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.