Environmental influence on reproductive tract function

National Institute Of Environmental Health Sciences

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Abstract

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. A second example is diethylstilbestrol (DES), 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. 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 either genistein or DES are infertile at reproductive age and develop uterine cancer as older adults. We already published work showing that neonatal DES exposure causes genome-wide changes in epigenetic marks at enhancer regions of altered genes at the completion of treatment on postnatal day 5. We have now performed studies to examine on a genome-wide basis whether there are alterations in open chromatin sites or additional epigenetic marks such as DNA methylation in the uterus after neonatal DES exposure. We found that there are persistent alterations in epigenetic marks in both juvenile and adults mice following neonatal DES exposure and that there are specific transcription factors that mediate some of these changes. We characterized genome wide epigenetic changes associated with the mouse estrous cycle; this work was published and forms the basis for our current additional studies to examine how DES exposure changes these epigenetic marks. We are also using single cell RNA sequencing to examine the short-term effects of neonatal estrogenic chemical exposure on uterine cellular differentiation. These studies identified abnormal patterns of differentiation, particularly in uterine epithelial cells, and will be submitted for publication soon.