Prenatal alcohol exposure: foetal programming, the hypothalamic-pituitary-adrenal axis and sex differences in outcome

Abstract

Prenatal exposure to alcohol has adverse effects on offspring neuroendocrine and behavioural functions. Alcohol readily crosses the placenta, thus directly affecting developing foetal endocrine organs. In addition, alcohol-induced changes in maternal endocrine function can disrupt the normal hormonal interactions between the pregnant female and foetal systems, altering the normal hormone balance and, indirectly, affecting the development of foetal metabolic, physiological and endocrine functions. The present review focuses on the adverse effects of prenatal alcohol exposure on offspring neuroendocrine function, with particular emphasis on the hypothalamic-pituitary-adrenal (HPA) axis, a key player in the stress response. The HPA axis is highly susceptible to programming during foetal and neonatal development. Here, we review data demonstrating that alcohol exposure in utero programmes the foetal HPA axis such that HPA tone is increased throughout life. Importantly, we show that, although alterations in HPA responsiveness and regulation are robust phenomena, occurring in both male and female offspring, sexually dimorphic effects of alcohol are frequently observed. We present updated findings on possible mechanisms underlying differential effects of alcohol on male and female offspring, with special emphasis on effects at different levels of the HPA axis, and on modulatory influences of the hypothalamic-pituitary-gonadal hormones and serotonin. Finally, possible mechanisms underlying foetal programming of the HPA axis, and the long-term implications of increased exposure to endogenous glucocorticoids for offspring vulnerability to illnesses or disorders later in life are discussed.

Fig. 1.

Anterior pituitary corticotrophin-releasing hormone (CRH)-R1 mRNA and pro-opiomelanocortin (POMC) mRNA levels in male and female rats from prenatal alcohol exposure (E), pair-fed (PF) and control (C) groups, 7 days following sham surgery or adrenolectomy (ADX) without or with corticosterone replacement. Values represent the mean ± SEM of 5–6 rats per group. Main effect of prenatal treatment (*E < C, P < 0.05; ^#E < C, P = 0.065). Reprinted with permission [49].

Fig. 2.

Mineralocorticoid receptor (MR) mRNA in prenatal alcohol exposure (E), pair-fed (PF) and control (C) males (a–c) and females (d–f) in dorsal hippocampal subfields CA1a, CA3 and the dentate gyrus (DG), 7 days following sham surgery or adrenolectomy (ADX) without or with corticotrophin (CORT) replacement. Values represent the mean ± SEM of semi-quantitative densitometry of slides hybridized with a ³⁵S-dUTP-labeled riboprobe for MR (n = 4–6 rats per group). *P < 0.05; **P < 0.005; ***P < 0.001 compared to PF and control; ^#P = 0.07 compared to PF; ^{^}P < 0.07 compared to PF and control. Reprinted with permission [49].

Fig. 3.

Working models to illustrate possible effects of testosterone on neuropeptide and steroid receptor expression within the limbic forebrain circuits that project to the mpd PVN in normal (a) and prenatal alcohol exposed (PAE) (b) adult male rats. Findings suggest a reduced capacity for testosterone to regulate corticotrophin-releasing hormone (CRH) mRNA expression in central CRH pathways, but enhanced effects of testosterone on central arginine vasopressin (AVP) pathways in PAE and/or pair-fed (PF) compared to control males. PAE males had lower CRH mRNA levels in the fusiform nucleus of the anterior division of the bed nucleus of stria terminalis (aBNST) and higher CRH mRNA levels in the central nucleus of amygdala (CeA). In addition, basal CRH mRNA levels were increased by GDX in PF and control but not PAE males in the medial parvocellular dorsal part of the paraventricular nucleus (mpd PVN). By contrast, both PAE and PF males showed higher AVP mRNA levels in the posterior division of the BNST (pBNST) following high testosterone replacement compared to either intact or low testosterone replacement conditions, and intact PAE had higher AVP mRNA levels in the medial nucleus of amygdala (MeA) than intact control males. See text for further discussion. CORT, corticosterone; aBNST fu, Fusiform nucleus of the anterior division of the bed nucleus of stria terminalis; MPOA: medial preoptic area; MPN: medial preoptic nucleus; AR: androgen receptor; MR: mineralocorticoid receptor; GR: glucocorticoid receptor; NTS: nucleus of the solitary tract [155].

Fig. 4.

Working model illustrating kisspeptin regulation of the hypothalamic-pituitary-gonadal axis in normal (a) and prenatal alcohol exposure (PAE) (b) adult female rats. Kisspeptin released by neurons in the anteroventral periventricular (AVPV) and arcuate nucleus (ARC) stimulates gonadotrophin-releasing hormone (GnRH) release, which induces the release of luteinising hormone (LH) and follicle-stimualting hormone (FSH). The ovaries respond to gonadotrophins by secreting oestradiol, which feeds back to regulate the activity of kisspeptin neurons, inhibiting kisspeptin expression in the ARC and inducing the expression in the AVPV (modified from Dungan et al., 2006). Adult PAE females had a decreased number of kisspeptin-immunoreactive neurons in the ARC, which would result in less GnRH and LH/FSH release, and decreased stimulation of the ovary. We speculate that PAE females show increased sensitivity to oestradiol, which leads to downregulation of kisspeptin-immunoreactive neurones in the ARC. The role of kisspeptin regulation at the level of AVPV is currently under investigation. See text for further discussion. +, Stimulation; − and − − − −, inhibition; ?, unknown action.