Atanasova S, Wieland E, Schlumbohm C, Korecka M, Shaw L, von Ahsen N, Fuchs E, Oellerich M, Armstrong V
Department of Clinical Chemistry, Georg-August University, Goettingen, Germany.
Stress. 2009 May;12(3):215-24. doi: 10.1080/10253890802305075.
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 F(2)-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 (5 mg/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 (p < 0.023), MnSOD (p < 0.016), GCLM (p < 0.019) and GSR (p < 0.014) in comparison to the controls was observed. Aortic expression in the early dexamethasone group was statistically significantly higher only for GSR mRNA (p < 0.038). No significant changes in urinary F(2)-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.
人类流行病学研究表明，与不良子宫内环境相关的低出生体重与日后心血管疾病的较高发病率有关。在胎儿中，如果存在子宫内营养缺乏，内源性糖皮质激素通常会增加。由此产生的糖皮质激素过度暴露被认为会导致动脉粥样硬化基因的子宫内编程。我们研究了在狨猴怀孕早期或晚期口服合成糖皮质激素地塞米松对后代氧化和抗氧化状态的影响。将尿中F(2)-异前列腺素的浓度定量作为体内氧化应激的标志物。测定主动脉中抗氧化酶胞质谷胱甘肽过氧化物酶（GPx-1）、磷脂氢过氧化物谷胱甘肽过氧化物酶（GPx-4）、胞质铜锌超氧化物歧化酶（SOD1）、线粒体锰超氧化物歧化酶（SOD2）、谷胱甘肽还原酶（GSR）、谷氨酸半胱氨酸连接酶修饰亚基（GCLM）和过氧化氢酶的mRNA表达。三组怀孕的狨猴（每组10只动物）在两个妊娠窗口期用赋形剂或地塞米松（每日5 mg/kg）口服治疗一周：早期地塞米松组，妊娠第42 - 48天；晚期地塞米松组，妊娠第90 - 96天。在每窝的一只雄性同胞（每组10只雄性）中，在2岁时采集主动脉。与对照组相比，晚期地塞米松组中GPx-1（p < 0.023）、MnSOD（p < 0.016）、GCLM（p < 0.019）和GSR（p < 0.014）的主动脉mRNA表达较高。早期地塞米松组中仅GSR mRNA的主动脉表达在统计学上显著更高（p < 0.038）。在2岁时，对照组、早期和晚期地塞米松组之间尿中F(2)-异前列腺素浓度未观察到显著变化。因此，孕期第三个月暴露于地塞米松会导致后代主动脉中几种抗氧化酶的mRNA表达增加。这种表达模式与氧化应激在时间上无关，它可能反映了产前糖皮质激素暴露期间主动脉抗氧化基因表达的子宫内重新编程。
