Prenatal dexamethasone exposure in the common marmoset monkey enhances gene expression of antioxidant enzymes in the aorta of adult offspring

Abstract

Human epidemiological studies have indicated that low birth weight associated with an adverse intrauterine environment is related to a greater incidence of cardiovascular disorders in later life. In the foetus, endogenous glucocorticoids generally increase if there is intrauterine nutrient deficiency. The consequent glucocorticoid hyperexposure has been hypothesised to cause in utero programming of atherogenic genes. We investigated the effect of oral treatment with the synthetic glucocorticoid dexamethasone during early or late pregnancy in marmoset monkeys on oxidative and antioxidant status in the offspring. Urinary concentrations of F2-isoprostanes were quantified as markers for in vivo oxidative stress. Expression of the mRNAs for the antioxidant enzymes cytosolic glutathione peroxidase (GPx-1), phospholipid hydroperoxide glutathione peroxidase (GPx-4), cytosolic Cu,Zn-superoxide dismutase (SOD1), mitochondrial Mn-superoxide dismutase (SOD2), glutathione reductase (GSR), modifier subunit of glutamate-cysteine ligase (GCLM) and catalase were determined in the aorta. Three groups of pregnant marmosets (10 animals per group) were treated orally for one week with vehicle, or with dexamethasone (5mg/kg daily) during two gestation windows: early dexamethasone group, pregnancy day 42-48, and late dexamethasone group, pregnancy day 90-96. In one male sibling of each litter (10 males per group), aortas were taken at 2 years of age. In the late dexamethasone group a higher aortic mRNA expression for GPx-1 (p0.023), MnSOD (p0.016), GCLM (p0.019) and GSR (p0.014) in comparison to the controls was observed. Aortic expression in the early dexamethasone group was statistically significantly higher only for GSR mRNA (p0.038). No significant changes in urinary F2-isoprostane concentrations between controls, early and late dexamethasone groups at 2 years of age were observed. Hence, prenatal exposure to dexamethasone in the third trimester leads to increased mRNA expression of several aortic antioxidant enzymes in the offspring. This expression pattern was not temporally related to oxidative stress, and it may reflect in utero re-programming of aortic antioxidant gene expression during prenatal glucocorticoid exposure.