Seckl Jonathan R, Meaney Michael J
Endocrinology Unit, Centre for Cardiovascular Science, Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK.
Ann N Y Acad Sci. 2006 Jul;1071:351-78. doi: 10.1196/annals.1364.027.
Epidemiological data have linked an adverse fetal environment with increased risks of cardiovascular, metabolic, neuroendocrine, and psychiatric disorders in adulthood. Prenatal stress and/or glucocorticoid excess might underlie this link. In animal models, prenatal stress, glucocorticoid exposure or inhibition/knockout of 11 beta-hydroxysteroid dehydrogenase type 2 (11 beta-HSD-2), the feto-placental barrier to maternal glucocorticoids, reduces birth weight and causes permanent hypertension, hyperglycemia, increased hypothalamic-pituitary-adrenal (HPA) axis activity and behavior resembling of anxiety. In humans, 11 beta-HSD-2 gene mutations cause low birth weight and placental 11 beta-HSD-2 activity correlates directly with birth weight and inversely with infant blood pressure. Low birth weight babies have higher plasma cortisol levels throughout adult life, indicating HPA programming. In human pregnancy, severe maternal stress affects the offspring HPA axis and associates with neuropsychiatric disorders. Posttraumatic stress disorder (PTSD) appears to be a variable in the effects. Intriguingly, some of these effects appear to be 'inherited' into a further generation, itself unexposed to exogenous glucocorticoids at any point in the lifespan from fertilization, implying epigenetic marks persist into subsequent generation(s). Overall, the data suggest that prenatal exposure to excess glucocorticoids programs peripheral and CNS functions in adult life, predisposing to some pathologies, perhaps protecting from others, and these may be transmitted perhaps to one or two subsequent generations.
流行病学数据显示，不良的胎儿环境与成年后患心血管疾病、代谢紊乱、神经内分泌失调和精神疾病的风险增加有关。产前应激和/或糖皮质激素过量可能是这种关联的潜在原因。在动物模型中，产前应激、糖皮质激素暴露或抑制/敲除2型11β-羟类固醇脱氢酶（11β-HSD-2）（这是胎儿-胎盘对母体糖皮质激素的屏障）会降低出生体重，并导致永久性高血压、高血糖、下丘脑-垂体-肾上腺（HPA）轴活性增加以及类似焦虑的行为。在人类中，11β-HSD-2基因突变会导致低出生体重，胎盘11β-HSD-2活性与出生体重直接相关，与婴儿血压呈负相关。低出生体重儿在整个成年期血浆皮质醇水平较高，表明HPA轴编程异常。在人类妊娠中，严重的母体应激会影响后代的HPA轴，并与神经精神疾病有关。创伤后应激障碍（PTSD）似乎是这些影响中的一个变量。有趣的是，其中一些影响似乎会“遗传”给下一代，而下一代在从受精开始的整个生命周期中都未接触过外源性糖皮质激素，这意味着表观遗传标记会持续到后代。总体而言，数据表明产前暴露于过量糖皮质激素会对成年后的外周和中枢神经系统功能进行编程，使人易患某些疾病，也许对另一些疾病有保护作用，并且这些影响可能会传递给一到两代后代。
