Effects of Fetal Bisphenol A Exposure on Oogenesis in Primates

胎儿双酚 A 暴露对灵长类动物卵子发生的影响

• 批准号: 7887291
• 负责人: Patricia Hunt
• 金额: $ 31.44万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-06 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7887291
• 关键词: Address; Adult; Affect; Animal Model; Animals; Attention; Blood; Chemicals; Chromosome Pairing; Chromosomes; Data; Developed Countries; Developing Countries; Development; Dose; Drug Kinetics; Endocrine Disruptors; Event; Exposure to; Female; Fetal Development; Fetal Tissues; Fetus; Food; Foundations; Genetic; Genetic Recombination; Growth; Health; Human; Incidence; Individual; Ingestion; Macaca mulatta; Measures; Meiosis; Metabolic; Metabolic Clearance Rate; Metabolism; Monitor; Monkeys; Mus; Oocytes; Oogenesis; Oral; Outcome; Ovary; Perinatal; Perinatal Exposure; Phenotype; Placenta; Plastics; Pregnancy; Primates; Process; Production; Prophase; Reporting; Reproduction; Research Personnel; Rodent; Route; Screening procedure; Serum; Staging; Testing; Time; Translating; Urine; base; bisphenol A; egg; fetal; in utero; offspring; pregnant; public health relevance; reproductive

DESCRIPTION (provided by applicant): Reports of deleterious reproductive effects ascribed to the actions of endocrine disrupting chemicals are steadily increasing. One chemical in particular, bisphenol A (BPA), has been the focus of considerable attention and controversy. . BPA is one of the highest volume chemicals in production and humans are exposed to low levels on a daily basis. Recent studies in the mouse indicate that exposure to low levels of BPA during three distinct developmental stages in utero can adversely affect the genetic quality of the egg. Thus, these findings, and those from a host of other rodent studies, raise grave concerns about human fetal exposures. Directly assessing the effects of this chemical in humans, however, is neither ethically nor experimentally feasible. The proposed studies represent the first attempt to use a more relevant animal model, the rhesus monkey, to answer questions about the pharmacokinetics of BPA and to directly assess its effects on the early events of oogenesis in the fetal ovary. The oral dose of BPA used in these studies will be carefully monitored so that the resulting blood levels will be within the range currently found in humans. Aim 1 will test the hypothesis that BPA clearance rates differ in pregnant and non-pregnant female monkeys and that BPA levels accumulate in fetal tissues. Aim 2 will test the effect of BPA exposure on the earliest events of oogenesis in the fetal ovary. The BPA dose will be carefully timed during the pregnancy to coincide with the time of meiotic entry of the fetal oocytes to determine if BPA disrupts the processes of synapsis and recombination between homologous chromosomes. Aim 3 will test the hypothesis that perinatal BPA exposure disrupts follicle formation in the female rhesus monkey. Although BPA exposure has been suggested to induce a variety of effects in experimental animals, to date, no study has measured blood or urine levels of BPA in relation to any health outcome in any species. The combined data from these studies will provide the first direct analysis of the effects of BPA exposure on the developing primate fetus and, as such, will have important implications for humans. PUBLIC HEALTH RELEVANCE: Bisphenol A (BPA) is a widely used compound found in plastics and the lining of cans used for food that has been shown to have deleterious effects on offspring of mice when the pregnant dams are exposed to low doses. This project will measure BPA metabolism in non-pregnant and pregnant monkeys and determine if effects on eggs or ovaries are seen in developing offspring in primates as they are in mice. Because the dose used will be similar to current human blood levels of BPA, the results should have direct relevance to human health.

描述（由申请人提供）：归因于内分泌破坏化学物质的作用的有害生殖作用的报告正在稳步增加。尤其是一种化学物质，双酚A（BPA）一直是引起极大关注和争议的重点。 。 BPA是生产中最高的化学物质之一，人类每天暴露于低水平。在小鼠中的最新研究表明，在子宫内三个不同的发育阶段，暴露于BPA水平较低会对卵子的遗传质量产生不利影响。因此，这些发现以及其他许多啮齿动物研究的发现引起了人们对人类胎儿暴露的严重关注。但是，直接评估该化学物质对人类的影响既不是道德上的，也不是实验可行的。拟议的研究是使用更相关的动物模型The Rhesus Monkey的首次尝试回答有关BPA药代动力学的问题，并直接评估其对胎儿卵巢中卵子发生早期事件的影响。这些研究中使用的BPA的口服剂量将仔细监测，以使所得的血液水平将在人类当前发现的范围内。 AIM 1将检验以下假设：孕妇和非孕妇雌性猴子的BPA清除率不同，并且BPA水平在胎儿组织中积累。 AIM 2将测试BPA暴露对胎儿卵巢中卵子作用最早事件的影响。 BPA剂量将在怀孕期间仔细定时，以与胎儿卵母细胞减数分裂的进入时，以确定BPA是否破坏了突触的过程和同源染色体之间的重组。 AIM 3将检验以下假设：围产期BPA暴露会破坏雌性恒河猴的卵泡形成。尽管已建议BPA暴露在实验动物中诱导各种作用，但迄今为止，尚无研究与任何物种中任何健康结果有关的BPA的血液或尿液水平。这些研究的合并数据将对BPA暴露对发展中的灵长类胎儿的影响进行首次直接分析，因此，将对人类具有重要意义。公共卫生相关性：双足A（BPA）是一种在塑料中发现的广泛使用的化合物，并且用于食品的罐衬里，当怀孕的大坝暴露于低剂量时，已证明对小鼠的后代具有有害作用。该项目将测量非妊娠和怀孕猴子中的BPA代谢，并确定对卵或卵巢的影响是否在卵子在小鼠中发展为卵子的后代。由于所使用的剂量将类似于当前的BPA人体血液水平，因此结果应与人类健康有直接相关。