Impact of Bisphenol A on neural stem cells and development in the adult brain

描述(申请人提供)：双酚A(BPA)是世界上最流行的人造化学品之一。它是一种具有雌激素效应的有机化合物，用于生产塑料复合材料和环氧树脂，用于制造食品容器、牙科产品、热收据和我们日常遇到的许多其他物品。由于双酚A广泛存在于我们的环境和生态系统中，因此了解我们偶然接触双酚A的生理影响是至关重要的。这项建议的目标是关注成熟的中枢神经系统，并确定双酚A在神经干细胞和成年大脑神经元发育中的作用。成体神经可塑性最显著的例子之一是海马齿状回中终生神经元的新生形成。 海马体。一致的数据表明，这一现象在认知和情感行为的调节中起着关键作用。这些功能角色中的许多似乎是反馈环路的一部分，在反馈环路中，环境因素可以改变成人神经发生的水平，进而可能改变我们应对环境需求的能力。因此，最重要的是确定这种形式的成人神经可塑性与环境之间相互作用的性质和机制。其中一个需要系统研究的领域是经常遇到的环境化学品对神经的影响。为了开始解决这一知识差距，这里的重点是以BPA为切入点，严格分析一种几乎无处不在的化学污染物可能如何影响神经干细胞的激活和命运选择及其神经元后代的发育。为了实现这一目标，本实验室开发和改进的新的定量方法将用于分析双酚A如何调节干细胞行为和成年海马区新生神经元的特性。利用最近开发的“克隆分析”方法，将测试全身暴露于双酚A后成人大脑中单个干细胞和干细胞群体的识别和量化特性(具体目标1)。进一步量化双酚A对新生神经元发育轨迹的影响将使用逆转录病毒介导的荧光标记来实现形态和电生理分析(具体目标2)。这些实验的结果应该会为暴露于双酚A的潜在健康风险及其对成人中枢神经系统的影响提供关键的新信息。

DESCRIPTION (provided by applicant): Bisphenol A (BPA) is one of the most prevalent manufactured chemicals in the world. An organic compound with estrogenic effects, it is used in the production of plastic composites and epoxy resins that are used to make food containers, dental products, thermal receipt paper, and many other items that we encounter on a daily basis. Because of its pervasive presence in our environment and ecosystem, it is critical that we understand the physiological effects of our incidental contact with BPA. The objective in this proposal is to focus on the mature central nervous system and identify the role of BPA on neural stem cells and neuronal development in the adult brain. One of the most striking examples of adult neural plasticity is the de novo formation of neurons throughout life in the dentate gyrus of the hippocampus. Convergent data suggests that this phenomenon plays a critical role in cognition and the regulation of affective behavior. Many of these functional roles appear to be part of a feedback loop in which environmental factors can alter the levels of adult neurogenesis, which in turn may alter our ability to cope with environmental demands. It is therefore paramount that one identifies the nature and mechanisms underlying the interaction between this form of adult neural plasticity and the environment. One such area in need of systematic investigation is the neural impact of frequently encountered environmental chemicals. To begin to address this gap in knowledge, the focus here is on BPA as an entry point for a rigorous analysis of how a near ubiquitous chemical contaminant may affect the activation and fate choice of neural stem cells and the development of their neuronal progeny. To accomplish this objective, novel quantitative approaches developed and refined in this laboratory will be used to analyze how BPA may regulate stem cell behavior and the properties of newborn neurons in the adult hippocampus. Taking advantage of a recently developed "clonal analysis" approach, both the identifying and quantifying properties of individual stem cells and stem cell populations in the adult brain following systemic exposure to BPA will be tested (Specific Aim 1). Further quantification of the impact of BPA on the developmental trajectory of newborn neurons will be accomplished using retroviral-mediated fluorescent labeling to enable morphological and electrophysiological analyses (Specific Aim 2). The results of these experiments should provide critical new information on the potential health risks of exposure to BPA and its effect on the adult central nervous system.