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The mechanism of antiandrogenic activity of vinclozolin (3-(3,5-dichlorophenyl)-5-methyl-5-vinyloxazolidine-2,4-dione), a dicarboximide fungicide under investigation for its potential adverse effects on human male reproduction, was investigated using recombinant human androgen receptor (AR). The two primary metabolites of vinclozolin in plants and mammals are M1 (2-[[3,5-dichlorophenyl)-carbamoyl]oxy]-2-methyl-3-butenoic acid) and M2 (3',5'-dichloro-2-hydroxy-2-methylbut-3-enanilide). Both metabolites, in a dose-dependent manner, target AR to the nucleus and inhibit androgen-induced transactivation mediated by the mouse mammary tumor virus promoter. M2 is a 50-fold more potent inhibitor than M1 and only 2-fold less than hydroxyflutamide. In the presence of dihydrotestosterone (50 nM), M2 (0.2-10 microM) inhibits androgen-induced AR binding to androgen response element DNA. In the absence of dihydrotestosterone, concentrations of 10 microM M2 or hydroxyflutamide promote AR binding to androgen response element DNA and activation of transcription. Agonist activities of M2 and hydroxyflutamide occur at 10-fold lower concentrations with the mutant AR (Thr877 to Ala) endogenous to LNCaP human prostate cancer cells. The results indicate that androgen antagonists can act as agonists, depending on ligand binding affinity, concentration, and the presence of competing natural ligands.

Industrial chemicals and environmental pollutants can disrupt reproductive development in wildlife and humans by mimicking or inhibiting the action of the gonadal steroid hormones, estradiol and testosterone. The toxicity of these so-called environmental endocrine disruptors is especially insidious during sex differentiation and development due to the crucial role of gonadal steroid hormones in regulating these processes. This review describes the mechanism of toxicity and clinical implications of a new class of environmental chemicals that inhibit androgen-mediated sex development. For several of these chemicals, including the agricultural fungicide vinclozolin and the ubiquitous and persistent 1,1,1-trichloro-2,2-bis (p-chlorophenyl)ethane metabolite, 1,1-dichloro-2,2-bis(p-chlorophenyl) ethylene, the molecular mechanism of action and the adverse developmental effects on male sex differentiation have been elucidated and are used as examples. Environmental chemicals with antiandrogenic activity offer profound implications with regard to recent clinical observations that suggest an increasing incidence of human male genital tract malformations, male infertility, and female breast cancer. Finally, in light of increasing concern over the potential endocrine disrupting effects of environmental pollutants, an in vitro/in vivo investigational strategy is presented which has proved useful in identifying chemicals with antiandrogen activity and their mechanism of action.

mals. For example, Khera and Ruddick (1973) reported that Male rats exposed in utero to 2,3,7,8-tetrachlorodibenzo-p-dioxin prenatal administration of TCDD at 0.5 mg/kg/day from Day (TCDD) display reduced fertility as a consequence of the direct 6 to Day 15 of gestation reduced the viability, growth, and action of TCDD on the epididymides, as well as delayed puberty fertility of the Wistar rat offspring without inducing maternal and altered reproductive organ weights. The current study provides toxicity. In a three generation reproduction study, Murray generation. These studies demonstrate that the reproductive TCDD/kg on Day 15 of gestation. After birth, growth, viability, and developmental landmarks were monitored in both male and female system is extremely sensitive to TCDD during perinatal life, offspring. Shortly after puberty (49 and 63 days of age) and at 15 with effects occurring at dosage levels that are orders of months of age, male offspring were necropsied. Growth and viability magnitude below those required to produce reproductive alof the pups were reduced only at 0.80 mg TCDD/kg, eye opening terations in adult rats (Johnson et al., 1992;Moore et al., was accelerated (all dosage groups), and puberty was delayed (at 1985). ing from 0.064 to 1 mg/kg altered reproductive hormonal, greater degree than were cauda or caput/corpus epididymal or testicmorphological, and behavioral development including reular (unaffected) sperm numbers. In conclusion, administration of TCDD on Day 15 of pregnancy at 0.05 mg/kg altered eye opening duced fetal and neonatal serum testosterone levels, shortand reduced ejaculated sperm counts, while higher dosage levels ened anogenital distance, and reduced numbers of testicualso delayed puberty and permanently reduced cauda epididymal lar and cauda epididymal sperm and sex accessory gland sperm reserves. ᭧ 1997 Academic Press size. Even the lowest dosage level of TCDD altered reproductive development. For example, at 0.064 mg TCDD/ kg, latencies to mount and intromission were increased, In humans and rodents, exposure to hormonally active and sex accessory gland and cauda epididymal weights chemicals during sex differentiation can produce pseudoher-(down 40% at this dose) were significantly reduced at 63 days of age. Although subsequent studies (Chen et al., 1 The research described in this article has been reviewed by the National 1993; Gray et al., 1995a; Bjerke et al., 1994a) using Health and Environmental Effects Research Laboratory, U.S. EnvironmenHoltzman, Sprague -Dawley, or Long Evans rats exposed tal Protection Agency, and approved for publication. Approval does not to TCDD at 0.7 -1.0 mg/kg on gestational Day 15 have signify that the contents necessarily reflect the views and policies of the been unable to replicate the robust nature of some of the Agency nor does mention of trade names or commercial products constitute endorsement or recommendation for use.hormonal and behavioral alterations reported by Mably 11

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