Prenatal Alcohol Exposure Alters Response of Kisspeptin-ir Neurons to Estradiol and Progesterone in Adult Female Rats

BackgroundPrenatal alcohol exposure (PAE) has adverse effects on reproductive function and hypothalamic-pituitary-gonadal (HPG) activity. Kisspeptin neurons play a role in mediating feedback effects of estradiol (E-2) and progesterone (P-4) on the HPG axis. We hypothesized that PAE will have long-term effects on the response of kisspeptin neurons to E-2 and P-4. MethodsAdult female rats (53 to 58days) from prenatal ad libitum-fed control (C), pair-fed (PF), and alcohol-exposed (PAE) groups were subjected to Sham ovariectomy (OVX) or OVX without or with replacement with low or high physiological levels of E-2 and P-4, and terminated under basal conditions. E-2 and P-4 levels, and the response of kisspeptin-ir neurons in the arcuate (ARC) and anteroventral periventricular (AVPV) nuclei to these hormones, were measured. As the E-2 signal is conveyed to kisspeptin neurons via estrogen receptor- (ER-), we investigated PAE effects on the number of kisspeptin-ir/ER--ir neurons. To determine whether PAE alters interactions between kisspeptin and gonadotropin-releasing hormone (GnRH) neurons, close contacts between kisspeptin-ir fibers and GnRH-ir cell bodies were examined. ResultsOur data present the novel finding that kisspeptin-ir neurons in the ARC of PAE females show differential responses to E-2 and to the combined treatment with E-2 and P-4 compared with controls: (i) OVX increased the number of kisspeptin-ir neurons in C and PF, but not PAE females compared with their Sham counterparts; (ii) E-2 replacement restored kisspeptin-ir cell numbers to Sham levels in C and PF females but caused a robust down-regulation of kisspeptin-ir neurons below Sham levels in PAE females; (iii) OVX and replacement with high physiological concentrations of E-2 resulted in fewer kisspeptin-ir cells in PAE than C females; (iv) OVX and replacement with high levels of both E-2 and P-4 markedly decreased the number of kisspeptin-ir neurons, below levels observed following E-2 alone, in PF and C females, but had no significant effect in PAE females. ConclusionsThese data suggest that a possible mechanism underlying adverse effects of PAE on HPG function involves actions of alcohol on the kisspeptin system.