occur at fetal TCDD levels of about 5-10 ppt [187]. Similar or slightly higher levels are toxic to some embryonic fish [188] and avian [189] species in the field and in the laboratory.

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