Chromium VI-induced toxicity on Female Reproductive Function

描述(申请人提供)：由于铬在工业上的广泛应用，六价铬对环境的污染是对人类健康的主要威胁，并且一直在增加。在铬行业工作和生活在铬污染环境中的妇女会出现月经异常、不孕不育、死产等各种生殖问题，并伴随着血和尿中铬含量的升高。CrVI可以通过母乳传染给新生儿。由于潜在的分子和细胞机制在很大程度上仍不清楚，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。我们最近在大鼠身上的发现表明，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，延缓青春期，延长发情周期；而补充维生素C和CrVI一起减轻CrVI的不利影响，恢复正常的卵泡发育，并在F1代开始青春期。这项应用的目的是了解哺乳期暴露于CrVI影响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，哺乳期暴露于CrVI可诱导颗粒细胞和卵泡闭锁，减少排卵，影响妊娠，并诱导F1雌性后代早产；维生素C可减轻CrVI诱导的生殖毒性。特异性AIM-1将确定哺乳期暴露于CrVI导致F1子代卵泡闭锁的分子机制，并评价维生素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，并评价维生素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。本项目概述的研究的成功完成有望证实：(I)CrVI将诱导颗粒细胞和卵泡闭锁，降低卵母细胞质量，降低排卵和妊娠率，并导致早产；以及(Ii)维生素C将减轻CrVI的毒性，保护F1后代的生殖健康。这些成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产生翻译意义，特别是那些在工业中工作或生活在接触高水平CrVI的地区的妇女和儿童。此外，该项目的新发现有望提供有关CrVI引起的卵毒性和不孕不育以及维生素C的保护作用的新知识，并将填补关于CrVI引起的生殖毒性的实质性知识空白。这是针对NIH/NIEHS关于环境重金属毒物和人类健康的使命以及NIH/NICHD关于妇女和儿童生殖健康的R21申请。 公共卫生相关性：这项应用的目的是了解哺乳期接触六价铬(CrVI)损害卵巢功能和怀孕的机制，以及预防维生素C对CrVI诱导的F1后代生殖毒性的影响。本项目的预期结果是：(I)CrVI将诱导颗粒细胞和卵泡闭锁，降低卵母细胞质量，降低排卵和妊娠率，并导致早产；(Ii)维生素C将减轻CrVI的毒性，保护F1后代的生殖健康；(Iii)为CrVI诱导的卵毒性和不孕症以及维生素C的保护作用提供新的知识，从而填补CrVI诱导生殖毒性的实质性知识空白。该项目的新发现预计将对妇女及其子女的生殖健康产生重要的积极影响和翻译相关性，特别是那些在铬工业工作或生活在接触高水平铬VI地区的妇女及其子女。

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. 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.