Kapoor Amita, Leen Jason, Matthews Stephen G
Department of Physiology, Faculty of Medicine, University of Toronto, Medical Sciences Building, 1 King's College Circle, Toronto, Ontario, Canada, M5S 1A8.
J Physiol. 2008 Sep 1;586(17):4317-26. doi: 10.1113/jphysiol.2008.153684. Epub 2008 Jul 17.
Studies in humans and animals have demonstrated that maternal stress during fetal development can lead to altered hypothalamic-pituitary-adrenal (HPA) axis function and behaviour postnatally. We have previously shown adult male guinea pigs that were born to mothers exposed to a stressor during the phase of rapid fetal brain growth (gestational days (GD) 50, 51 and 52; prenatal stress (PS)50) exhibit significantly increased basal plasma cortisol levels. In contrast, male guinea pig offspring whose mothers were exposed to stress later in gestation (GD60, 61 and 62; PS60) exhibited a significantly higher plasma cortisol response to activation of the HPA axis. In the present study, we hypothesized that the endocrine changes in HPA axis function observed in male guinea pig offspring would be reflected by altered molecular regulation of the HPA axis. Corticosteroid receptors in the hippocampus, hypothalamus and pituitary were measured, as well as corticotropin-releasing hormone (CRH), pro-opiomelanocortin (POMC) and adrenal enzymes in the paraventricular nucleus, pituitary and adrenal cortex, respectively, by in situ hybridization and Western blot. PS50 male offspring exhibited a significant reduction in glucocorticoid receptor (GR) mRNA (P <0.01) in the CA3 region of the hippocampus and significantly increased POMC mRNA (P <0.05) in the pituitary, consistent with the increase in basal HPA axis activity observed. In line with elevated activity of the HPA axis, both PS50 and PS60 male offspring exhibited significantly higher steroidogenic factor (SF)-1 (P <0.001) and melanocortin 2 receptor (MC2-R) mRNA (P <0.001) in the adrenal cortex. This study demonstrates that short periods of prenatal stress during critical windows of neuroendocrine development affect the expression of key regulators of HPA axis activity leading to the changes in endocrine function observed in prenatally stressed male offspring. Further, these changes are dependent on the timing of the maternal stressor, a pattern that is emerging in human studies.
对人类和动物的研究表明，胎儿发育期间母体应激可导致出生后下丘脑 - 垂体 - 肾上腺（HPA）轴功能和行为改变。我们之前已经表明，在胎儿脑快速生长阶段（妊娠第50、51和52天；产前应激（PS）50）其母亲暴露于应激源的成年雄性豚鼠，表现出基础血浆皮质醇水平显著升高。相比之下，其母亲在妊娠后期（妊娠第60、61和62天；PS60）暴露于应激的雄性豚鼠后代，对HPA轴激活表现出显著更高的血浆皮质醇反应。在本研究中，我们假设在雄性豚鼠后代中观察到的HPA轴功能的内分泌变化将通过HPA轴分子调节的改变而反映出来。通过原位杂交和蛋白质免疫印迹分别测量海马体、下丘脑和垂体中的皮质类固醇受体，以及室旁核、垂体和肾上腺皮质中的促肾上腺皮质激素释放激素（CRH）、阿黑皮素原（POMC）和肾上腺酶。PS50雄性后代在海马体CA3区的糖皮质激素受体（GR）mRNA显著降低（P<0.01），而垂体中POMC mRNA显著增加（P<0.05），这与观察到的基础HPA轴活性增加一致。与HPA轴活性升高一致，PS50和PS60雄性后代在肾上腺皮质中均表现出显著更高的类固醇生成因子（SF）-1（P<0.001）和促黑素细胞激素2受体（MC2-R）mRNA（P<0.001）。本研究表明，神经内分泌发育关键窗口期的短期产前应激会影响HPA轴活性关键调节因子的表达，导致在产前应激雄性后代中观察到的内分泌功能变化。此外，这些变化取决于母体应激源的时间，这一模式在人类研究中也逐渐显现。
