Combined Exposure to Anti-Androgens Exacerbates Disruption of Sexual Differentiation in the Rat

Abstract

ObjectiveThe aim of this study was to assess whether the joint effects of three androgen receptor antagonists (vinclozolin, flutamide, procymidone) on male sexual differentiation after in utero and postnatal exposures can be predicted based on dose–response data of the individual chemicals.MethodsTest chemicals and mixtures were administered by gavage to time-mated nulliparous, young adult Wistar rats from gestational day 7 to the day before expected birth, and from postnatal days 1–16. Changes in anogenital distance (AGD) and nipple retention (NR) in male offspring rats were chosen as end points for extensive dose–response studies. Vinclozolin, flutamide, and procymidone were combined at a mixture ratio proportional to their individual potencies for causing retention of six nipples in male offspring.ResultsWith AGD as the end point, the joint effects of the three anti-androgens were essentially dose additive. The observed responses for NR were slightly higher than those expected on the basis of dose addition. A combination of doses of each chemical, which on its own did not produce statistically significant AGD alterations, induced half-maximal mixture effects. At individual doses associated with only modest effects on NR, the mixture induced NR approaching female values in the males.ConclusionsEffects of a mixture of similarly acting anti-androgens can be predicted fairly accurately on the basis of the potency of the individual mixture components by using the dose addition concept. Exposure to anti-androgens, which individually appears to exert only small effects, 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.…”

Intrauterine exposure to mild analgesics is a risk factor for development of male reproductive disorders in human and rat

“…Observations made in wildlife after environmental accidents have yielded substantial evidence of adverse developmental effects caused by endocrine disrupters and studies on phthalates in humans have shown that there is an association between maternal exposure and reduction in AGD and cryptorchidism among newborn boys (Swan et al, 2005). Recent studies also indicate that anti-androgens, which in low concentrations exert no effects, when combined induce reproductive disorders (Hass et al, 2007). Thus, since pregnant women in the Western world are constantly and inevitably exposed to low concentrations of a large number of different anti-androgens (Diamanti-Kandarakis et al, 2009;Scott et al, 2009), of which many are PG synthesis inhibitors (D. M. Kristensen et al, submitted for publication), consumption of mild analgesics such as paracetamol could in combination with exposure to environmental PG inhibitory and anti-androgenic compounds be a contributing factor to the increased incidence of cryptorchidism and later life reproductive problems.…”

Disruption of reproductive development in male rat offspring following gestational and lactational exposure to di-(2-ethylhexyl) phthalate and genistein

“…However, their focus has been mostly on exposure to endocrine disruptors of the same category or which act as anti-androgens, such as phthalates (Hass et al, 2007;Rider et al, 2008;Rider et al, 2009;Rider et al, 2010). Research on diff erent species of endocrine disruptors has been seldom published.…”