Chromium VI-induced toxicity on Female Reproductive Function

六价铬对女性生殖功能的毒性

• 批准号: 8177399
• 负责人: Sakhila Banu
• 金额: $ 21.98万
• 依托单位: TEXAS A&M UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-16 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8177399
• 关键词: Address; Adverse effects; Antioxidants; Apoptosis; Apoptotic; Area; Ascorbic Acid; Birth; Blood; Bos taurus PARP protein; Breeding; Carcinogens; Cells; Child; Chromium; Cleaved cell; Cytochromes; Data; Delayed Puberty; Development; Environment; Environmental Pollution; Estrous Cycle; Exposure to; Failure; Female; Follicular Atresia; GDF9 gene; Gene Proteins; Generations; Goals; Health; Heavy Metals; Human; Hydrogen Peroxide; Industry; Infertility; Intervention; Knowledge; Lactation; Life; Lung; Mediating; Menstruation; Milk; Mission; Mitochondria; Molecular; Mothers; Mutagens; National Institute of Child Health and Human Development; National Institute of Environmental Health Sciences; Oocytes; Organ; Outcome; Ovarian; Ovary; Ovulation; Phosphorylation; Pregnancy; Pregnancy Outcome; Pregnancy Rate; Premature Labor; Prevention; Protein p53; Proteins; Proto-Oncogene Protein c-kit; Puberty; Rattus; Reproductive Health; Research; Solid; Steroid biosynthesis; Steroids; Supplementation; Testing; Therapeutic Intervention; Time; Tissues; Toxic effect; United States National Institutes of Health; Urine; Woman; Work; Working Women; base; bcl-xlong protein; bone morphogenetic protein 15; caspase-3; catalase; chromium hexavalent ion; experience; granulosa cell; granulose; innovation; member; neonate; novel; offspring; ovotoxicity; postnatal; pregnancy prevention; protective effect; pup; reproductive; reproductive function; response; toxicant

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.

描述（由申请人提供）：CRVI的环境污染是对人类健康的主要威胁，并且由于铬的工业用途广泛而一直在增加。在CR行业工作和围绕CR污染的环境工作的妇女经历了各种生殖问题，例如异常月经，不育，仍然出生，伴随着其血液和尿液中的CR水平高。 CRVI可以通过母亲的牛奶转移到新生儿。尚未确定治疗干预策略以保护妇女的生殖健康免受CRVI毒性的不利影响，因为基本的分子和细胞机制仍然很大程度上未知。我们最近在大鼠中的发现表明，对CRVI的泌乳暴露会诱导颗粒状细胞的卵泡闭锁和凋亡，减少类固醇的发生，延迟青春期并延伸发情周期。补充维生素C以及CRVI会减轻CRVI的不良影响，恢复正常的卵泡发育以及F1代的青春期发作。该应用的目的是了解泌乳暴露于CRVI的机制，会损害卵巢功能和妊娠，并评估预防维生素C，以抗CRVI诱导的F1后代的生殖毒性。我们的中心假设是，泌乳暴露于CRVI会诱导颗粒细胞和卵泡闭锁的凋亡，减少排卵，损害妊娠并诱导F1女性后代的早产；维生素C减轻CRVI诱导的生殖毒性。具体的AIM-1将确定乳酸暴露于CRVI的分子机制可在F1后代诱导卵巢卵泡闭锁，并评估维生素C对CRVI毒性的保护作用。具体的AIM-2将确定泌乳暴露于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。具体的AIM-3将确定乳酸暴露于CRVI对F1女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。预计该项目中概述的研究成功完成：（i）CRVI将诱导颗粒细胞和滤泡性闭锁，降低卵母细胞质量，降低排卵和妊娠率，并诱导早产劳动； （ii）维生素C将减轻CRVI毒性并保护F1后代的生殖健康。这样的结果将产生重要的积极影响，并有望在妇女和儿童的生殖健康方面具有转化相关性，尤其是那些从事行业或居住在高水平CRVI的地区的人。此外，该项目的新发现有望提供有关CRVI诱导的卵子性和不育和维生素C的保护作用的新知识，这将填补CRVI诱导的生殖毒性知识的巨大差距。这是R21应用程序，旨在解决NIH/NIEHS在环境重金属有毒物质和人类健康以及NIH/NICHD上的使命，以及NIH/NICHD关于妇女和儿童的生殖健康。 公共卫生相关性：该应用的目的是了解乳管暴露于六价铬（CRVI）的机制，损害了卵巢功能和妊娠，并预防CRVI诱导的F1后代繁殖毒性的维生素C。该项目的预期结果是：（i）CRVI将诱导颗粒细胞和卵泡闭锁的细胞凋亡，降低卵母细胞质量，降低排卵和妊娠率，并诱导早产； （ii）维生素C将减轻CRVI毒性并保护F1后代的生殖健康； （iii）提供有关CRVI诱导的卵子毒性和不育和维生素C保护作用的新知识，从而填补了CRVI诱导的生殖毒性的大幅度空白。预计该项目的新发现将对妇女及其子女的生殖健康产生重要的积极影响和转化相关性，尤其是那些在CR行业工作的人或居住在其高水平CRVI的地区。