Developmental nicotine exposure engenders intergenerational downregulation and aberrant posttranslational modification of cardinal epigenetic factors in the frontal cortices, striata, and hippocampi of adolescent mice
Developmental nicotine exposure engenders intergenerational downregulation and aberrant posttranslational modification of cardinal epigenetic factors in the frontal cortices, striata, and hippocampi of adolescent mice
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DOI：
10.1186/s13072-020-00332-0
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发表时间：
2020-03-05
影响因子：
3.9
通讯作者：
Stitzel, Jerry A.
中科院分区：
文献类型：
--
作者：
Buck, Jordan M.;O'Neill, Heidi C.;Stitzel, Jerry A.
孕妇在怀孕期间吸传统烟或电子烟，构成发育性尼古丁暴露（DNE），增加了儿童患多动症、自闭症和精神分裂症等神经发育障碍的风险。在对怀孕期间吸烟的代际传播影响进行建模时，我们之前已经证明，尼古丁暴露的雌性小鼠的第一代和第二代青春期后代都表现出增强的尼古丁偏好、多动和冒险行为、家笼活动的异常节律、尼古丁乙酰胆碱受体和多巴胺转运蛋白功能障碍、furin介导的proBDNF蛋白水解受损。低皮质酮血症相关的糖皮质激素受体活性降低，以及额叶皮质和纹状体的整体DNA低甲基化。这种多代DNA诱导的行为、神经药理学、神经营养、神经内分泌和DNA甲基化异常的集合概括了神经发育障碍（如ADHD、自闭症和精神分裂症）的病理症状。为了进一步探究dna诱导的多代表型畸变的表观遗传基础，本研究通过一系列免疫印迹实验检测了关键表观遗传因子的表达和磷酸化。结果数据表明，DNE导致皮质纹状体DNA甲基转移酶3A （DNMT3A）表达的代际缺陷，并伴有额叶皮质和海马中甲基cpg结合蛋白2 （MeCP2）和组蛋白去乙酰化酶2 （HDAC2）的下调，而10 - 11转位酶甲基胞嘧啶双加氧酶2 （TET2）的表达不变。此外，DNE会引起HDAC2 （Ser(394)）磷酸化的多代异常，但不会引起额叶皮质、纹状体和海马体中MeCP2 （Ser(421)）磷酸化的多代异常。鉴于DNMT3A、MeCP2和HDAC2广泛的基因调控作用，本研究发现DNE在第一代和第二代DNE小鼠中均引起这些因子的下调和异常的翻译后修饰，这表明表观遗传扰动可能构成了DNE诱导的神经发育障碍样表型代际传递的机制枢纽。
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 (Ser(394)) but not MeCP2 (Ser(421)) 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.