Mode of action: inhibition of androgen receptor function--vinclozolin-induced malformations in reproductive development.

Abstract

Vinclozolin is a fungicide that has been shown to cause Leydig cell tumors and atrophy of the accessory sex glands in adult rodents. In addition, exposure of rats during pregnancy causes a pattern of malformations in the male urogenital tract. A wealth of standard toxicological studies and targeted research efforts is available related to this adverse effect, and these were used to evaluate the Human Relevance Framework (HRF) for noncancer health effects. Vinclozolin and two of its metabolites, designated M1 and M2, have been shown to bind and inhibit the function of the rat and human androgen receptor. Other means of interfering with androgen receptor function (e.g., by exposure to the pharmaceutical agent flutamide) lead to similar adverse health outcomes. There is direct in vivo evidence in the rat prostate that androgen-dependent gene expression changes occur after exposure to vinclozolin. There are no proposed alternatives to the androgen receptor-mediated mode of action. Based on what is known about kinetic and dynamic factors, confidence is high that the animal mode of action (MOA) for vinclozolin-induced malformation of the male reproductive tract is highly plausible in humans.

• Authors: Robert Kavlock, Audrey Cummings
• Journal: Critical reviews in toxicology (Crit Rev Toxicol) 2005 Oct-Nov Vol. 35 Issue 8-9 Pg. 721-6 ISSN: 1040-8444 [Print] England
• PMID: 16417039 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Review)

Chemical References

• Androgen Antagonists
• Androgen Receptor Antagonists
• Oxazoles
• vinclozolin

Topics

• Abnormalities, Drug-Induced (pathology)
• Androgen Antagonists (toxicity)
• Androgen Receptor Antagonists
• Animals
• Female
• Genitalia (abnormalities, embryology)
• Humans
• Male
• Oxazoles (toxicity)
• Pregnancy
• Species Specificity