Investigating the Developmental Mechanisms of TCDD-Induced Reproductive Dysregulation

点击翻译按钮获取中文摘要

PROJECT SUMMARY: Environmental exposure to endocrine-disrupting chemicals is heavily implicated in the increasing incidence of infertility and adverse reproductive outcomes across industrialized countries. As early critical periods are highly susceptible to endocrine system disruption, even very low-doses of these chemicals can shift developmental trajectories, leading to lifelong and/or multigenerational disease consequences. Therefore, the long-term goal of our work is to investigate both the specific genetic and epigenetic mechanisms through which toxicant exposures induce later-life reproductive effects and the windows during which this disruption occurs, in order to inform the development of clinical and therapeutic interventions. To address this goal, our lab has previously used zebrafish (Danio rerio), an NIH-validated model organism allowing easy developmental access to toxicological endpoints, to study the effects of early toxicant exposures on adult disease outcomes. Findings of skewed sex ratios and male-mediated transgenerational infertility guided us to further discover specific histologic and transcriptomic changes in the testes of adult male fish, all of which were heavily implicated in infertility. These outcomes told a compelling story of genetic and epigenetic changes in reproductive tissues persisting across the lifespan and inherited to the unexposed F2 generation. However, as everything to this point was assessed in adults, the developmental mechanisms behind these outcomes remain to be determined. The aims of this project propose, initially, the creation of a sex-specific transgenic fish line using well-established methods, in order to gain early developmental access to reproductive tissues and track their development over time. Creation of this line will not only be invaluable to this project, but will also provide a beneficial tool widely applicable to the field of developmental and reproductive toxicology. Using this line, the remaining aims propose to use a variety of physiological, behavioral, genetic, and epigenetic techniques to longitudinally investigate the developmental mechanisms of toxicant-induced infertility. This work promises to provide novel insights into pathways of reproductive development, closely linking adult and multigenerational disease with corresponding developmental origins.