ИСТИНА

Prenatal hypoxia (PH) is a risk factor of numerous neurological disorders. Maternal stress response to hypoxia determines the epigenetic impairment of the perinatal expression of glucocorticoid receptors (GR) in the hippocampus of the progeny, but so far no detailed study of how this affects the functional state of the glucocorticoid system during further ontogenesis has been performed. The aim of this study was to examine the long-term effects of the PH on functioning of the glucocorticoid system throughout life. PH was induced at days 14-16 of gestation (180 Torr, 5% oxygen, 3 hours). The activity of the glucocorticoid system was assessed in newborn, juvenile, adult, and aged male rats. The PH resulted in continuously elevated baseline corticosterone blood levels in the adult and aged rats. The chronic elevation of the corticosterone levels was accompanied by a progressive deficit of the GR expression in the liver, increased hepatic glycogen content, dysregulated glucose-6-phosphatase activity and hypoglycemia. Elevated corticosterone appears to result from the impairment of the mechanisms of glucocorticoid negative feedback since substantial decrease in both total number of GR and their nuclear localization was observed already in the hippocampus of newborn rat pups and persisted throughout the life. Corresponding stable hippocampal down-regulation of GR-dependent genes was observed as well. Suppression of maternal glucocorticoid stress response to hypoxia by metyrapone injection to pregnant rats prior to each hypoxic challenge considerably reduced corticosterone over-response to hypoxia and prevented reduced hippocampal GR. Our findings demonstrate that in progeny a deficit of hippocampal GR resulting from maternal glucocorticoid response to hypoxia remains stable throughout the life and is accompanied by severe disturbances of baseline glucocorticoid levels and its peripheral reception. Negative consequences of PH can be prevented by injection with an inhibitor of corticosterone synthesis (metyrapone) to pregnant females undergoing hypoxia.