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

基本信息

批准号：
7458151
负责人：
CSABA LERANTH
金额：
$ 16.21万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-07-01 至 2010-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7458151
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

项目摘要

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（由适用提供）：双酚A（BPA）是一种雌激素化学物质，可广泛用于制造政治碳酸盐塑料和环氧树脂树脂。由于BPA摆脱了包括婴儿瓶在内的塑料食品和饮料容器，以及含BPA的牙科假肢和密封剂，因此人类暴露于该化合物的可能存在巨大潜力。我们首次证明了用BPA剂量依赖性地抑制卵巢剂量的卵巢雌性大鼠抑制雌激素给药的阳性认知作用。 BPA的这些影响已经可以观察到40 g/kg的剂量，该剂量低于当前美国环境保护局的人类暴露日期限制。此外，一些出版物也提出了相同的令人担忧的问题，低剂量BPA可能会损害大脑的正常性发展和功能。但是，包括我们自己的大多数研究研究BPA对大脑的影响是在大鼠中进行的。因此，这些令人震惊的结果对人类健康的影响是激烈的争论。因此，我们建议揭示BPA对非人类私人私人大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相关。有足够的证据表明，突触接触的重塑可能会介导雌激素对海马和前额叶皮层依赖的执行功能，尤其是工作记忆的有益作用。这就是我们假设BPA暴露可能会干扰海马CA1和CA3区域的雌激素诱导的突触发生，以及齿状回，以及非人类隐私的前额叶皮质。该假设将使用卵巢切除术，成年的年轻Vervet猴子进行检验，该猴子将通过媒介物（对照组），雌激素，BPA-和雌激素+BPA进行处理。此外，关于BPA的受体靶标，我们将测试BPA是否会干扰雌激素对氧气（O）和孕激素受体（PR）下丘脑表达的阳性作用。产生PR和O的神经元分别包含不同的ERA和ER？。光和电子微观无偏的立体计算将用于确定海马和额叶皮层中脊柱突触的总数，以及含有下丘脑PR的数量含有下丘脑PR-含有和O的神经元。双酚A（BPA）是一种雌激素化学物质，广泛用于制造政治塑料和环氧树脂。由于BPA摆脱了包括婴儿瓶在内的塑料食品和饮料容器，以及含BPA的牙科假肢和密封剂，因此人类暴露于该化合物的可能存在巨大潜力。我们首次证明了用40 g/kg bpa治疗卵巢切除的雌性大鼠，该大鼠低于当前美国环境保护局的人类暴露的参考限制，抑制了海马突触塑性和雌激素给药的正面认知作用。这项研究已在大鼠中进行。这就是化学工业对这些令人震惊的结果对人类健康的影响。因此，我们建议揭示BPA对非人类素数大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相关性。