Biological impact of xenobiotics in the female reproductive tract

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Environmental pollutants are resistant to biodegradation, accumulate in the food chain and affect various biological functions. Dioxin-type chemicals interfere with steroid hormone action and impair reproductive functions. There is increasing evidence that prenatal exposure to dioxin-type environmental chemicals results in long-term reproductive disturbances in the offspring of exposed mothers and even in further generations. The molecular mechanisms underlying these heritable reproductive dysfunctions are not fully understood. The proposed research will investigate the molecular mechanisms induced by these chemicals using unique cell models and transgenic mice. Utilizing immortalized cells of female reproductive organs we will study the impact of these chemicals on the functional differentiation of epithelial cells which is regulated under the influence of estrogen and progesterone. We hypothesize that dioxin-type chemicals interfere with molecular mechanisms essential for secretory and resorptive functions. Using dioxin-responsive mouse models we will determine the most sensitive time windows for dioxin exposure during pre- and post-natal development. We will employ modern fluorescence imaging techniques and novel highly sensitive detection and analysis techniques to investigate extra-chromosomal DNA sequences and alterations in microRNA patterns following pre-natal exposure to dioxin. Our long-term goal is to identify the mechanisms of genome dynamics which may confer heritable functional reproductive disorders.