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，广泛用于聚碳酸酯塑料和环氧树脂的制造。由于双酚A会从塑料食品和饮料容器中渗出，包括婴儿奶瓶，以及含有双酚A的牙科修复体和密封剂，因此人类接触这种化合物的可能性很大。我们首次证明了双酚A对去卵巢雌性大鼠的治疗剂量依赖地抑制了海马区突触的可塑性和雌激素的积极认知效应。BPA的这些影响已经可以在40？g/kg的剂量下观察到，该剂量低于目前美国环境保护局对人类接触的参考每日限量。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，这些研究中的大多数，包括我们自己的研究，都是在大鼠身上进行的，调查BPA对大脑的影响。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，我们拟揭示BPA在雌激素诱导的非人灵长类动物脑内脊髓突触形成中的作用，这将为人类健康提供更多的相关信息。有充分的证据表明，突触接触的重塑可能会介导雌激素对依赖海马体和前额叶皮质的执行功能，特别是工作记忆的有益影响。因此，我们假设BPA暴露可能干扰雌激素诱导的非人类灵长类动物海马CA1和CA3区和齿状回以及前额叶皮质的突触发生。这一假设将在切除卵巢的成年幼年马尾猴身上得到验证，这些猴子将接受赋形剂(对照组)、雌激素、双酚A和雌激素+双酚A的治疗。此外，关于双酚A的受体靶点(S)，我们将测试双酚A是否干扰雌激素对下丘脑催产素(O)和孕激素受体(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。光镜和电子显微镜无偏的体视学计算将用于确定海马区和前额叶皮质中的脊突触总数，以及下丘脑中含有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，广泛用于聚碳酸酯塑料和环氧树脂的制造。由于双酚A会从塑料食品和饮料容器中渗出，包括婴儿奶瓶，以及含有双酚A的牙科修复体和密封剂，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？g/kg双酚A治疗去卵巢的雌性大鼠，低于目前美国环境保护局对人类每日暴露的参考限值，既抑制了海马区突触的发育，也抑制了雌激素的积极认知效应。这项研究是在老鼠身上进行的。因此，这些令人震惊的结果对人类健康的影响引起了化学工业的激烈辩论。因此，我们打算揭示BPA在雌激素诱导的非人类灵长类动物脑内脊髓突触形成中的作用，这将为人类健康提供更多的相关信息。

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.