Molecular regulation of the hypothalamic‐pituitary‐adrenal axis in adult male guinea pigs after prenatal stress at different stages of gestation

Abstract

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.

Developmental programming of adult adrenal structure and steroidogenesis: effects of fetal glucocorticoid excess and postnatal dietary omega-3 fatty acids

“…to ACTH). This is consistent with a recent report in the guinea pig showing that prenatal stress resulted in increased adrenal expression of Mc2r mRNA in the offspring (Kapoor et al 2008a). Interestingly, the highn-3 diet appeared to negate this increased adrenal expression of Mc2r, at least in female offspring, consistent with a previous human study showing that a dietary fish oil supplementation limits the adrenal responsiveness to a mental stress (Delarue et al 2003).…”

Early adversity and serotonin transporter genotype interact with hippocampal glucocorticoid receptor mRNA expression, corticosterone, and behavior in adult male rats.

“…Although we expected that prenatal stress would also enhance the corticosterone response in adulthood (Kapoor, Leen, & Matthews, 2008;Welberg, Seckl, & Holmes, 2001), an inhibitory early experience stress effect on CORT, as we reported, is also not without precedent. There are an increasing number of studies now that show in some species and for some paradigms a reduction, rather than an enhancement, in the stress response in adulthood following periods of early prenatal, preweaning, or postweaning "adversity" or stress (Fan, Chen, Jin, & Du, 2009;Glover et al, 2009;Jodi, Maxim, Jamie, & Gina, 2009;Weinstock, 2008).…”

Induction of Tyrosine Hydroxylase Gene Expression by Glucocorticoids in the Perinatal Rat Brain is Age-Dependent

“…Besides, TH transcription is regulated by specific sets of factors in embryonic and adult tissues [62] and the involvement of different transcriptional and post-transcriptional events in the regulation of TH gene expression in fetuses and neonates may also occur [21,63]. Dependence of adverse neurobehavioral outcomes of early life stress events or glucocorticoid exposures from developmental stage was shown recently [14,64,65]. More profound effects of glucocorticoids and a moderate stressor on long-term synaptic and behavioral changes were observed just during the prenatal period of the rapid fetal brain growth.…”