Chromium VI-induced toxicity on Female Reproductive Function

描述（由申请人提供）：CrVI对环境的污染是对人类健康的主要威胁，并且由于铬的广泛工业用途而不断增加。在铬工业中工作和生活在铬污染环境中的妇女会遇到各种生殖问题，如月经异常、不孕症、死产，并伴有血液和尿液中的高铬水平。CrVI可以通过母乳传给新生儿。目前还没有确定任何治疗干预策略来保护妇女的生殖健康免受crvi毒性的不利影响，因为潜在的分子和细胞机制在很大程度上仍然未知。我们最近在大鼠身上的研究结果表明，哺乳期暴露于CrVI可诱导卵泡闭锁和颗粒细胞凋亡，减少类固醇生成，延迟青春期，延长发情周期；而补充维生素C和CrVI可以减轻CrVI的不良影响，恢复正常的卵泡发育，并在F1代开始青春期。本应用的目的是了解哺乳期暴露于CrVI损害卵巢功能和妊娠的机制，并评估维生素C对CrVI诱导的F1后代生殖毒性的预防作用。我们的中心假设是，在哺乳期暴露于CrVI会导致颗粒细胞凋亡和卵泡闭锁，减少排卵，危及妊娠，并诱发F1雌性后代早产；维生素C可以减轻crvi引起的生殖毒性。特异性Aim-1将确定哺乳期暴露于CrVI诱导F1子代卵巢卵泡闭锁的分子机制，并评估维生素C对CrVI毒性的保护作用。特异性Aim-2将确定哺乳期暴露于CrVI对F1后代排卵和卵母细胞质量的影响，并评估维生素C对CrVI毒性的保护作用。特异性Aim-3将确定哺乳期暴露于CrVI对F1雌性后代妊娠结局的影响，并评估维生素C对CrVI毒性的保护作用。本项目所概述的研究的成功完成预计将确定：(1)CrVI会导致颗粒细胞凋亡和卵泡闭锁，降低卵母细胞质量，降低排卵和妊娠率，诱发早产；（ii）维生素C将减轻CrVI的毒性并保护F1后代的生殖健康。这些结果将产生重要的积极影响，预计将对妇女和儿童的生殖健康具有转化意义，特别是对那些在工业中工作或生活在接触高水平重金属污染地区的妇女和儿童。此外，本项目的新发现有望为crvi诱导的卵巢毒性和不孕症以及维生素C的保护作用提供新的认识，填补crvi诱导的生殖毒性知识的实质性空白。这是一项R21申请，旨在解决NIH/NIEHS关于环境重金属毒物与人类健康的任务以及NIH/NICHD关于妇女和儿童生殖健康的任务。

DESCRIPTION (provided by applicant): 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.