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Disruptors of Androgen Action and Synthesis

Sanderson, J. Thomas (2015). Disruptors of Androgen Action and Synthesis In: Endocrine Disruption and Human Health. Elsevier Inc., Amsterdam, p. 76-90.

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Résumé

Various environmental chemicals have been found to exert antiandrogenic effects in exposed animals and there is a concern that such compounds may also result in adverse effects in humans. Attempts to elucidate potential mechanisms of antiandrogenic action require knowledge of the functions of androgens in the body and the various ways in which environmental chemicals may disrupt these functions. Environmental antiandrogens may compete with the endogenous androgens testosterone and dihydrotestosterone (DHT) for the androgen receptor (AR), thus blocking its intracellular signaling pathway, which is responsible for the majority of androgenic functions. Other disruptions of androgen function may be caused by inhibition of androgen biosynthesis via catalytic inhibition of key steroidogenic enzymes. Two important enzymes that can be targets for environmental chemicals are cytochrome P450 17-mediated steroid 17α-hydroxylase/17,20-lyase and steroid 5α-reductase activity, which are responsible for the production of the precursor C19-steroids dehydroepiandrosterone (DHEA) and androstenedione, and the conversion of testosterone to its more potent androgenic metabolite DHT, respectively. Various environmental chemicals, most notably pesticides, such as the DDT metabolite p,p-DDE, and fungicides, such as vinclozolin, procymidone, and prochloraz, have been identified to act via several of these antiandrogenic mechanisms to cause reproductive malformations in male rats exposed either in utero or in adult life. In addition to in vivo models to screen for proandrogenic or antiandrogenic compounds (rodent Hershberger assay), several in vitro cell bioassays have been developed for the rapid, mechanism-based screening of disruptors of androgen action either at the level of AR signaling (LNCaP human prostate cancer cells or various reporter-gene systems) or at the level of steroidogenesis (H295R human adrenocortical carcinoma cells). Interestingly, very few if any environmental chemicals have been found to act as androgen mimics, in contrast to the many compounds found to act as estrogens in the environment. The consequences of human exposure to environmental levels of antiandrogens remains unclear.

Type de document:
Mots-clés libres: Androgen receptor; androgen action; testosterone; dihydrotestosterone (DHT); steroidogenesis; antiandrogens; bioassays; vinclozolin; prochloraz
Centre: Centre INRS-Institut Armand Frappier
Date de dépôt: 31 mai 2017 19:49
Dernière modification: 31 mai 2017 19:49
URI: http://espace.inrs.ca/id/eprint/3252

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