Different environmental chemicals can affect the reproductive capability of a variety of organisms, depending on the timing and dose of exposure, and are thought to impact human reproduction as well. One example is the phytoestrogen, genistein, which when given to neonatal female mice has long-term effects on their ability to reproduce. The underlying causes of their infertility, however, are not known. A second example is diethylstilbestrol, which causes reproductive tract malformations when given prenatally (before birth) and reproductive tract dysfunction and cancer when given neonatally (around the time of birth). We are using both neonatal genistein and DES treatments to determine how estrogenic compounds affect female reproductive tract development and function, and how these compounds influence embryo development within the female reproductive tract through the time of implantation. These studies are relevant to human fertility because genistein levels similar to those reached in our mouse model are measured in babies on soy-based infant formula, and many other estrogenic compounds are found in the environment and could affect reproductive tract development and function. Female mice treated neonatally with DES are infertile at reproductive age and develop uterine cancer as older adults. We performed a series of experiments to determine how the neonatal exposure changes gene expression profiles in the adult uterus that may explain these phenotypes. We found that neonatal DES exposure changes protein levels of several chromatin-modifying proteins and causes permanent alterations in epigenetic marks at specific gene loci. This work was published. We are now performing studies to examine on a genome-wide basis whether there are permanent alterations in epigenetic marks in the uterus after neonatal DES exposure. This work is ongoing. Development of uterine endometrial receptivity for implantation is orchestrated by cyclic steroid hormone-mediated signals. It is unknown if these signals are necessary for oviduct function in supporting preimplantation development. We have found that conditional knockout (cKO) mice lacking estrogen receptor alpha in oviduct epithelial cells have reduced fertilization and all their embryos die before the 2-cell stage due to persistence of secreted innate immune mediators, including proteases. Elevated protease activity in cKO oviducts causes premature cleavage of the zona pellucida protein, ZP2, and wild-type embryos transferred into cKO oviducts fail to develop normally unless rescued by concomitant transfer of protease inhibitors. Thus, oviductal innate immune suppression mediated by epithelial cell estrogen receptor alpha signaling is required for fertilization and preimplantation embryo development. This work has been submitted for publication.
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