Modulation of PAH ovarian toxicity by biotransformation enzyme polymorphisms

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DESCRIPTION (provided by applicant): Infertility or impaired fecundity affects 12% of American women. Ovarian dysfunction, including premature ovarian failure is a major cause of infertility. It is likely that exposure to environmental toxicants is responsible for many more cases of impaired ovarian function than is currently appreciated. Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental contaminants, which are known to impair ovarian function and cause ovarian failure in rodents and are probable ovarian toxicants in women. Tobacco smoke, foods, and air pollution are among the sources of exposure to PAHs. The mechanistic basis for interindividual variation in susceptibility to PAH ovarian toxicity is not understood, but polymorphisms in enzymes that metabolize PAHs likely play an important role. The work outlined in this proposal will demonstrate the feasibility of a larger study to test the hypothesis that genetic variations in Phase 1 and Phase 2 biotransformation enzymes involved in metabolizing PAHs modulate the ovarian toxicity of PAHs in women. Specific Aim 1: To test the feasibility of prospectively measuring time to pregnancy and PAH exposure and of using genomewide genotyping methods to determine PAH biotransformation enzyme polymorphisms for a study analyzing the associations between PAH exposure and biotransformation enzyme polymorphisms and fecundability (time to pregnancy). Specific Aim 2: To test the feasibility of using microelectronic dipstick monitors to measure daily urinary reproductive hormone concentrations over multiple menstrual cycles for study of the associations between PAH metabolizing enzyme polymorphisms and PAH exposure and menstrual cycle abnormalities. Specific Aim 3: To pilot test serum anti-M|llerian hormone, follicle stimulating hormone, and inhibin B concentrations as markers of ovarian reserve for study of the associations between PAH exposure and diminished ovarian reserve. PUBLIC HEALTH RELEVANCE: The primary and long-term goal of this research is to understand how toxicants cause ovarian dysfunction so that we can prevent it. These studies will provide insights that will help us to understand why some women are more sensitive to ovarian toxicants than other women. In so doing, they will also lay the groundwork for possible interventions to protect against ovarian dysfunction.