Bisphenol A Effect on Primate Brain

描述（由申请人提供）：双酚A（BPA）是一种雌激素化学品，广泛用于聚碳酸酯塑料和环氧树脂的生产。由于BPA从塑料食品和饮料容器以及婴儿奶瓶中滤出，因此人类广泛接触这种化合物。我们首次证明，低剂量BPA治疗性腺切除的雌性和雄性大鼠和猴子抑制性类固醇在海马和前额皮质的突触发生作用。越来越多的证据表明，海马和前额叶棘突触的重塑是学习和记忆的形态学基础，这表明BPA的负性突触发生效应与认知能力受损有关。根据国家毒理学计划，现有的证据提供了关注的基础，但食品和药物管理局（FDA）得出结论，迄今为止收集的数据不足以解决BPA暴露是否对人类健康构成威胁的问题。FDA呼吁进一步研究与人类健康更相关的BPA。在本申请中，我们提出了三个具体目标，这些目标是按照FDA最新发布的BPA报告中的指导方针沿着设计的。使用我们建立的非人灵长类动物模型，我们将检验以下假设：BPA诱导的海马和前额叶棘突触丢失和受损的多巴胺能神经传递与认知能力受损相关。此外，我们将分析BPA的影响是否是累积的，以及它们是否是可逆的。最后，婴儿和儿童似乎尤其处于BPA暴露的最高风险水平，因为低剂量的BPA干扰啮齿动物的神经元发育，导致潜在的不可逆行为改变。我们的最后一个具体目标是通过分析围产期BPA暴露是否会对我们的非人灵长类动物模型造成不可逆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BPA暴露风险信息，这对管理机构适当监管BPA的使用非常有价值。 公共卫生相关性：最近的啮齿动物研究表明，环境中发现的异雌激素双酚A能够降低人的学习能力，并干扰大脑发育。由于啮齿类动物和人类的大脑之间存在相当大的差异，这一建议受到了激烈的争论。因此，我们将研究双酚A如何影响成年和幼年猴子的大脑和学习能力，以提供与人类健康更相关的结果，并可能指导未来有关双酚A的环境政策。

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.