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Choline ameliorates adult learning deficits and reverses epigenetic modification of chromatin remodeling factors related to adolescent nicotine exposure.

ABSTRACT: Earlier initiation of smoking correlates with higher risk of nicotine dependence, mental health problems, and cognitive impairments. Additionally, exposure to nicotine and/or tobacco smoke during critical developmental periods is associated with lasting epigenetic modifications and altered gene expression. This study examined whether adolescent nicotine exposure alters adult hippocampus-dependent learning, involving persistent changes in hippocampal DNA methylation and if choline, a dietary methyl donor, would reverse and mitigate these alterations. Mice were chronically treated with nicotine (12.6?mg/kg/day) starting at post-natal day 23 (pre-adolescent), p38 (late adolescent), or p54 (adult) for 12?days followed by a 30-day period during which they consumed either standard chow or chow supplemented with choline (9?g/kg). Mice then were tested for fear-conditioning and dorsal hippocampi were dissected for whole genome methylation and selected gene expression analyses. Nicotine exposure starting at p21 or p38, but not p54, disrupted adult hippocampus-dependent fear conditioning. Choline supplementation ameliorated these deficits. 462 genes in adult dorsal hippocampus from mice exposed to nicotine as adolescents showed altered promoter methylation that was reversed by choline supplementation. Gene network analysis revealed that chromatin remodeling genes were the most enriched category whose methylation was altered by nicotine and reversed by choline dietary supplementation. Two key chromatin remodeling genes, Smarca2 and Bahcc1, exhibited inversely correlated changes in methylation and expression due to nicotine exposure; this was reversed by choline. Our findings support a role for epigenetic modification of hippocampal chromatin remodeling genes in long-term learning deficits induced by adolescent nicotine and their amelioration by dietary choline supplementation.

SUBMITTER: Gitik M

PROVIDER: S-EPMC6524779 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Choline ameliorates adult learning deficits and reverses epigenetic modification of chromatin remodeling factors related to adolescent nicotine exposure.

Gitik Miri M Holliday Erica D ED Leung Ming M Yuan Qiaoping Q Logue Sheree F SF Tikkanen Roope R Goldman David D Gould Thomas J TJ

Neurobiology of learning and memory 20180809

Earlier initiation of smoking correlates with higher risk of nicotine dependence, mental health problems, and cognitive impairments. Additionally, exposure to nicotine and/or tobacco smoke during critical developmental periods is associated with lasting epigenetic modifications and altered gene expression. This study examined whether adolescent nicotine exposure alters adult hippocampus-dependent learning, involving persistent changes in hippocampal DNA methylation and if choline, a dietary meth ...[more]

PMID: 30099202

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Project description:BACKGROUND:Maternal smoking of traditional or electronic cigarettes during pregnancy, which constitutes developmental nicotine exposure (DNE), heightens the risk of neurodevelopmental disorders including ADHD, autism, and schizophrenia in children. Modeling the intergenerationally transmissible impacts of smoking during pregnancy, we previously demonstrated that both the first- and second-generation adolescent offspring of nicotine-exposed female mice exhibit enhanced nicotine preference, hyperactivity and risk-taking behaviors, aberrant rhythmicity of home cage activity, nicotinic acetylcholine receptor and dopamine transporter dysfunction, impaired furin-mediated proBDNF proteolysis, hypocorticosteronemia-related glucocorticoid receptor hypoactivity, and global DNA hypomethylation in the frontal cortices and striata. This ensemble of multigenerational DNE-induced behavioral, neuropharmacological, neurotrophic, neuroendocrine, and DNA methylomic anomalies recapitulates the pathosymptomatology of neurodevelopmental disorders such as ADHD, autism, and schizophrenia. Further probing the epigenetic bases of DNE-induced multigenerational phenotypic aberrations, the present study examined the expression and phosphorylation of key epigenetic factors via an array of immunoblot experiments. RESULTS:Data indicate that DNE confers intergenerational deficits in corticostriatal DNA methyltransferase 3A (DNMT3A) expression accompanied by downregulation of methyl-CpG-binding protein 2 (MeCP2) and histone deacetylase 2 (HDAC2) in the frontal cortices and hippocampi, while the expression of ten-eleven translocase methylcytosine dioxygenase 2 (TET2) is unaltered. Moreover, DNE evokes multigenerational abnormalities in HDAC2 (Ser394) but not MeCP2 (Ser421) phosphorylation in the frontal cortices, striata, and hippocampi. CONCLUSIONS:In light of the extensive gene regulatory roles of DNMT3A, MeCP2, and HDAC2, the findings of this study that DNE elicits downregulation and aberrant posttranslational modification of these factors in both first- and second-generation DNE mice suggest that epigenetic perturbations may constitute a mechanistic hub for the intergenerational transmission of DNE-induced neurodevelopmental disorder-like phenotypes.

Dataset Information

Choline ameliorates adult learning deficits and reverses epigenetic modification of chromatin remodeling factors related to adolescent nicotine exposure.

Publications

Choline ameliorates adult learning deficits and reverses epigenetic modification of chromatin remodeling factors related to adolescent nicotine exposure.

Similar Datasets

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