An important way in which developmental Pb exposure may influence cognitive development and later life cognitive functioning is through epigenetic modifications and specifically, through modulating DNA methylation. Recent studies show that DNA methylation in the adult brain is highly dynamic and that the dynamic regulation of methylation in the prefrontal cortex (PFC) and hippocampus together play integral roles in memory formation, consolidation, and maintenance. Preliminary data show that DNA methylation in PFC and hippocampus are affected by developmental Pb exposure under resting conditions and during learning and memory, interfering with normal dynamic regulation of methylation and gene transcription necessary during learning and memory, leading to cognitive deficits. These effects of Pb appear to be expressed differently in males and females, are influenced by developmental timing of Pb exposure, and may be modified by individual genetic makeup through strain-specific epigenetic influences. Our long-term goal is to understand how developmental Pb exposure exerts long-term effects on the brain and behavior. The objective here, which is our next step in pursuit of these goals, is to better understand epigenetic effects of Pb on the brain and how these effects influence behavior. Our goal is to determine how low level Pb exposure affects dynamic methylation of specific genes in PFC and hippocampus during learning and memory and the extent to which these effects contribute to cognitive deficits in males and females and in different strains of rats. Our central hypothesis, is that Pb exposure will alter the dynamic regulation of DNA methylation of key learning/memory related genes in the PFC and hippocampus and that this epigenetic influence of Pb will vary by sex and strain. The objectives of this research will be accomplished by pursuing the following aims: 1) Determine effects of low level Pb exposure on the dynamic modulation of DNA methylation during learning and memory and examine how these effects influence behavior and cognition-related gene expression in males and females in a strain identified by us to be highly susceptible to the effects of Pb (Long Evans) and a strain relatively resistant (Sprague Dawley). Our hypothesis is that there will be aberrant dynamic DNA methylation resulting in abnormal modulation of learning/memory-related genes with associated cognitive deficits and these effects will be modified by sex and strain; 2) Determine the extent to which pharmacological modulation of DNA methylation influences cognitive outcomes in Pb-exposed animals and modulates learning/memory-related gene expression. We postulate that aberrant DNA methylation can be pharmacologically manipulated, potentially re-setting Pb-induced changes and positively influencing cognitive outcome. The proposed studies extend from the current grant and will identify epigenetic mechanisms through which Pb exposure may influence behavior. Results are expected to have important positive impact because of the widespread danger from low level Pb exposure and the possibility of identifying potential interventions that may improve negative outcomes assumed to be permanent.

Public Health Relevance

The proposed research will result in new information on the extent to which early life exposure to the ubiquitous environmental toxicant lead results in aberrant modulation of DNA methylation in frontal cortex and hippocampus during critical processes of learning and memory. This research will also provide new insight into factors that may interact with and modulate the influence of lead on epigenetics and behavior and perhaps suggest potential strategies for remediation of lead-induced cognitive deficits through epigenetic modification. A greater understanding of the molecular, epigenetic, and functional correlates of early life lead exposure on the brain could make possible development of new therapies to remediate negative outcomes from developmental lead exposure, which have been thought to be permanent.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
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Special Emphasis Panel (ZRG1-DKUS-C (90)S)
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Hollander, Jonathan
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Thomas Jefferson University
Schools of Medicine
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Singh, Garima; Singh, Vikrant; Sobolewski, Marissa et al. (2018) Sex-Dependent Effects of Developmental Lead Exposure on the Brain. Front Genet 9:89
Singh, G; Singh, V; Wang, Zi-Xuan et al. (2018) Effects of developmental lead exposure on the hippocampal methylome: Influences of sex and timing and level of exposure. Toxicol Lett 290:63-72
Verma, Megha; Schneider, J S (2017) Strain specific effects of low level lead exposure on associative learning and memory in rats. Neurotoxicology 62:186-191
Anderson, D W; Mettil, W; Schneider, J S (2016) Effects of low level lead exposure on associative learning and memory in the rat: Influences of sex and developmental timing of exposure. Toxicol Lett 246:57-64
Schneider, Jay S; Talsania, Keyur; Mettil, William et al. (2014) Genetic diversity influences the response of the brain to developmental lead exposure. Toxicol Sci 141:29-43
Anderson, D W; Mettil, W A; Schneider, J S (2013) Rearing environment, sex and developmental lead exposure modify gene expression in the hippocampus of behaviorally naive animals. Neurochem Int 62:510-20
Schneider, J S; Kidd, S K; Anderson, D W (2013) Influence of developmental lead exposure on expression of DNA methyltransferases and methyl cytosine-binding proteins in hippocampus. Toxicol Lett 217:75-81
Schneider, Jay S; Anderson, David W; Talsania, Keyur et al. (2012) Effects of developmental lead exposure on the hippocampal transcriptome: influences of sex, developmental period, and lead exposure level. Toxicol Sci 129:108-25
Schneider, J S; Mettil, W; Anderson, D W (2012) Differential effect of postnatal lead exposure on gene expression in the hippocampus and frontal cortex. J Mol Neurosci 47:76-88
Anderson, D W; Pothakos, K; Schneider, J S (2012) Sex and rearing condition modify the effects of perinatal lead exposure on learning and memory. Neurotoxicology 33:985-95

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