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ToxSci Advance Access published online on October 20, 2004
Toxicological Sciences, doi:10.1093/toxsci/kfi011
Toxicological Sciences © Society of Toxicology 2004; all rights reserved
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Received June 3, 2004
Accepted September 15, 2004

Review

Peroxisome Proliferator-Activated Receptors: Mediators of Phthalate Ester-Induced Effects in the Male Reproductive Tract?

J. Christopher Corton 1* and Paula J. Lapinskas 2

1 ToxicoGenomics, Chapel Hill, NC 27514
2 Cubist Pharmaceuticals, 65 Hayden Ave., Lexington, MA 02421

* To whom correspondence should be addressed.
J. Christopher Corton, E-mail: ccorton{at}msn.com


  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 (PPAR{alpha},{beta},{gamma}). An obligate role for PPAR{alpha} 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 PPAR{alpha} 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.

Keywords: phthalate ester; PPAR; testis; peroxisome proliferator; male reproductive tract.
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