Dysgenesis and Histological Changes of Genitals and Perturbations of Gene Expression in Male Rats after In Utero Exposure to Antiandrogen Mixtures

Abstract

We investigated the ability of a mixture of three androgen receptor antagonists to induce disruption of male sexual differentiation after perinatal exposure. The aim was to assess whether the joint effects of vinclozolin, flutamide, and procymidone can be predicted based on dose-response data of the individual chemicals. Chemicals were administered orally to pregnant Wistar rats from gestational day 7 to postnatal day 16. Changes in reproductive organ weights and of androgen-regulated gene expression in prostates from male rat pups were chosen as end points for extensive dose-response studies. With all end points, the joint effects of the three antiandrogens were dose additive. Histological evaluations showed that dysgenesis and hypoplasia of prostates, seminal vesicles, and epididymis were seen with the highest mixture doses. No changes were observed in any single-compound low-dose group for these lesions, nor were there histopathological changes in the testes. Pronounced dysgenesis of external genitals was observed with all doses of the mixture, and severe dysgenesis was seen with a mixture for which the individual compounds caused no effects. A combination of doses of each chemical that on its own did not produce significant reductions in the weights of seminal vesicles and PBP C3 expression induced a marked mixture effect. Thus, antiandrogens cause additive effects on end points of various molecular complexities such as alterations at the morphological and the molecular level. Exposure to antiandrogens, which appears to exert only small effects when judged on a chemical-by-chemical basis, may induce marked responses in concert with, possibly unrecognized, similarly acting chemicals.

Cumulative Effects of In Utero Administration of Mixtures of “Antiandrogens” on Male Rat Reproductive Development

“…The combination exposure, however, resulted in a 96% incidence of hypospadias and 54% incidence of vaginal pouch in treated animals (Figure 2). Similar effects have been seen in studies of F1 male rats exposed to mixtures of vinclozolin and procymidone during sexual differentiation (Christiansen et al 2008;Gray et al 2001;Gray et al 2006;Hass et al 2007;Metzdorff et al 2007;Rosen et al 2005;Wilson et al 2008). Short-term studies using castrated, immature male androgen-treated rats (Gray et al 2001;Nellemann et al 2003) also demonstrate that vinclozolin and procymidone induce cumulative effects when coadministered.…”

Mixtures of endocrine-disrupting contaminants induce adverse developmental effects in preweaning rats

“…external genitals in males were scored (score 0-3) (as described in Metzdorff et al (2007)). In males, alternately the right and the left testes, both epididymides, ventral prostate, seminal vesicles, levator ani/bulbocavernosus muscle (LABC), and bulbouretral gland were excised and weighed.…”

Investigation of the state of the science on combined actions of chemicals in food through dissimilar modes of action and proposal for science‐based approach for performing related cumulative risk assessment

“…These of course have no direct relevance for human toxicology. However, according to the experience of the authors with the statistical analysis of actual data from chronic mammalian toxicity studies (Christiansen et al 2008;Christiansen et al 2009;Metzdorff et al 2007), it can be stated that the dose response curves resulting from such studies are typically not steeper than those observed for algal reproduction. On the contrary, dose response curves for reproductive toxicity in rodents often appear to be less steep.…”