Both developmental lead (Pb) exposure and prenatal stress (PS) impact low socioeconomic status communities and target the brain mesocorticolimbic (MESO) system and the hypothalamic-pituitary-adrenal (HPA) axis. Combined Pb and PS in rodents can produce enhanced behavioral toxicity that is related to underlying inter-correlated MESO and HPA axis changes. Preliminary data in Pb+/-PS mice demonstrates hypomethylation of the hippocampal glucocorticoid receptor (GR) gene NR3C1 in both sexes with consequent increased expression in Pb+PS mice only. Pb differentially alters frontal cortex histone acetylation (AcH3K9) levels by gender. Thus MESO GR epigenetic changes may be important mechanisms of Pb+/-PS-induced CNS toxicity. Behavioral experience is a critical determinant of later behavior and brain function, and epigenetic marks can be modified by behavioral experiences. In our studies, positive vs. negative behavioral experience not only differentiated MESO neurotransmitter levels, but also altered the effects of Pb, PS and Pb+PS on neurotransmitter levels. Thus critical to a full understanding of the consequences of Pb+/-PS is a determination of how the nature of behavioral experience might either mitigate/reverse vs. further enhance Pb and PS- associated epigenetic marks, and associated CNS and HPA toxicity. The proposed studies test the hypotheses that: 1) developmental Pb+/-PS induce sex-dependent MESO GR epigenetic changes, including enhanced alterations in response to Pb+PS;2) different behavioral experiences (i.e., those associated with 'resilience'vs. further pathology) after birth will result in differential profile of epigenetic marks per se that can be related to differences in their ability to mitigate or enhance Pb and/or PS-associated toxicity. These studies will significantly enhance the understanding of CNS epigenetic-behavioral relationships, provide critical information on mechanisms of Pb+/-PS effects, and provide a foundation for establishing behavioral interventions that could assist in mitigating effects of Pb+/-PS effects, two ubiquitous developmental risk factors.

Public Health Relevance

By examining epigenetic changes in brain coupled with brain neurotransmitters and stress hormones, these studies will determine how positive vs. negative behavioral experience after birth could either reverse/alleviate or even further worsen the epigentic as well as behavioral, neurotransmitter and stress-related effects of developmental exposures to low levels of lead or prenatal stress alone or in combination.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Research Project (R01)
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Neurotoxicology and Alcohol Study Section (NAL)
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Kirshner, Annette G
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University of Rochester
Public Health & Prev Medicine
Schools of Dentistry
United States
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Sobolewski, Marissa; Singh, Garima; Schneider, Jay S et al. (2018) Different Behavioral Experiences Produce Distinctive Parallel Changes in, and Correlate With, Frontal Cortex and Hippocampal Global Post-translational Histone Levels. Front Integr Neurosci 12:29
Singh, Garima; Singh, Vikrant; Sobolewski, Marissa et al. (2018) Sex-Dependent Effects of Developmental Lead Exposure on the Brain. Front Genet 9:89
Sobolewski, Marissa; Conrad, Katherine; Marvin, Elena et al. (2018) Endocrine active metals, prenatal stress and enhanced neurobehavioral disruption. Horm Behav 101:36-49
Cory-Slechta, Deborah A; Sobolewski, Marissa; Varma, G et al. (2017) Developmental Lead and/or Prenatal Stress Exposures Followed by Different Types of Behavioral Experience Result in the Divergence of Brain Epigenetic Profiles in a Sex, Brain Region, and Time-Dependent Manner: Implications for Neurotoxicology. Curr Opin Toxicol 6:60-70
Varma, G; Sobolewski, M; Cory-Slechta, D A et al. (2017) Sex- and brain region- specific effects of prenatal stress and lead exposure on permissive and repressive post-translational histone modifications from embryonic development through adulthood. Neurotoxicology 62:207-217
Schneider, Jay S; Anderson, David W; Kidd, Sarah K et al. (2016) Sex-dependent effects of lead and prenatal stress on post-translational histone modifications in frontal cortex and hippocampus in the early postnatal brain. Neurotoxicology 54:65-71
Sobolewski, Marissa; Allen, Joshua L; Morris-Schaffer, Keith et al. (2016) A novel, ecologically relevant, highly preferred, and non-invasive means of oral substance administration for rodents. Neurotoxicol Teratol 56:75-80