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Tara Lovekamp-Swan^1,2 and Barbara J. Davis²

¹Department of Environmental and Molecular Toxicology, North Carolina State University, Raleigh, North Carolina, USA; ²Laboratory of Women's Health, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA

Abstract

Phthalates are high-production-volume synthetic chemicals with ubiquitous human exposures because of their use in plastics and other common consumer products. Recent epidemiologic evidence suggests that women have a unique exposure profile to phthalates, which raises concern about the potential health hazards posed by such exposures. Research in our laboratory examines how phthalates interact with the female reproductive system in animal models to provide insights into the potential health effects of these chemicals in women. Here we review our work and the work of others studying these mechanisms and propose a model for the ovarian action of di-(2-ethylhexyl) phthalate (DEHP) . In vivo, DEHP (2 g/kg) causes decreased serum estradiol levels, prolonged estrous cycles, and no ovulations in adult, cycling rats. In vitro, monoethylhexyl phthalate (MEHP ; the active metabolite of DEHP) decreases granulosa cell aromatase RNA message and protein levels in a dose-dependent manner. MEHP is unique among the phthalates in its suppression of aromatase and in its ability to activate peroxisome proliferator-activated receptors (PPARs) . We hypothesize that MEHP activates the PPARs to suppress aromatase in the granulosa cell. MEHP-, PPAR-, and PPAR-specific ligands all similarly decreased estradiol production and RNA message levels of aromatase in vitro. Our model shows that MEHP acts on the granulosa cell by decreasing cAMP stimulated by follicle stimulating hormone and by activating the PPARs, which leads to decreased aromatase transcription. Thus, the environmental contaminant DEHP, through its metabolite MEHP, acts through a receptor-mediated signaling pathway to suppress estradiol production in the ovary, leading to anovulation. Key words: aromatase, diethylhexyl phthalate, estradiol, female reproductive toxicity, granulosa cells, monoethylhexyl phthalate, phthalates, ovary, peroxisome proliferator, proliferator-activated receptors. Environ Health Perspect 111:139-145 (2003) . doi:10.1289/ehp.5658 available via http://dx.doi.org/ [Online 28 October 2002]