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首页> 美国卫生研究院文献>The Journal of Neuroscience >Early Prenatal Stress Epigenetically Programs Dysmasculinization in Second-Generation Offspring via the Paternal Lineage
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Early Prenatal Stress Epigenetically Programs Dysmasculinization in Second-Generation Offspring via the Paternal Lineage

机译：早期产前应激通过父系沿袭在第二代后代中进行男性化

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Studies have linked sex-biased neurodevelopmental disorders, including autism and schizophrenia, with fetal antecedents such as prenatal stress. Further, these outcomes can persist into subsequent generations, raising the possibility that aspects of heritability in these diseases involve epigenetic mechanisms. Utilizing a mouse model in which we previously identified a period in early gestation when stress results in dysmasculinized and stress-sensitive male offspring, we have examined programming effects in second-generation offspring of prenatally stressed (F2-S) or control (F2-C) sires. Examination of gene expression patterns during the perinatal sensitive period, when organizational gonadal hormones establish the sexually dimorphic brain, confirmed dysmasculinization in F2-S males, where genes important in neurodevelopment showed a female-like pattern. Analyses of the epigenomic miRNA environment detected significant reductions in miR-322, miR-574, and miR-873 in the F2-S male brain, levels that were again more similar to those of control females. Increased expression of a common gene target for these three miRNAs, β-glycan, was confirmed in these males. These developmental effects were associated with the transmission of a stress-sensitive phenotype and shortened anogenital distance in adult F2-S males. As confirmation that the miRNA environment is responsive to organizational testosterone, neonatal males administered the aromatase inhibitor formestane exhibited dramatic changes in brain miRNA patterns, suggesting that miRNAs may serve a previously unappreciated role in organizing the sexually dimorphic brain. Overall, these data support the existence of a sensitive period of early gestation when epigenetic programming of the male germline can occur, permitting transmission of specific phenotypes into subsequent generations.
机译：研究已将包括自闭症和精神分裂症在内的性别偏向性神经发育障碍与胎儿前因（如产前压力）联系起来。此外，这些结果可以持续到后代，增加了这些疾病的遗传学方面涉及表观遗传机制的可能性。利用小鼠模型，我们先前确定了应激会导致男性化和对压力敏感的雄性后代的早期妊娠期，我们研究了在产前应激（F2-S）或对照（F2-C）的第二代后代中的编程作用）的父亲。在围产期敏感时期，当组织性腺激素建立了性二形性大脑时，对基因表达模式的检查证实了F2-S雄性的男性不正常，其中对神经发育重要的基因呈雌性样。表观基因组miRNA环境的分析检测到F2-S男性大脑中的miR-322，miR-574和miR-873显着降低，其水平再次与对照女性相似。在这些雄性中证实了这三个miRNA的共同基因靶标β-聚糖的表达增加。这些发育效应与成年F2-S雄性的压力敏感表型的传播和缩短的生殖器距离有关。作为证实miRNA环境对组织睾丸激素有反应的证据，使用芳香化酶抑制剂福尔马坦的新生男性在大脑miRNA模式上表现出了巨大的变化，这表明miRNA在组织性二态性大脑中可能起着以前未被认识的作用。总体而言，这些数据支持当雄性种系可以进行表观遗传编程时允许存在一个敏感的早期妊娠期，从而允许将特定的表型传递给后代。

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