Peroxisome proliferator-activated receptors: mediators of phthalate ester-induced effects in the male reproductive tract?

Toxicol Sci. 2005 Jan;83(1):4-17. doi: 10.1093/toxsci/kfi011. Epub 2004 Oct 20.

Abstract

Many phthalate ester plasticizers are classified as peroxisome proliferators (PP), a large group of industrial and pharmaceutical chemicals. Like PP, exposure to some phthalates increases hepatocyte peroxisome and cellular proliferation, as well as the incidence of hepatocellular adenomas in mice and rats. Most effects of PP are mediated by three nuclear receptors called peroxisome proliferator-activated receptors (PPARalpha,beta,gamma). An obligate role for PPARalpha in PP-induced events leading to liver cancer is well-established. Exposure of rats in utero or in the neonate to a subset of phthalate esters causes profound, sometimes irreversible malformations in the male reproductive tract. We review here the data that supports or discounts roles for PPARs in phthalate-induced testis toxicity including (1) toxic effects of phthalates on the male reproductive tract, (2) expression of PPARs in the testis, (3) activation of PPARs by phthalates, (4) role of PPARalpha in testis toxicity, (5) gene targets of phthalates involved in steroid biosynthesis and catabolism, and (6) interactions between PPARs and other nuclear receptors that play roles in testis development and homeostasis. Critical research needs are identified that will help determine the significance of PPARs in phthalate-induced effects in the rat male reproductive tract and the relevance of toxicity to humans.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Esters
  • Genitalia, Male / drug effects*
  • Genitalia, Male / metabolism
  • Humans
  • Male
  • Peroxisome Proliferator-Activated Receptors / metabolism*
  • Phthalic Acids / toxicity*
  • Plasticizers / toxicity*

Substances

  • Esters
  • Peroxisome Proliferator-Activated Receptors
  • Phthalic Acids
  • Plasticizers