Environmental contamination with CrVI is a major threat to human health and has been increasing due to the wide range of industrial uses of chromium. Women working in Cr industries and living around Cr-contaminated environment experience various reproductive problems such as abnormal menses, infertility, still birth, which is accompanied by high Cr levels in their blood and urine. CrVI can be transferred through mother's milk to neonates. No therapeutic intervention strategy has been identified to protect reproductive health of women against adverse effects of CrVI-toxicity, because the underlying molecular and cellular mechanisms remain largely unknown. Our recent findings in rats demonstrate that lactation exposure to CrVI induces follicular atresia and apoptosis of granulose cells, decreases steroid genesis, delays puberty, and extends the estrous cycle;while vitamin C supplementation along with CrVI mitigates the adverse effect of CrVI, restores normal follicular development, and the onset of puberty in F1 generation. The objective of this application is to understand mechanisms through which lactational exposure to CrVI compromises ovarian function and pregnancy, and to evaluate prevention of vitamin C against CrVI-induced reproductive toxicity of F1 offspring. Our central hypothesis is that lactation exposure to CrVI induces apoptosis of granulosa cells and follicular atresia, decreases ovulation, compromises pregnancy, and induces preterm labor in the F1 female offspring;and vitamin C mitigates CrVI-induced reproductive toxicity. Specific Aim-1 will determine the molecular mechanisms through which lactational exposure to CrVI induces ovarian follicular atresia in F1 offspring, and to evaluate the protective effects of vitamin C against CrVI toxicity. Specific Aim-2 will determine the effects of lactation exposure to CrVI on ovulation and oocyte quality in F1 offspring, and to evaluate the protective effects of vitamin C against CrVI toxicity. Specific Aim-3 will determine the effects of lactational exposure to CrVI on pregnancy outcomes in F1 female offspring and to evaluate the protective effects of vitamin C against CrVI toxicity. Successful completion of studies outlined in this project is expected to establish that: (i) CrVI will induce apoptosis of granulosa cells and follicular atresia, decrease oocyte quality, decrease ovulation and pregnancy rate, and induce preterm labor;and (ii) vitamin C will mitigate CrVI toxicity and protect the reproductive health of F1 offspring. Such results will have an important positive impact and are expected to have translational relevance for reproductive health in women and children, especially those working in industries or living in areas in which they are exposed to high levels of CrVI. In addition, the novel findings from this project are expected to provide a new knowledge on CrVI-induced ovotoxicity and infertility and protective effects of vitamin C, and that will fill the substantial gap in knowledge of CrVI-induced reproductive toxicity. This is an R21 application addressing the mission of NIH/NIEHS on environmental heavy metal toxicants and human health and NIH/NICHD on reproductive health of women and children. PUBLIC HEALTH RELEVANCE: The objective of this application is to understand mechanisms through which lactational exposure to hexavalent chromium (CrVI) compromises ovarian function and pregnancy, and prevention of vitamin C against CrVI-induced reproductive toxicity of F1 offspring. Expected outcomes of this project are that: (i) CrVI will induce apoptosis of granulosa cells and follicular atresia, decrease oocyte quality, decrease ovulation and pregnancy rate, and induce preterm labor;(ii) vitamin C will mitigate CrVI toxicity and protect the reproductive health of F1 offspring;(iii) provide new knowledge on CrVI-induced ovotoxicity and infertility and protective effects of vitamin C, and thus fill the substantial gap in knowledge of CrVI-induced reproductive toxicity. The novel findings of this project are expected to have an important positive impact and translational relevance for reproductive health in women and their children, especially those working in Cr industries or living in areas in which they are exposed to high levels of CrVI.