Mechanism of Prenatal Chromium-VI Exposure and Germ Cell Apoptosis in the Ovary

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 DESCRIPTION (provided by applicant): In utero exposure to environmental endocrine disrupting chemicals (EDCs) during prenatal development results in germ cell loss, oocyte damage, early menopause, and increased miscarriages in F1 progeny. Hexavalent chromium (CrVI) is a heavy metal endocrine disruptor. CrVI levels in drinking water sources in the United States have been increasing due to increased industrial use of CrVI and improper disposal of industrial waste, imposing a major threat to human health. Cr traverses the placental barrier and reaches the growing fetus in utero, affecting embryonic development, fetal viability, and reproductive functions. Women exposed to CrVI through environmental or occupational exposures suffer from gynecological illnesses such as abnormal menses, increased postpartum bleeding, pre-term birth, stillbirth, and infertility, accompanied by high Cr levels in their urine peripheral and umbilical cord blood, and placental tissue. Cr can reach the ovary and accumulate in the follicular fluid in women. This significant occupational and public health concerns underscore the importance of understanding CrVI-induced reproductive dysfunctions. The objective of the proposed research is to understand the molecular, cellular, and epigenetic mechanisms by which prenatal exposure to CrVI disrupts germ cell survival, germ cell nest breakdown and early events of follicular development, oocyte quality, and blastocyst development in F1 progeny. The overarching hypothesis is that prenatal exposure to CrVI increases apoptosis of germ cells, accelerates germ cell nest breakdown, impairs oocyte quality, and disrupts blastocyst development in F1 progeny. Specific Aim 1 will determine the molecular and cellular mechanism of prenatal exposure to CrVI on germ cell apoptosis and germ cell nest breakdown in F1 progeny. Specific Aim 2 will establish the selective and interactive roles of reactive oxygen species (ROS), p53, and caspase-3 pathways in CrVI-induced germ cell apoptosis and germ cell nest breakdown. Specific Aim 3 will determine the impact of prenatal exposure to CrVI on oocyte quality and early embryonic development in F1 progeny. The experimental approaches include exposure to environmentally relevant and regulatory doses of CrVI during fetal ovarian development using in vivo rat models, in vitro fetal whole ovary organ culture, pharmacological and genomic approaches, superovulation, oocyte and blastocyst developmental competence and cellular, molecular, and microscopy-based techniques. The novel findings from this project are expected to fill the gap in knowledge needed to understand how the in utero exposure to CrVI affects reproductive functions in the F1 progeny. Results will identify the effect of CrVI on early windows of great vulnerability of fetal ovarian development, and this new knowledge may help to educate pregnant women to avoid exposures to CrVI during such critical windows. The experimental model used and outcomes identified in this study can be extrapolated to understand the adverse effects of other heavy metals and EDCs on ovarian development and prenatal programming of health and disease across the mammalian species including human.