Male Germline Development and Estrogenic Exposures

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 DESCRIPTION (provided by applicant): Declining male fertility and an increased incidence of reproductive tract abnormalities have been postulated to be a consequence of increasing environmental exposure to chemicals with estrogenic activity. This project is an outgrowth of recent studies of mice and sheep in our laboratory that have uncovered a new phenotype induced by exogenous estrogens: We have found that exposures during testis development affect the events of meiotic prophase in the adult male, significantly and permanently reducing levels of meiotic recombination in the exposed individual. Because recombination is an essential feature of male meiosis, and decreasing levels below a specific threshold (i.e., one exchange per homologous chromosome pair) results in the demise of the cell, this new testicular phenotype is consistent with the hypothesis that exposure to exogenous estrogens adversely affects male fertility. In addition, because recombination creates genetic diversity, our findings have important evolutionary implications. The exposure windows used in our preliminary studies coincide with the epigenetic reprogramming of the male germline. In addition, because the effect on recombination is permanent and the phenotype is evident when germ cells from exposed males are transplanted into a control testis, we hypothesize that estrogenic exposures act directly on the germ cells of the developing testis, altering the epigenome of the spermatogonial stem cell. We will test this hypothesis by defining the developmental window(s) during which the testis is susceptible to the meiotic effects of exogenous estrogens and the cell type(s) that are vulnerable, and by characterizing the epigenetic modifications of the germline that result from exposure. Importantly, the recombination phenotype used in these studies provides a novel, sensitive, and quantitative approach to measuring the effects of exposures on an essential aspect of spermatogenesis and for tracking effects across generations.