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.

Public Health Relevance

BPA is one of the most prevalent chemicals in our environment but there are little data on its effect on the adult central nervous system. Our proposed experiments will provide critical new information regarding the effect of BPA on neural stem cells and development in the adult brain and provide a foundation for future regulatory evaluation of this chemical.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21ES021957-01
Application #
8388604
Study Section
Special Emphasis Panel (ZES1-TN-D (ST))
Program Officer
Reinlib, Leslie J
Project Start
2012-08-24
Project End
2014-07-31
Budget Start
2012-08-24
Budget End
2013-07-31
Support Year
1
Fiscal Year
2012
Total Cost
$243,000
Indirect Cost
$93,000
Name
Johns Hopkins University
Department
Neurology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Bonaguidi, Michael A; Stadel, Ryan P; Berg, Daniel A et al. (2016) Diversity of Neural Precursors in the Adult Mammalian Brain. Cold Spring Harb Perspect Biol 8:a018838
Qian, Xuyu; Nguyen, Ha Nam; Song, Mingxi M et al. (2016) Brain-Region-Specific Organoids Using Mini-bioreactors for Modeling ZIKV Exposure. Cell 165:1238-54
Felling, Ryan J; Song, Hongjun (2015) Epigenetic mechanisms of neuroplasticity and the implications for stroke recovery. Exp Neurol 268:37-45
Huang, Wei; Ming, Guo-Li; Song, Hongjun (2015) Experience matters: enrichment remodels synaptic inputs to adult-born neurons. Neuron 85:659-61
Yu, Huimei; Su, Yijing; Shin, Jaehoon et al. (2015) Tet3 regulates synaptic transmission and homeostatic plasticity via DNA oxidation and repair. Nat Neurosci 18:836-43
Guo, Junjie U; Su, Yijing; Shin, Joo Heon et al. (2014) Distribution, recognition and regulation of non-CpG methylation in the adult mammalian brain. Nat Neurosci 17:215-22
Wen, Zhexing; Nguyen, Ha Nam; Guo, Ziyuan et al. (2014) Synaptic dysregulation in a human iPS cell model of mental disorders. Nature 515:414-8
Guo, Junjie U; Szulwach, Keith E; Su, Yijing et al. (2014) Genome-wide antagonism between 5-hydroxymethylcytosine and DNA methylation in the adult mouse brain. Front Biol (Beijing) 9:66-74
Christian, Kimberly M; Song, Hongjun; Ming, Guo-li (2014) Functions and dysfunctions of adult hippocampal neurogenesis. Annu Rev Neurosci 37:243-62
Song, Hongjun; Ming, Guo-Li (2014) Reprogram to pluripotency: a new logic and a chemical cocktail. Natl Sci Rev 1:6-7

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