Effects of Lactational Exposure to Chromium (VI) on Ovarian Development

描述（由申请人提供）：六价铬，Cr(VI)，一个多世纪以来一直广泛应用于镀铬，焊接，油漆和金属饰面等行业。铬酸盐工业作为废物沉积在垃圾填埋场和水道中是一种重大的潜在环境危害。然而，尽管美国在保护和回收方面做出了努力，每年仍有超过20,000公吨的铬（VI）排放到环境中，其中超过5,000公吨作为大气排放。因此，数以百万计的人，包括大多数产业工人，都暴露在铬（VI）中。通过阴离子运输机制，铬（VI）很容易进入细胞，对健康的影响尚不完全清楚。在工业化国家，女性不孕症有所增加。在铬行业工作的妇女月经异常，血液中铬（VI）含量高，可通过乳汁从母亲传递给后代。如果哺乳期妇女在铬行业工作或生活在通过食物或饮用水接触高铬摄入量的地区，则母乳中的铬（VI）可能会影响后代的卵巢发育。哺乳期暴露于铬（VI）对卵巢卵泡发育、青春期和后代生殖健康的毒性作用仍然是一个谜，铬毒性对卵巢发育的主要细胞和分子机制尚不清楚。本研究的主要目的是揭示哺乳期暴露于Cr（VI）损害卵巢发育和诱导卵泡闭锁的机制。这一目的将通过验证以下假设来实现：哺乳期暴露于铬（VI）会损害卵巢卵泡发育并诱导后代卵泡闭锁和细胞凋亡。我们的具体目的是：(1)确定哺乳期暴露于铬（VI）对子代卵巢卵泡发育的影响；(2)确定哺乳期暴露于铬（VI）对子代卵巢卵泡闭锁和细胞凋亡的影响。哺乳期大鼠在产后三周内通过饮水接触铬（VI），使青春期前（哺乳期）大鼠通过母乳摄入铬。Cr（VI）毒性对子代卵巢卵泡发育、卵泡闭锁和颗粒细胞凋亡的影响将在出生后25、35和65天进行研究。研究Cr（VI）对caspase-3依赖性凋亡通路的影响。本项目所概述的研究的完成有望提供新的知识，并增加对Cr（VI）诱导的卵巢卵泡发育和卵泡闭锁毒性机制的理解。这些来自大鼠模型的发现可以转化为保护妇女及其雌性后代生殖健康的策略，特别是那些暴露于铬的妇女，从而支持NIH和NIEHS的任务。公共卫生相关性：六价铬（Cr(VI)）广泛用于各种工业，数百万人和大多数工业工人在工作场所、垃圾填埋场和水道以及每天的大气排放中接触到Cr（VI）废物。已知Cr（VI）可导致肺癌，破坏胚胎和胎儿发育，并诱发女性生殖异常。本项目的重点是确定哺乳期接触铬（VI）对子代不同发育年龄卵巢卵泡发育和退行性变（闭锁和凋亡）的影响，本项目研究的完成将为了解铬（VI）毒性对卵巢卵泡发育和卵泡闭锁的作用机制提供新的知识，从而保护妇女的生殖健康。特别是那些在接触六价铬的行业工作的人。

DESCRIPTION (provided by applicant): Hexavalent chromium, Cr(VI), has been used in a wide-range of industries, such as chrome plating, welding, painting, and metal finishes, for more than a century. Cr(VI) deposited as waste in landfills and waterways by chromate industries is a significant potential environmental hazard. Despite conservation and recycling efforts in the United States, however, over 20,000 metric tons of Cr(VI) are released into the environment every year with over 5,000 metric tons released as atmospheric emissions. Consequently, millions of people, including a majority of industrial workers, are exposed to Cr(VI). By an anion transport mechanism Cr(VI) readily enters the cell and the health consequences are not fully understood. Female infertility has increased in industrialized countries. Women working in Cr industries experience abnormal menses and have high blood levels of Cr(VI) that can be transported from mother to offspring through milk. If lactating women working in a Cr industry or living in an area exposed to high Cr intake through food or drinking water breast-feed their offspring, there is a potential risk that Cr(VI) in the mother's milk will affect ovarian development of the offspring. Toxic effects resulting from lactational exposure to Cr(VI) on ovarian follicular development, puberty, and reproductive health of developing offspring remain an enigma, and the principal cellular and molecular mechanisms underlying chromium toxicity on ovarian development are not known. The primary goal of the proposed research is to unravel the mechanisms by which lactational exposure to Cr(VI) impairs ovarian development and induces follicular atresia. This aim will be met by testing the hypothesis that lactational exposure to Cr(VI) impairs ovarian follicular development and induces follicular atresia and apoptosis in the offspring. Our Specific Aims are to: (1) Determine the effects of lactational exposure to Cr(VI) on ovarian follicular development in the offspring, and (2) Determine the effects of lactational exposure to Cr(VI) on ovarian follicular atresia and apoptosis in the offspring. Lactating rats will be exposed to Cr(VI) through drinking water during the first three weeks of postpartum so that the prepubertal (suckling) rats will receive chromium through mother's milk. Effects of Cr(VI) toxicity on ovarian follicular development, follicular atresia and granulosa cell apoptosis will be studied in these offspring on postnatal days 25, 35 and 65. Effect of Cr(VI) on caspase-3 dependent apoptotic pathway will be determined. Completion of studies outlined in this project are expected to provide new knowledge and increased understanding of mechanisms responsible for Cr(VI)-induced toxicity on ovarian follicular development and follicular atresia. These findings from a rat model can then be translated to strategies for protection of the reproductive health of women and their female offspring, especially those exposed to Cr, and thus support the missions of NIH and NIEHS. PUBLIC HEALTH RELEVANCE: Hexavalent chromium, Cr(VI), is used in a wide-range of industries, and millions of people and a majority of industrial workers have been exposed to Cr(VI) wastes in the workplace, landfills and waterways and every day atmospheric emissions. Cr(VI) is known to cause lung cancers, disrupt embryo and fetal development and induce reproductive abnormalities in women. The focus of the present project is to determine the effects of lactational exposure to Cr(VI) on ovarian follicular development and degeneration (atresia and apoptosis) in the offspring during their different developmental ages, and thus completion of studies outlined in this project should provide new knowledge essential to understand the mechanism of Cr(VI) toxicity on ovarian follicular development and follicular atresia which can be translated to protect reproductive health of women, especially those working in industries in which they are exposed to Cr(VI).