Perinatal exposure to nicotine alters spermatozoal DNA methylation near genes controlling nicotine action.
Perinatal exposure to nicotine alters spermatozoal DNA methylation near genes controlling nicotine action.
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DOI：
10.1096/fj.202100215r
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发表时间：
2021-07
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围产期烟雾/尼古丁暴露会改变肺部发育，并导致暴露的后代出现哮喘，并跨代传播。围产期烟雾/尼古丁诱发的哮喘跨代遗传的机制仍不清楚，但种系表观遗传调节可能发挥作用。使用成熟的围产期尼古丁诱发哮喘大鼠模型，我们确定了 F0 妊娠围产期暴露于尼古丁的 F1 大鼠精子的 DNA 甲基化模式。为了识别差异甲基化区域 (DMR)，对 F1 窝的精子进行了简化代表性亚硫酸氢盐测序。测试了顶部调控基因体和启动子DMR的肺基因表达水平，并确定了参与肺发育和修复的关键蛋白。 F1 精子中基因体、启动子、5'-UTR、外显子、内含子和 3'-UTR 的总体 CpG 甲基化不受尼古丁暴露的影响。然而，不同基因组区域之间的甲基化水平不同。 81 个 CpG 位点、16 个基因体和 3 个启动子区域被差异甲基化。 DMR 的基因富集分析揭示了参与氧化应激、尼古丁反应、肺泡和大脑发育以及细胞信号传导的途径。在 DMR 中，Dio1 和 Nmu 分别是甲基化程度最高和甲基化程度最低的基因。基因表达分析显示mRNA表达和DNA甲基化不一致。尼古丁治疗组和安慰剂治疗组之间参与肺发育和修复的关键蛋白质存在显着差异（FDR < 0.05）。我们的数据表明，在围产期接触尼古丁后，后代精子中的 DNA 甲基化发生了重塑。这些表观遗传改变可能在围产期烟雾/尼古丁诱发哮喘的跨代遗传中发挥作用。
Perinatal smoke/nicotine exposure alters lung development and causes asthma in exposed offspring, transmitted transgenerationally. The mechanism underlying the transgenerational inheritance of perinatal smoke/nicotine-induced asthma remains unknown, but germline epigenetic modulations may play a role. Using a well-established rat model of perinatal nicotine-induced asthma, we determined the DNA methylation pattern of spermatozoa of F1 rats exposed perinatally to nicotine in F0 gestation. To identify differentially methylated regions (DMRs), reduced representation bisulfite sequencing was performed on spermatozoa of F1 litters. The top regulated gene body and promoter DMRs were tested for lung gene expression levels, and key proteins involved in lung development and repair were determined. The overall CpG methylation in F1 sperms across gene bodies, promoters, 5′-UTRs, exons, introns, and 3′-UTRs was not affected by nicotine exposure. However, the methylation levels were different between the different genomic regions. Eighty one CpG sites, 16 gene bodies, and 3 promoter regions were differentially methylated. Gene enrichment analysis of DMRs revealed pathways involved in oxidative stress, nicotine response, alveolar and brain development, and cellular signaling. Among the DMRs, Dio1 and Nmu were the most hypermethylated and hypomethylated genes, respectively. Gene expression analysis showed that the mRNA expression and DNA methylation were incongruous. Key proteins involved in lung development and repair were significantly different (FDR < 0.05) between the nicotine and placebo-treated groups. Our data show that DNA methylation is remodeled in offspring spermatozoa upon perinatal nicotine exposure. These epigenetic alterations may play a role in transgenerational inheritance of perinatal smoke/nicotine induced asthma.