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.
Previous experimental studies of endocrine disrupting chemicals (EDCs) suggest that exposures during testis development affect spermatogenesis in the adult male. In some instances, these effects are reportedly transmitted to subsequent generations. These transgenerational findings, however, remain controversial, and extensive analyses of the cells responsible for transmitting effects to subsequent generations - i.e., the male germ cells - have not been conducted. Our preliminary data suggest that exposures during testis development permanently alter the spermatogonial stem cells. In the proposed studies, we will utilize novel techniques for sorting and culturing these cells to test the hypothesis that estrogenic EDCs act directly on the germline stem cells of the developing testis, inducing permanent changes to the epigenome.
| Horan, Tegan S; Pulcastro, Hannah; Lawson, Crystal et al. (2018) Replacement Bisphenols Adversely Affect Mouse Gametogenesis with Consequences for Subsequent Generations. Curr Biol 28:2948-2954.e3 |
| Horan, Tegan S; Marre, Alyssa; Hassold, Terry et al. (2017) Germline and reproductive tract effects intensify in male mice with successive generations of estrogenic exposure. PLoS Genet 13:e1006885 |
| Ahuja, Jasvinder S; Sandhu, Rima; Mainpal, Rana et al. (2017) Control of meiotic pairing and recombination by chromosomally tethered 26S proteasome. Science 355:408-411 |
| Sartain, Caroline V; Hunt, Patricia A (2016) An old culprit but a new story: bisphenol A and ""NextGen"" bisphenols. Fertil Steril 106:820-6 |
