Negative Effects of Bisphenol A on the Monkey CNS

双酚 A 对猴子中枢神经系统的负面影响

• 批准号: 7256153
• 负责人: CSABA LERANTH
• 金额: $ 28.88万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7256153
• 关键词: Address; Adverse effects; Affinity; Agonist; Anatomy; Androgen Receptor; Area; Behavioral; Beverages; Biological; Brain; Canned Foods; Cells; Cercopithecus tantalus; Characteristics; Chemical Industry; Chemicals; Chromosome Pairing; Clinical; Cognitive; Daily; Dendritic Spines; Dental Prosthesis; Development; Dose; Electrons; Endocrine; Endocrine system; Environment; Epoxy Resins; Estradiol; Estrogen Nuclear Receptor; Estrogen Receptors; Estrogens; Exposure to; Female; Food; Food Container; Foundations; Future; Goals; Gonadal Hormones; Health; Hippocampus (Brain); Hormones; Human; Hypothalamic structure; Laboratory Animals; Light; Mediating; Mediator of activation protein; Membrane; Memory; Menstrual cycle; Methods; Microscopic; Molecular; Monkeys; Neuraxis; Neurons; Numbers; Oxytocin; Oxytocin Receptor; Performance; Personal Satisfaction; Pit and Fissure Sealants; Plastics; Play; Prefrontal Cortex; Primates; Progesterone Receptors; Progestins; Prosthesis; Publications; Rattus; Rodent; Role; Safety; Sexual Development; Short-Term Memory; Solid; Standards of Weights and Measures; Synapses; System; Testing; Thinking; Thyroid Hormone Receptor; Time; United States Environmental Protection Agency; Vertebral column; base; bisphenol A; brain morphology; cognitive function; cost; dentate gyrus; drinking; executive function; exposed human population; human study; mimetics; nonhuman primate; polycarbonate; receptor; research study; synaptogenesis; young adult

DESCRIPTION (provided by applicant): Bisphenol A (BPA) is an estrogenic chemical that is widely used in the manufacture of policarbonate plastics and epoxy resins. Because BPA leaches out of plastic food and drink containers, including baby bottles, as well as the BPA-containing dental prostheses and sealants, considerable potential exists for human exposure to this compound. We have demonstrated for the first time that treatment of ovariectomized female rats with BPA dose- dependently inhibits both the hippocampal synaptoplastic and the positive cognitive effects of estrogen administration. These effects of BPA can already be observed at a dose of 40 ¿g/kg that is below the current U.S. Environmental Protection Agency reference daily limit for human exposure. Moreover, several publications have also raised the same worrysome issue that low- dose BPA might compromise normal sexual development and function of the brain. However, the majority of these studies, including our own, investigating BPA effects on the brain have been performed in rats. Hence, the implications of these alarming results to human health are intensively debated. Therefore, we propose to reveal the effect of BPA on estrogen-induced spine synapse formation in the brain of nonhuman primates, which will provide more relevance to human health. There is ample evidence that remodeling of synaptic contacts might mediate the beneficial effects of estrogen on both hippocampus- and prefrontal cortex-dependent executive functioning, particularly working memory. Thus, we hypothesize that BPA exposure may interfere with estrogen-induced synaptogenesis in the hippocampal CA1 and CA3 areas and dentate gyrus, as well as in the prefrontal cortex of nonhuman primates. This hypothesis will be tested using ovariectomized, adult young vervet monkeys that will be treated with vehicle- (controls), estrogen-, BPA- and estrogen+BPA. Furthermore, regarding the receptor target(s) of BPA, we will test whether BPA interferes with the positive effects of estrogen on the hypothalamic expression of oxytocin (O) and the progestin receptor (PR). Neurons producing PR and O contain different estrogen receptors, ERa and ER¿, respectively. Light and electron microscopic unbiased stereological calculations will be used to determine the total number of spine synapses in the hippocampus and prefrontal cortex, and the number of hypothalamic PR- containing and O-producing neurons. Bisphenol A (BPA) is an estrogenic chemical that is widely used in the manufacture of policarbonate plastics and epoxy resins. Because BPA leaches out of plastic food and drink containers, including baby bottles, as well as the BPA-containing dental prostheses and sealants, considerable potential exists for human exposure to this compound. We have demonstrated for the first time that treatment of ovariectomized female rats with 40 ¿g/kg BPA, which is below the the current U.S. Environmental Protection Agency reference daily limit for human exposure, inhibits both the hippocampal synaptoplastic and the positive cognitive effects of estrogen administration. This study, has been performed in rats. Thus, the implications of these alarming results to human health are intensively debated by the chemical industry. Therefore, we propose to reveal the effect of BPA on estrogen-induced spine synapse formation in the brain of non-human primates, which will provide more relevance to human health.

描述（由申请人提供）：双酚A（BPA）是一种雌激素化学品，广泛用于聚乙烯塑料和环氧树脂的生产。由于BPA会从塑料食品和饮料容器（包括婴儿奶瓶）以及含BPA的假牙和密封剂中滤出，因此人类接触这种化合物的可能性很大。我们首次证明，用BPA剂量依赖性地抑制了雌激素给药对去卵巢雌性大鼠的海马突触可塑性和积极认知效应。BPA的这些影响已经可以在40 μ g/kg的剂量下观察到，该剂量低于美国环境保护署目前对人类暴露的每日参考限值。此外，一些出版物也提出了同样令人担忧的问题，即低剂量的BPA可能会损害正常的性发育和大脑功能。然而，这些研究中的大多数，包括我们自己的，调查BPA对大脑的影响都是在大鼠中进行的。因此，这些令人震惊的结果对人类健康的影响引起了激烈的辩论。因此，我们建议揭示BPA对非人灵长类动物脑中雌激素诱导的脊柱突触形成的影响，这将为人类健康提供更多的相关性。有充分的证据表明，突触接触的重塑可能介导雌激素对海马和前额叶皮层依赖的执行功能，特别是工作记忆的有益影响。因此，我们假设BPA暴露可能会干扰雌激素诱导的突触在海马CA 1和CA 3区和齿状回，以及在非人灵长类动物的前额叶皮层。该假设将使用切除卵巢的成年幼年黑长尾猴进行检验，这些猴将接受溶媒（对照）、雌激素、BPA和雌激素+BPA治疗。此外，关于BPA的受体靶点，我们将测试BPA是否干扰雌激素对下丘脑催产素（O）和孕酮受体（PR）表达的积极作用。产生PR和O的神经元分别含有不同的雌激素受体ER α和ER <$。光镜和电子显微镜无偏体视学计算将用于确定海马和前额皮质中的棘突触总数以及下丘脑含PR和产生O的神经元的数量。双酚A（BPA）是一种雌激素化学品，广泛用于塑料和环氧树脂的生产。由于BPA会从塑料食品和饮料容器（包括婴儿奶瓶）以及含BPA的假牙和密封剂中滤出，因此人类接触这种化合物的可能性很大。我们首次证明，用40 μ g/kg BPA治疗卵巢切除的雌性大鼠（低于美国环境保护署目前对人类暴露的每日参考限值），可抑制海马突触发育和雌激素给药的积极认知效应。本研究在大鼠中进行。因此，这些令人震惊的结果对人类健康的影响在化学工业中引起了激烈的辩论。因此，我们建议揭示BPA对非人灵长类动物脑中雌激素诱导的脊柱突触形成的影响，这将为人类健康提供更多的相关性。