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

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.