Effects of environmental antiandrogens on reproductive development in experimental animals

Abstract

1Chemicals that act as androgen receptor (AR) agonists and antagonists or inhibit fetal steroidogenesis can induce reproductive malformations in humans and laboratory animals. Several environmental chemicals disrupt development in rats and/or rabbits at fetal concentrations at, or near, exposure levels seen in some segments of the human population. In rats, fetal tissues concentrations of 1 6 2 0 p.p.m. of the DDT metabolite, p,p'-DDE, are correlated with reproductive abnormalities in male offspring. These concentrations are similar to those measured in fist-trimester human fetal tissues in the late 1960s. The pesticides vinclozolin, procymidone, linuron and DDT are AR antagonists. They reduce male rat anogenital distance, and induce areolas at relatively low dosages. Hypospadias, agenesis of the sex accessory tissues and retained nipples are seen in the middle dosages, while undescended testes and epididymal agenesis are seen in the highest doses. Phthalate esters (PE) inhibit testosterone synthesis during fetal life, but do not appear to be AR antagonists. Prenatal administration of a single low dose of dioxin (50-1000 ng TCDDkg) alters the differentiation of androgen-dependent tissues at p.p.t. concentrations, but the mechanism of action likely involves interaction with a hormone-like nuclear transcription factor, the hormone-like receptor AhR, rather than AR. p,p'-DDT and p,p'-DDE, vinclozolin and di-n-butyl phthalate affect reproductive function in rabbits when administered during prenatal and/or neonatal life. Cryptorchidism and carcinoma in situ-like (CIS) testicular lesions were seen in male rabbits treated during development with p,p'-DDT or p,p'-DDE. Extrapolation of effects from rodents to humans would be enhanced if future studies incorporate determination of tissue concentrations of the active metabolites. Knowledge of the tissue concentrations of the active toxicants also would provide an important link to in-vitro studies, which provide more useful mechanistic information when they are executed at relevant concentrations.

Hypospadias: Interactions between environment and genetics

“…Male rat pups exposed to DES during gestation (at concentrations similar to those measured in first-trimester human fetal tissues) developed hypospadias [50,51]. Hypospadias was also found in male rodents after maternal treatment with vinclozolin (dose-response effect) [52], and similar findings were recorded for prenatal exposure to polychlorinated biphenyls (PCB), phthalates and dioxin [52][53][54].…”

Tobacco Use Increases Oxidative DNA Damage in Sperm - Possible Etiology of Childhood Cancer

“…Despite the certainty that androgen action is essential for the regulation of spermatogenesis in adult mammals, little is known about the mechanisms via which this regulation is exerted and by which smoking and its metabolites could affect these pathways. We can speculate that smoking and tobacco chewing; being estrogenic and antiandrogenic compounds could inhibit androgens from binding to their receptors, eventually leading to lower testosterone levels (Gray et al, 2001). However, binding to the specific receptors is only one of the several, and still unknown, ways a chemical can act as an endocrine disrupter (Tabb and Blumberg, 2006).…”

Aromatase activity in the ovary and brain of the eastern mosquitofish (Gambusia holbrooki) exposed to paper mill effluent.

“…The focus of many early studies was on the estrogenic and antiandrogenic actions of various agricultural chemicals such as dichlorodiphenyltrichloroethane (DDT) and its metabolites, methoxychlor, and vinclozlin and industrial compounds such as polychlorinated biphenyls (PCBs), alkylphenol ethoxylates (APEs), and phthalates (4)(5)(6)(7)(8)(9). To date, research has focused on the effects of environmental exposure to these chemicals on reproduction and development in wildlife and/or investigating the underlying mechanisms for some of the observed effects in laboratory and environmentally exposed wildlife species.…”