Impacts of Genetic and Environmental Factors on Reproductive Organ Development

National Institute Of Environmental Health Sciences

Investigators

Linked publications, trials & patents

Abstract

1. Identify the sources of somatic cell lineages in the fetal gonads and investigate how they acquire their organ-specific identities we identified a mechanism in fetal Sertoli cells that maintains their identity. Sertoli cell-derived AMH and activin B act as autocrine and paracrine factors on themselves through their expression of AMH and activin B receptors. These two factors maintain the testis program in Sertoli cells and when both are absent, the granulosa cell program emerges leading to partial sex reversal. The incomplete sex reversal of the Amh/Inhbb double knockout testis (ovotestis structure and feminized transcriptomes and cell populations) further indicates that other factors, such as other TGF-beta proteins 14,26,38-40, could compensate for the loss of Amh and Inhbb. The ovotestis structure of the dKO male resembles that of other ovotestis cases29,33; however, the formation of the ovotestis in dKO males is distinctly different. The ovotestis, in most cases, is established at the onset of testis determination in XY mouse embryos with the central part of the gonad following the testicular program and the flanking poles simultaneously developing into an ovarian structure32,41. In the absence of Amh and Inhbb, however, the fetal testes formed properly at first, with the ovarian domains only arising later when Sertoli cells transdifferentiate into their female counterparts. Most intriguingly, in contrast to most ovotestis cases that disappear before birth, the dKO ovotestes are not only maintained into adulthood, but also capable of sustaining both spermatogenesis and folliculogenesis. Finally, the results of the transplantation experiments support the dual properties of AMH and activin B: (1) AMH and activin B have autocrine/paracrine properties on fetal Sertoli cells and (2) AMH and activin B possess the endocrine property of the freemartin factors that can masculinize the fetal ovary. These results not only advance our understanding of gonadal sex differentiation, but also provide insight into the mechanisms behind cases of ovotestis and disorders of sex development in humans. 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 have identified a novel cell population that migrates from the hindgut into the external genitalia in the male mouse embryo. This cell population is positive for the orphan nuclear receptor Nr5a1, which serve as a lineage marker for this population. The Nr5a1+ cell population facilitates urethra closure by modulating the function and differentiation of peri-urethra mesenchymal cells via the EGF/Neuregulin pathway. Without the Nr5a1+ cell population, urethral closure fails to occur normally, consequently leading to hypospadias, one of the most common birth defects. We will use this knowledge and the models that we established to interrogate the potential impacts of maternal heat stress on the incidence of hypospadias in male offspring. As a result of climate change, pregnant women are at risk of being exposed to high temperatures during gestation. Such heat stress during pregnancy could lead to an increase in the incidence of hypospadias in male offspring. Males born with hypospadias are susceptible to other disorders later in life (infertility, kidney diseases, etc.), which affects reproductive outcomes and quality of life. Our work will establish a much needed animal model to better understand the impacts of maternal heat stress on hypospadias. The research outcomes will lay the foundation for future research and provide critical knowledge to the field. Our ultimate goal is to develop ways, based on the results of this project, to mitigate the systemic impacts of high heat on the health of mothers and their offspring.