Sex-specific programming of offspring emotionality after stress early in pregnancy.
Sex-specific programming of offspring emotionality after stress early in pregnancy.
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DOI：
10.1523/jneurosci.1424-08.2008
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发表时间：
2008-09-03
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：
Mueller BR;Bale TL
产前压力与神经发育障碍的易感性增加有关，包括自闭症和精神分裂症。为了确定胎儿前因可能诱导疾病易感性的关键时间窗口，我们研究了妊娠早期、中期和晚期暴露于压力的后代的行为反应。我们发现，男性后代在妊娠早期暴露于压力下，表现出适应不良的行为压力反应，快感缺乏，以及对SSRI治疗的敏感性增加。在这些小鼠中，中枢促肾上腺皮质激素释放因子（CRF）和糖皮质激素受体（GR）表达的长期改变，以及HPA轴反应性的增加，可能导致应激敏感性升高。CRF和GR基因甲基化的变化与基因表达的改变相关，为早期产前应激过程中表观遗传编程提供了重要证据。此外，我们发现男性脆弱性的核心机制可能涉及性别特异性胎盘反应性，妊娠早期的应激显著增加男性胎盘中的PPARα，IGFBP-1，HIF 3 α和GLUT 4的表达，而不是女性。胎盘表观遗传机制的检查揭示了基础的性别差异，提供了进一步的证据表明，性别特异性编程在妊娠早期就开始了，并可能有助于发育中的胎儿对母体扰动的时间和脆弱性。总体而言，这些结果表明，压力的经验，在怀孕早期可能有助于通过影响胎盘功能和胎儿发育的男性神经发育障碍。
Prenatal stress is associated with an increased vulnerability to neurodevelopmental disorders, including autism and schizophrenia. To determine the critical time window when fetal antecedents may induce a disease predisposition, we examined behavioral responses in offspring exposed to stress during early, mid, and late gestation. We found that male offspring exposed to stress early in gestation displayed maladaptive behavioral stress-responsivity, anhedonia, and an increased sensitivity to SSRI treatment. Long-term alterations in central corticotropin-releasing factor (CRF) and glucocorticoid receptor (GR) expression, as well as increased HPA axis responsivity were present in these mice and likely contributed to an elevated stress-sensitivity. Changes in CRF and GR gene methylation correlated with altered gene expression, providing important evidence of epigenetic programming during early prenatal stress. In addition, we found the core mechanism underlying male vulnerability may involve sex-specific placenta responsivity, where stress early in pregnancy significantly increased expression of PPARα, IGFBP-1, HIF3α, and GLUT4 in male placentas but not females. Examination of placental epigenetic machinery revealed basal sex-differences, providing further evidence that sex-specific programming begins very early in pregnancy, and may contribute to the timing and vulnerability of the developing fetus to maternal perturbations. Overall, these results indicate that stress experience early in pregnancy may contribute to male neurodevelopmental disorders through impacts on placental function and fetal development.