Early prenatal stress epigenetically programs dysmasculinization in second-generation offspring via the paternal lineage.
Early prenatal stress epigenetically programs dysmasculinization in second-generation offspring via the paternal lineage.
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DOI：
10.1523/jneurosci.1887-11.2011
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发表时间：
2011-08-17
期刊：
影响因子：
--
通讯作者：
Bale TL
中科院分区：
文献类型：
--
作者：
Morgan CP;Bale TL
研究表明，有性别偏见的神经发育障碍，包括自闭症和精神分裂症，与胎儿的前因，如产前压力有关。此外，这些结果可能会持续到后代，这增加了这些疾病的遗传性方面涉及表观遗传机制的可能性。利用小鼠模型，我们以前确定了一个时期，在妊娠早期，压力的结果在dysmasculinized和压力敏感的雄性后代，我们已经研究了编程的影响，在第二代后代的产前强调（F2-S）或控制（F2-C）公畜。在围产期的敏感期，组织性腺激素建立的性别二态性大脑的基因表达模式的检查，证实dysmasculinization在F2-S男性神经发育中的重要基因表现出女性样的模式。表观基因组miRNA环境的分析检测到F2-S雄性大脑中miR-322、miR-574和miR-873的显著减少，这些水平再次与对照雌性的水平更相似。在这些雄性动物中证实了这3种miRNA的共同基因靶点β-聚糖的表达增加。这些发展的影响与压力敏感的表型和缩短肛门生殖器的距离在成年F2-S男性的传输。作为miRNA环境对组织睾酮的响应的确认，给予芳香酶抑制剂福美司坦的新生男性表现出大脑miRNA模式的显著变化，表明miRNA可能在组织性二态性大脑中起着以前未被认识到的作用。总的来说，这些数据支持存在一个敏感的妊娠早期，当男性生殖系的表观遗传编程可以发生，允许特定的表型传递到后代。
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 3 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 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.