Impacts of Genetic and Environmental Factors on Reproductive Organ Development

National Institute Of Environmental Health Sciences

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Abstract

1. Identify the sources of somatic cell lineages in the fetal gonads and investigate how they acquire their organ-specific identities This project identifies the transcription factor RUNX1 and FOXL2 as critical regulators of granulose cell fate. The identity of the gonads hinges upon the balance between pro-testis and pro-ovary forces. It is clear that the fate determination process of the testis is linear and sequential: Removal of one of the top regulators (i.e. SRY or SOX9) has a domino effect that lead to complete testis to ovary sex-reversal. However, this is not the case in the mouse ovary, where no single-gene loss/mutation results in a complete ovary-to-testis sex-reversal. This sex difference implies a multi-component system in action in the ovary. In this study, we discovered unexpectedly the transcription factor RUNX1 as a new player in the fate specification process of the ovary. RUNX1 is known for its critical role in the differentiation of hematopoietic cells and its link to acute myeloid leukemia in humans. In the ovary, however, RUNX1 acts to maintain the identity of the ovary through an interplay with another ovarian transcription factor FOXL2. Using a combination of mouse genetic models and transcriptomic and genome-wide chromatin approaches, we uncovered RUNX1 functions as anti-testis factor that antagonizes the appearance of the testis program in the fetal mouse ovary. We also found that RUNX1 is enriched in the fetal ovary of various vertebrate species including humans, goats, rainbow trout, and turtles, suggesting its conserved role in ovarian differentiation. In addition, aberrant expression of FOXL2 in the ovary disrupted normal development of the ovary, indicating that a proper balance of ovarian factors is also required for proper functions. Defects in ovarian differentiation have dire consequences on reproductive outcomes of women, from sex-reversal to infertility, and the molecular mechanisms behind these defects are often not identified. Our findings provide new insights into the genomic control of ovarian differentiation, and pave the way for the identification of novel transcription factors and cis-signatures contributing to the normal functions and pathology of the ovary. The topic of granulosa cell development is fundamentally important, given that disorders in ovarian cell differentiation are implicated in ovarian diseases such as polycystic ovary syndrome (PCOS), premature ovarian failure, and ovarian cancers. 2. Investigate the effects of in utero exposure to endocrine disruptors on the development of fetal reproductive organs and its lingering impacts on fertility in adulthood Formation of fetal reproductive organs relies on an intricate interaction between steroid hormones and signaling molecules, therefore making this process a prime target of endocrine disruptors. Chemicals or compounds that mimic or interfere with the action of steroid hormone and signaling molecules are known to have detrimental impacts on fetal reproductive organ formation and long-term impacts on fertility when the affected animals reach adulthood. Arsenic, a human carcinogen found in underground water and food products, is known to impact reproductive systems. Exposure of mouse embryos to arsenic led to cancer development in the ovary and reproductive tracts. To investigate whether arsenic exposure during gestation has a long term impact on the individuals when they reach adulthood, we exposed pregnant mice with human relevant dose of arsenic in the drinking water. When some of the exposed male fetuses are allowed to develop to adulthood, they became obese and developed metabolic problems such as glucose intolerance. Our findings demonstrate a potential impact of in utero arsenic exposure on metabolism. 3. Decipher the process of external genitalia formation We found that the external genitalia of male and female mice begin exhibiting different cell populations early in fetal development. We made the discovery by examining the cells that give rise to the male penis and female clitoris. We also found that the genes that respond to androgen hormones, such as testosterone, in males and estrogens in females undergo changes that are sex specific. Identifying different cell populations within the developing penis may help scientists find ways to understand the causes of some external genitalia birth defects that occur in human males.