Negative Effects of Bisphenol A on the Monkey CNS

描述（由申请人提供）：双酚A （BPA）是一种雌激素化学物质，广泛用于制造碳酸酯塑料和环氧树脂。由于双酚a会从塑料食品和饮料容器（包括奶瓶）以及含双酚a的牙科假体和密封剂中滤出，因此人类暴露于这种化合物的可能性很大。我们首次证明，BPA剂量依赖性地抑制了切除卵巢的雌性大鼠的海马突触可塑性和雌激素给药的积极认知作用。BPA的这些影响在40克/千克的剂量下就已经可以观察到，这一剂量低于美国环境保护署目前对人体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，即低剂量的双酚a可能会损害正常的性发育和大脑功能。然而，大多数研究，包括我们自己的研究，都是在大鼠身上进行的，研究BPA对大脑的影响。因此，人们对这些令人震惊的结果对人类健康的影响进行了激烈的辩论。因此，我们建议揭示BPA对雌性激素诱导的非人类灵长类动物大脑中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体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暴露可能会干扰非人类灵长类动物海马CA1和CA3区、齿状回以及前额叶皮层中雌激素诱导的突触发生。这一假设将通过切除卵巢的成年年轻长尾猴进行验证，这些长尾猴将接受对照、雌激素、双酚a和雌激素+双酚a的治疗。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)和黄体酮受体（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ERa和ER¿。光镜和电镜无偏立体学计算将用于确定海马和前额叶皮层棘突触的总数，以及下丘脑含有PR和产生o的神经元的数量。双酚A （BPA）是一种雌激素化学物质，广泛用于制造聚碳酸酯塑料和环氧树脂。由于双酚a会从塑料食品和饮料容器（包括奶瓶）以及含双酚a的牙科假体和密封剂中滤出，因此人类暴露于这种化合物的可能性很大。我们首次证明，对切除卵巢的雌性大鼠使用40 g/kg BPA（低于目前美国环境保护署对人类暴露的每日参考限值）治疗，既抑制了海马突触可塑性，也抑制了雌激素给药的积极认知作用。这项研究是在大鼠身上进行的。因此，化学工业对这些令人震惊的结果对人类健康的影响进行了激烈的辩论。因此，我们建议揭示BPA对雌性激素诱导的非人类灵长类动物大脑中脊柱突触形成的影响，这将为人类健康提供更多的相关性。

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.