Periconceptional ethanol exposure alters the stress axis in adult female but not male rat offspring

Abstract

Abstract Ethanol consumption during pregnancy alters offspring hypothalamus–pituitary–adrenal (HPA) axis regulation. However, little is known about the outcomes of alcohol consumption confined to the periconceptional period. This study investigated the effects of periconceptional ethanol (PC:EtOH) exposure on corticosterone concentrations, response to restraint stress and gene expression of adrenal, hypothalamic, and hippocampal glucocorticoid-related pathways in rat offspring. Female Sprague-Dawley rats were treated with PC:EtOH (12.5% v/v EtOH liquid diet) or a control diet from four days before conception, until embryonic day 4. At 6 (adult) and 12–14 (aged) months of age, basal corticosterone concentrations were measured, while in a separate cohort of aged rats, blood pressure, heart rate, and plasma corticosterone concentrations were measured during a 30-minute restraint stress. Adrenal gland, hypothalamic and hippocampal tissue from aged rats were subjected to transcriptomic analysis. PC:EtOH exposure reduced basal plasma corticosterone concentrations in adult and aged female but not male offspring (p < .05). The corticosterone and pressor response were significantly reduced in aged PC:EtOH female offspring following restraint (p < .05). Expression of adrenal steroidogenesis genes (Mc2r, Cyp11a1, Cyp21a1, 11bhsd2, and Nr3c1) and hypothalamic genes (Crh, Crh-r1, Nr3c1, and Hsp90a1) was not affected by PC:EtOH. In aged female offspring exposed to PC:EtOH, adrenal mRNA expression of Hsp90a1 was significantly elevated, and within the hippocampus, mRNAs for glucocorticoid receptor (Nr3c1) and Hsp90a1 were increased (p < .05). This study supports the hypothesis that prenatal alcohol exposure programs sex-specific alterations in the HPA axis and provides the first evidence that the periconceptional period is a critical window for programing of this axis. Lay summary This study investigated the impact of alcohol consumption around the time of conception on offspring stress reactivity in a rat model. Offspring exposed to alcohol displayed altered cardiovascular responses to stress and had reduced circulating concentrations of the stress hormone corticosterone both under basal conditions and following a stressful challenge. This study also identified altered expression of key genes in an important part of the brain known to be involved in stress responsiveness; the hippocampus. If similar outcomes occur in humans, these results would suggest that alcohol consumption, even before a woman knows she is pregnant, may significantly impact stress-related outcomes in children.