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: 7651242
• 负责人: Patricia Hunt
• 金额: $ 47.79万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-15 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7651242
• 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）：有关内分泌干扰化学品的作用对生殖产生有害影响的报告正在稳步增加。尤其是双酚 A (BPA) 等一种化学物质，一直是备受关注和争议的焦点。 。 BPA 是生产量最大的化学品之一，人类每天接触的浓度很低。最近对小鼠的研究表明，在子宫内三个不同的发育阶段接触低水平的 BPA 会对卵子的遗传质量产生不利影响。因此，这些发现以及许多其他啮齿动物研究的结果引起了人们对人类胎儿接触的严重担忧。然而，直接评估这种化学物质对人类的影响在伦理上和实验上都不可行。拟议的研究首次尝试使用更相关的动物模型（恒河猴）来回答有关 BPA 药代动力学的问题，并直接评估其对胎儿卵巢卵子发生早期事件的影响。这些研究中使用的 BPA 口服剂量将受到仔细监测，以便最终的血液浓度处于目前人类发现的范围内。目标 1 将检验以下假设：怀孕和未怀孕的雌性猴子的 BPA 清除率不同，并且 BPA 水平在胎儿组织中积累。目标 2 将测试 BPA 暴露对胎儿卵巢中最早的卵子发生事件的影响。在怀孕期间，BPA 剂量将被仔细安排，以与胎儿卵母细胞进入减数分裂的时间一致，以确定 BPA 是否会破坏同源染色体之间的突触和重组过程。目标 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。尽管双酚 A 暴露被认为会对实验动物产生多种影响，但迄今为止，还没有研究测量血液或尿液中双酚 A 的水平与任何物种的健康结果之间的关系。这些研究的综合数据将首次直接分析 BPA 暴露对发育中的灵长类胎儿的影响，因此将对人类产生重要影响。公共健康相关性：双酚 A (BPA) 是一种广泛使用的化合物，存在于塑料和食品罐内衬中，已证明当怀孕的母鼠接触低剂量时，会对小鼠后代产生有害影响。该项目将测量未怀孕和怀孕猴子的 BPA 代谢，并确定灵长类动物发育中的后代是否会像小鼠一样对卵子或卵巢产生影响。由于所使用的剂量与当前人体血液中的 BPA 水平相似，因此结果应与人类健康直接相关。