: Phthalate compounds are ubiquitous environmental contaminants and because they are endocrine disruptors with weak estrogenic properties, there is concern about their toxic effects on male reproductive organs. Phthalates are also peroxisome proliferators which activate a receptor called the peroxisome proliferator-activated receptor (PPAR). The goal of this proposal is to identify the underlying molecular and cellular mechanisms by which phthalates and peroxisome proliferators disrupt testicular function. The hypothesis to be tested is that exposure to phthalates or other peroxisome proliferators cause PPAR activation which interferes with the retinoid signaling pathway that is vital for embryonic and postnatal testis development. A heterodimer of retinoic acid receptor alpha (RARalpha) and retinoid X receptor (RXR) is essential for normal testicular function. RXR also forms a heterodimer with PPAR which is required for its transcriptional activity, thus RXR is a common factor for retinoic acid and peroxisome proliferator action.
Specific aims are to determine the signaling mechanisms by which phthalates and other peroxisome proliferators activate PPAR and show that PPAR may interfere with normal retinoid signaling in the testis. The dose dependent and developmental -specific changes in the expression of PPAR, retinoid receptors, and target genes involved in lipid, retinoid, or steroid metabolism, will be examined in testes from embryos and postnatal rats. and testes from PPARalpha knockout mice treated with phthalates and other peroxisome proliferators. The PI will also examine the effects of peroxisome proliferators on transcriptional activation of PPAR and retinoid receptors in Sertoli cells to establish whether there is a potential competition for RXR. Over expression of RARalpha or PPARalpha will be achieved to ascertain whether PPARalpha and RARalpha compete for endogenous RXR. The results will demonstrate that exposure to phthalates and other peroxisome proliferators leads to alteration in the activation of PPAR and RAR mediated by increased activities of protein kinase C and MAP kinase, and decreased activities of FSH and CAMP, and this activation will lead to altered expression of target genes in testes of embryonic and postnatal rats. Completion of this research will elucidate the mechanism by which phthalates and other peroxisome proliferators alter testicular function and contribute to our understanding of the health risks from these compounds to humans. Understanding the molecular signaling mechanism may facilitate development of a method to screen for other chemicals that have similar properties as phthalates on the male reproductive system.
| Bhattacharya, Nandini; Dufour, Jannette M; Vo, My-Nuong et al. (2005) Differential effects of phthalates on the testis and the liver. Biol Reprod 72:745-54 |
| Li, Hui; Kim, Kwan Hee (2003) Effects of mono-(2-ethylhexyl) phthalate on fetal and neonatal rat testis organ cultures. Biol Reprod 69:1964-72 |
| Okita, R T; Okita, J R (2001) Cytochrome P450 4A fatty acid omega hydroxylases. Curr Drug Metab 2:265-81 |
