Dissecting the Role of Lrh1 in Phthalate-Related Reproductive Impairments: A Cellular and Molecular Approach

Project Summary/Abstract The World Health Organization reports that approximately 20% of couples worldwide experience infertility. Phthalates, widely utilized as plasticizers or solvents in a vast array of consumer products, have been implicated in reproductive disturbances, as evidenced by human epidemiological studies and rodent research. This proposal is dedicated to offering comprehensive mentorship and career development in reproductive toxicology research for pre-doctoral health professionals and graduate students. The project is centered on the premise that exposure to phthalates at environmentally relevant concentrations during critical developmental windows for the testis (from embryonic day 15.5 to postnatal day 3) adversely affects spermatogenesis. This is hypothesized to occur through the disruption of Lrh1 signaling in Sertoli cells, crucial for germ cell development. Our approach comprises two innovative aims: The first aims to elucidate how phthalates may impair germ cell development by disrupting Lrh1-mediated regulation of steroidogenesis and metabolism in mouse Sertoli cells. The second seeks to determine the effects of phthalates on the functional capacities of both mouse and human Sertoli cells (using primary cells and cell lines) in vitro by targeting LRH1. The successful completion of these objectives will significantly advance our understanding of the molecular dynamics through which phthalates influence gonadal function and germ cell maturation. Gaining insight into the sex-specific effects of phthalates will facilitate the development of tailored healthcare interventions for diseases related to development, reproduction, and endocrine function. This research, alongside the career development activities proposed, will empower pre-doctoral health professionals and graduate students pursuing careers in healthcare, setting the stage for pivotal breakthroughs in medical science. Ultimately, this project aligns with the National Institute of Environmental Health Sciences (NIEHS) goal to explore the consequences of environmental exposures on human health, marking a critical step forward in environmental and reproductive health research.