Diverse mechanisms of anti‐androgen action: impact on male rat reproductive tract development

Abstract

Scientists have identified environmental chemicals that display anti-androgenic activity via multiple mechanisms of action. Early studies focused on pesticides acting as androgen receptor (AR) antagonists but it soon became apparent that was not the only endocrine mode by which compounds affected the androgen signalling pathway. Classes of chemicals currently known to interfere with the androgen signalling pathway include dicarboximide fungicides (e.g. vinclozolin), organochlorine-based insecticides (e.g. p,p'-DDT and -DDE), conazole fungicides (e.g. prochloraz), plasticizers (phthalates) and urea-based herbicides (linuron). Phthalate esters (PEs) and vinclozolin appear to act primarily via a single mechanism of action, while others such as linuron and prochloraz, appear to display dual mechanisms of action. Exposure to PEs decreases mRNA expression of key steroidogenic enzymes and also the peptide hormone insulin-like peptide 3 (insl3) from the foetal Leydig cells. Hence, both androgen- and inls3-dependent tissues are affected. Vinclozolin and procymidone act solely through binding to the AR as antagonists thus blocking the action of androgen at the cellular level but do not affect foetal testosterone synthesis or insl3 gene expression. The compounds linuron and prochloraz are AR antagonists but also inhibit foetal testosterone synthesis, although unlike the PEs, mRNA expression of steroidogenic enzymes and insl3 are not affected. All the above chemicals disrupt androgen signalling in the foetal male rat and produce some malformations in common, but the precise profiles of effects in the offspring are pathognomonic for each mode of action. For example, the 'phthalate syndrome' vs. the 'vinclozolin syndrome' each displays a profile of effects which is clearly different. In summary, as more and more molecular studies with anti-androgenic compounds are conducted, the number of mechanisms by which compounds can affect the androgen signalling pathway is likely to increase. Furthermore, the effects of mixtures of these compounds are just beginning to be explored.

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.…”

Antiandrogenic and Estrogenic Compounds: Effect on Development and Function of Male Reproductive System

“…Insl-3 is an important regulator of testicular descent and phthalateinduced reduction of Insl-3 is consistent with the high incidence of cryptorchidism (Gray et al, 2006;Laguë & Tremblay, 2008;Wilson et al, 2004). In contrast to phthalates, in utero exposure to prochloraz decreases testosterone production by direct inhibition of the activity of steroidogenic enzymes without affecting the mRNA expression of these enzymes Wilson et al, 2008). As mentioned above, biosynthesis of estrogens is catalyzed by the enzyme aromatase.…”

Evolutionary Perspectives on Sex Steroids in the Vertebrates

“…In vitro induction of estrogen-responsive breast cancer cell lines (Klotz et al 1996) and tests of transcription in response to estrogen receptor binding (Ernst et al 1991) were also primary means of screening compounds for estrogenic activity. With mechanistic knowledge came distinctions between feminizing and demasculinizing effects, and the concept of anti-androgens were more carefully considered (Wilson et al 2008) in addition to estrogens or anti-estrogens. Key anti-androgens were originally characterized by their antagonism of androgen receptor (AR).…”