Bisphenol A Effect on Primate Brain

描述（由申请人提供）：双酚A （BPA）是一种雌激素化学物质，广泛用于制造聚碳酸酯塑料和环氧树脂。由于双酚a会从塑料食品、饮料容器和婴儿奶瓶中滤出，因此人类广泛接触到这种化合物。我们首次证明，低剂量双酚a处理性腺去角质的雌性和雄性大鼠和猴子，可以抑制海马和前额皮质性类固醇的突触形成作用。越来越多的证据表明，海马和前额叶脊柱突触的重塑是学习和记忆的形态学基础，这表明BPA的负突触原效应与认知能力受损有关。根据国家毒理学计划，现有的证据提供了担忧的基础，但食品和药物管理局（FDA）得出结论，迄今收集的数据不足以解决BPA暴露是否对人体健康构成威胁的问题。美国食品和药物管理局呼吁对BPA进行进一步的研究，这与人类健康更为相关。在本申请中，我们提出了三个具体目标，这些目标是根据FDA关于BPA的最新报告中公布的指导方针设计的。利用我们建立的非人类灵长类动物模型，我们将验证BPA诱导的海马和前额叶脊柱突触的丧失以及多巴胺能神经传递受损与认知能力受损有关的假设。此外，我们将分析BPA的影响是否具有累积性，以及它们是否可逆。最后，婴儿和儿童似乎是BPA暴露的最高风险，因为低剂量的BPA会干扰啮齿动物的神经发育，导致潜在的不可逆转的行为改变。我们的最后一个具体目标是通过分析围产期BPA暴露是否会对非人灵长类动物模型造成不可逆转的伤害来解决这个问题。这些研究将提供与人类健康最相关的双酚a暴露风险的信息，这对理事机构适当管制双酚a的使用将非常有价值。

DESCRIPTION (provided by applicant): Bisphenol A (BPA) is an estrogenic chemical that is widely used in the manufacture of polycarbonate plastics and epoxy resins. Because BPA leaches out of plastic food and drink containers and baby bottles, there is a wide human exposure to this compound. We have demonstrated for the first time that low-dose BPA treatment of gonadectomized female and male rats and monkeys inhibits the synaptogenic effect of sex steroids in the hippocampus and prefrontal cortex. Mounting evidence indicates that remodeling of hippocampal and prefrontal spine synapses is a morphological basis for learning and memory, suggesting that the negative synaptogenic effects of BPA are associated with impaired cognitive performance. According to the National Toxicology Program, available evidence provides a basis for concern, yet the Food and Drug Administration (FDA) concludes that data collected so far is not sufficient to resolve the problem whether BPA exposure represents a threat to human health. The FDA calls for further studies on BPA that are more relevant to human health. In this application, we propose three specific aims that are designed along guidelines published in the most recent FDA report on BPA. Using our established nonhuman primate model, we will test the hypothesis that BPA- induced loss of hippocampal and prefrontal spine synapses and compromised dopaminergic neurotransmission are associated with impaired cognitive performance. In addition, we will analyze whether the effects of BPA are cumulative and whether they are reversible. Finally, infants and children in particular seem to be at the highest level of risk from BPA exposure, because low- dose BPA interferes with neuronal development in rodents, leading to potentially irreversible alterations in behavior. Our last specific aim is designed to address this problem by analyzing whether perinatal BPA exposure causes irreversible harm in our nonhuman primate model. These studies will provide information on the risks of BPA exposure with most relevance to human health, which will be highly valuable for governing bodies to appropriately regulate the use of BPA. PUBLIC HEALTH RELEVANCE: Recent rodent studies suggest that the xenoestrogen, bisphenol A, at levels found in the environment, is capable of diminishing one's ability to learn and interferes with brain development. Because there are considerable differences between the brains of rodents and humans, this suggestion is intensively debated. Therefore, we will investigate how bisphenol A affects the brain and learning capability of adult and juvenile monkeys, to provide results that are more relevant to human health and may guide future environmental policy about bisphenol A.