Early life environmental tobacco smoke (ETS) exposure is associated with detrimental outcomes on neurodevelopment, including Attention-Deficit / Hyperactivity Disorder (ADHD), but the mechanisms are unclear. Epi-genetic changes induced by ETS exposure may underlie these associations. Our long-term goal is to utilize DNA methylation profiles to identify children at risk for developing adverse neurodevelopmental outcomes. The objective is to uncover the epigenetic mechanism linking ETS exposure in early life to phenotypes associated with ADHD. We hypothesize that early life ETS exposure induces persistent and targeted functional changes in DNA methylation that associate with neurodevelopmental phenotypes. The rationale for is that defining the repertoire of ETS-induced functional DNA methylation changes will offer exciting new opportunities for risk stratification and early interventions to reduce and prevent adverse behavioral and cognitive outcomes of ETS exposure.
Our aims are as follows: 1) Identify ETS-related methylation targets. We will test the hypothesis that early life ETS exposure in rats will induce measurable shifts in methylation at loci relevant to neurobehav-loral outcomes that are detectable in both brain and blood. Whole genome bisulfite sequencing will identify ETS-vulnerable loci with validation by pyrosequencing. 2) Identify ETS-altered methylation-expression relationships in frontal cortex. We hypothesize that early life ETS exposure in rats induces changes in frontal cortex gene expression at ADHD-relevant genes. Whole transcriptome profiling will identify these changes. We will also evaluate methylation expression relationships from the in vivo results and in an in vitro model of neuronal differentiation. 3) Determine if DNA methylation varies with ETS dose in humans. Prenatal and peri-natal cotinine levels and DNA methylation in children, from bisulfite pyrosequencing at ADHD-related genes and candidate loci from the above aims, will determine if methylation varies with exposure. The proposed research is expected to reveal ETS-related epigenetically vulnerable genes that mechanistically explain the link between ADHD and exposure to ETS and that may serve as biomarkers of past exposure.

Public Health Relevance

The proposed research is relevant to public health because the results will for the first time mechanistically link tobacco smoke exposure in early life to neurobehavioral aspects of ADHD through epigenetics. The identified genes are highly likely to pave the way for epigenetic biomarkers and provide for development of novel diag-nostic, prognostic and therapeutic tools that will ultimately improve children's health by allowing for earlier recognition of risk and intervention opportunities.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
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Duke University
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King, Katherine E; Kane, Jennifer B; Scarbrough, Peter et al. (2016) Neighborhood and Family Environment of Expectant Mothers May Influence Prenatal Programming of Adult Cancer Risk: Discussion and an Illustrative DNA Methylation Example. Biodemography Soc Biol 62:87-104
Fuemmeler, Bernard F; Wang, Lin; Iversen, Edwin S et al. (2016) Association between Prepregnancy Body Mass Index and Gestational Weight Gain with Size, Tempo, and Velocity of Infant Growth: Analysis of the Newborn Epigenetic Study Cohort. Child Obes 12:210-8
Slotkin, Theodore A; Stadler, Ashley; Skavicus, Samantha et al. (2016) Adolescents and adults differ in the immediate and long-term impact of nicotine administration and withdrawal on cardiac norepinephrine. Brain Res Bull 122:71-5
Fuemmeler, Bernard F; Lee, Chien-Ti; Soubry, Adelheid et al. (2016) DNA Methylation of Regulatory Regions of Imprinted Genes at Birth and Its Relation to Infant Temperament. Genet Epigenet 8:59-67
Slotkin, Theodore A; Skavicus, Samantha; Card, Jennifer et al. (2016) Diverse neurotoxicants target the differentiation of embryonic neural stem cells into neuronal and glial phenotypes. Toxicology 372:42-51
Slotkin, Theodore A; Skavicus, Samantha; Card, Jennifer et al. (2015) Developmental Neurotoxicity of Tobacco Smoke Directed Toward Cholinergic and Serotonergic Systems: More Than Just Nicotine. Toxicol Sci 147:178-89
Murphy, Susan K; Erginer, Erin; Huang, Zhiqing et al. (2015) Genotype-Epigenotype Interaction at the IGF2 DMR. Genes (Basel) 6:777-89
Levin, Edward D (2015) Learning about cognition risk with the radial-arm maze in the developmental neurotoxicology battery. Neurotoxicol Teratol 52:88-92
Slotkin, Theodore A; Skavicus, Samantha; Card, Jennifer et al. (2015) Amelioration strategies fail to prevent tobacco smoke effects on neurodifferentiation: Nicotinic receptor blockade, antioxidants, methyl donors. Toxicology 333:63-75
Nye, Monica D; Hoyo, Cathrine; Murphy, Susan K (2015) In vitro lead exposure changes DNA methylation and expression of IGF2 and PEG1/MEST. Toxicol In Vitro 29:544-50

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