Paternal stress exposure alters sperm microRNA content and reprograms offspring HPA stress axis regulation.
Paternal stress exposure alters sperm microRNA content and reprograms offspring HPA stress axis regulation.
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DOI：
10.1523/jneurosci.0914-13.2013
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发表时间：
2013-05-22
期刊：
影响因子：
--
通讯作者：
Bale TL
中科院分区：
文献类型：
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作者：
Rodgers AB;Morgan CP;Bronson SL;Revello S;Bale TL
神经精神疾病经常表现为HPA应激轴的潜在低反应性或高反应性，这表明该回路对外部干扰的异常脆弱性。父母终生暴露于环境挑战与后代神经精神疾病风险增加有关，并可能导致压力失调。虽然母亲的影响已被广泛研究，少得多的是已知的父亲因素的具体作用。为了研究父系压力可能导致后代下丘脑-垂体-肾上腺（HPA）轴失调的潜在机制，我们在繁殖前将小鼠暴露于6周的慢性压力中。由于流行病学研究支持父源生殖细胞在整个生命周期中对重编程的易感性的变化，男性压力暴露发生在整个青春期或成年期。值得注意的是，来自两个父系压力组的公畜的后代表现出显着降低的HPA轴压力反应性。在后代压力调节脑区，室旁核（PVN）和终纹床核（BNST）的基因集富集分析，揭示了全球模式的变化，转录暗示表观遗传重编程和改变后代的压力反应，包括增加糖皮质激素反应基因的表达PVN一致。在研究生殖细胞传播的潜在表观遗传机制时，我们发现精子miRNA（miR）含量发生了显著变化，其中9种特定的miR在两个父亲压力组中显著增加。总的来说，这些结果表明，整个生命周期的父亲的经验可以诱导生殖细胞表观遗传重编程和影响后代HPA应激轴调节，因此可能提供新的见解影响神经精神疾病的风险因素。
Neuropsychiatric disease frequently presents with an underlying hypo- or hyper- reactivity of the HPA stress axis, suggesting an exceptional vulnerability of this circuitry to external perturbations. Parental lifetime exposures to environmental challenges are associated with increased offspring neuropsychiatric disease risk, and likely contribute to stress dysregulation. While maternal influences have been extensively examined, much less is known regarding the specific role of paternal factors. To investigate the potential mechanisms by which paternal stress may contribute to offspring hypothalamic-pituitary-adrenal (HPA) axis dysregulation, we exposed mice to six weeks of chronic stress prior to breeding. As epidemiological studies support variation in paternal germ cell susceptibility to reprogramming across the lifespan, male stress exposure occurred either throughout puberty or in adulthood. Remarkably, offspring of sires from both paternal stress groups displayed significantly reduced HPA axis stress responsivity. Gene set enrichment analyses in offspring stress regulating brain regions, the paraventricular nucleus (PVN) and the bed nucleus of stria terminalis (BNST), revealed global pattern changes in transcription suggestive of epigenetic reprogramming and consistent with altered offspring stress responsivity, including increased expression of glucocorticoid-responsive genes in the PVN. In examining potential epigenetic mechanisms of germ cell transmission, we found robust changes in sperm miRNA (miR) content, where nine specific miRs were significantly increased in both paternal stress groups. Overall, these results demonstrate that paternal experience across the lifespan can induce germ cell epigenetic reprogramming and impact offspring HPA stress axis regulation, and may therefore offer novel insight into factors influencing neuropsychiatric disease risk.