Seckl Jonathan R, Holmes Megan C
College of Medicine and Veterinary Medicine, University of Edinburgh, UK.
Nat Clin Pract Endocrinol Metab. 2007 Jun;3(6):479-88. doi: 10.1038/ncpendmet0515.
Epidemiological evidence suggests that an adverse prenatal environment permanently 'programs' physiology and increases the risk of cardiovascular, metabolic, neuroendocrine and psychiatric disorders in adulthood. Prenatal stress or exposure to excess glucocorticoids might provide the link between fetal maturation and adult pathophysiology. In a variety of animal models, prenatal stress, glucocorticoid exposure and inhibition (or knockout of) 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2)--the fetoplacental barrier to maternal glucocorticoids--reduce birth weight and cause increases in adult blood pressure, glucose levels, hypothalamic-pituitary-adrenal (HPA) axis activity and anxiety-related behaviors. In humans, mutations in the gene that encodes 11beta- hydroxysteroid dehydrogenase type 2 are associated with low birth weight. Babies with low birth weight have higher plasma cortisol levels throughout life, which indicates HPA-axis programming. In human pregnancy, severe maternal stress affects the offspring's HPA axis and is associated with neuropsychiatric disorders; moreover, maternal glucocorticoid therapy alters offspring brain function. The molecular mechanisms that underlie prenatal programming might reflect permanent changes in the expression of specific transcription factors, including the glucocorticoid receptor; tissue specific effects reflect modification of one or more of the multiple alternative first exons or promoters of the glucocorticoid receptor gene. Intriguingly, some of these effects seem to be inherited by subsequent generations that are unexposed to exogenous glucocorticoids at any point in their lifespan from fertilization, which implies that these epigenetic effects persist.
流行病学证据表明，不良的产前环境会永久性地“设定”生理机能，并增加成年后患心血管、代谢、神经内分泌和精神疾病的风险。产前应激或暴露于过量糖皮质激素可能是胎儿成熟与成年期病理生理学之间的联系。在多种动物模型中，产前应激、糖皮质激素暴露以及抑制（或敲除）2型11β-羟类固醇脱氢酶（11β-HSD2）——胎儿胎盘对母体糖皮质激素的屏障——会降低出生体重，并导致成年后血压升高、血糖水平升高、下丘脑-垂体-肾上腺（HPA）轴活性增加以及与焦虑相关的行为增加。在人类中，编码2型11β-羟类固醇脱氢酶的基因突变与低出生体重有关。低出生体重的婴儿一生中血浆皮质醇水平较高，这表明HPA轴被设定。在人类妊娠中，母亲的严重应激会影响后代的HPA轴，并与神经精神疾病有关；此外，母亲的糖皮质激素治疗会改变后代的脑功能。产前设定背后的分子机制可能反映了特定转录因子（包括糖皮质激素受体）表达的永久性变化；组织特异性效应反映了糖皮质激素受体基因多个可变的首个外显子或启动子中一个或多个的修饰。有趣的是，其中一些效应似乎会被随后几代继承，这些后代在从受精开始的整个生命周期中任何时候都未接触过外源性糖皮质激素，这意味着这些表观遗传效应会持续存在。
