You are here:
Diverse mechanisms of anti-androgen action: impact on male rat reproductive tract development.
Citation:
WILSON, V. S., C. R. BLYSTONE, M. G. HOTCHKISS, C. V. RIDER, AND L. E. GRAY. Diverse mechanisms of anti-androgen action: impact on male rat reproductive tract development. International Journal of Andrology. Blackwell Publishing, Malden, MA, 31(2):178-187, (2008).
Impact/Purpose:
This paper details a presentation made at the 4th Copenhagen Workshop on Endocrine Disrupting compounds and covers research on antiandrogenic compounds conducted in our lab over the last few years. The review summarizes the effects of in utero exposure to antiandrogenic compounds and the resultant impact on the male rat reproductive tract. Mechanism-based groups of antiandrogens are discussed with focus on the characteristic effects of each class of antiandrogen. This research reveals that environmental chemicals can alter the androgen signaling pathway via several distinct modes of action. Knowledge of the modes of action of these compounds also allows more confident predictions of how individual tissues will be affected when antiandrogens are combined.
Description:
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.
