Prenatal Dexamethasone Exposure Programs the Development of the Pancreas and the Secretion of Insulin in Rats.

BACKGROUND: There is increasing epidemiological evidence indicating that many chronic diseases originate during early life, even before birth, through what are termed fetal programming effects. Prenatal glucocorticoid is frequently used clinically to accelerate the maturation of the lung, but its long-term effects remain unclear. METHODS: We gave pregnant Sprague-Dawley rats either intraperitoneal dexamethasone (0.1 mg/kg body weight) or vehicle at Gestational Days 14-20 and assessed the effects to pancreas at Postnatal Days 7 and 120. RESULTS: We found fewer pancreatic ß cell fractions (0.31±0.05 % vs. 0.49±0.05 %, p=0.013) and tissues (0.0017±0.0002 % vs. 0.0025±0.0002 %, p=0.042) and decreased secretion of insulin in response to a glucose challenge at Postnatal Day 105 (1.00±0.19 ng/mL vs. 1.57±0.17 ng/mL at the 15-minute time-point, p=0.046) in rats treated prenatally with dexamethasone. At Postnatal Day 7 in rats treated prenatally with dexamethasone, the expression of pancreatic duodenal homeobox gene-1 and V-maf avian musculoaponeurotic fibrosarcoma oncogene homolog A was lower than that in the rats in the Vehicle group (0.22±0.07 vs. 1.00±0.41 fold, p=0.01, 0.20±0.12 vs. 1.00±0.35 fold, p=0.01) while the histone deacetylases activity (54.2±3.7 ng/h/mL vs. 37.6±3.5 ng/h/mL, p=0.012) and 8-hydroxy-2-deoxyguanosine staining (1.34±0.01 vs. 1.00±0.02 fold, p<0.01) were higher. CONCLUSION: Prenatal dexamethasone exposure affects early postnatal gene expression related to pancreas development and may exert an effect on ß-cell development at 120 postnatal days.

Programming Effects of Prenatal Glucocorticoid Exposure with a Postnatal High-Fat Diet in Diabetes Mellitus.

Increasing evidence has shown that many chronic diseases originate from early life, even before birth, through what are termed as fetal programming effects. Glucocorticoids are frequently used prenatally to accelerate the maturation of the lungs of premature infants. High-fat diets are associated with insulin resistance, but the effects of prenatal glucocorticoid exposure plus a postnatal high-fat diet in diabetes mellitus remain unclear. We administered pregnant Sprague-Dawley rats' intraperitoneal dexamethasone (0.1 mg/kg body weight) or vehicle at gestational days 14-20. Male offspring were administered a normal or high-fat diet starting from weaning. We assessed the effects of prenatal steroid exposure plus postnatal high-fat diet on the liver, pancreas, muscle and fat at postnatal day 120. At 15 and 30 min, sugar levels were higher in the dexamethasone plus high-fat diet (DHF) group than the vehicle plus high-fat diet (VHF) group in the intraperitoneal glucose tolerance test (IPGTT). Serum insulin levels at 15, 30 and 60 min were significantly higher in the VHF group than in the vehicle and normal diet group. Liver insulin receptor and adenosine monophosphate-activated protein kinase mRNA expressions and protein levels were lower in the DHF group. Insulin receptor and insulin receptor substrate-1 mRNA expressions were lower in the epididymal adipose tissue in the VHF and DHF groups. "Programming" of liver or epididymal adipose tissue resulted from prenatal events. Prenatal steroid exposure worsened insulin resistance in animals fed a high-fat diet.

Roles of melatonin in fetal programming in compromised pregnancies.

Compromised pregnancies such as those associated with gestational diabetes mellitus, intrauterine growth retardation, preeclampsia, maternal undernutrition, and maternal stress may negatively affect fetal development. Such pregnancies may induce oxidative stress to the fetus and alter fetal development through the epigenetic process that may affect development at a later stage. Melatonin is an oxidant scavenger that reverses oxidative stress during the prenatal period. Moreover, the role of melatonin in epigenetic modifications in the field of developmental programming has been studied extensively. Here, we describe the physiological function of melatonin in pregnancy and discuss the roles of melatonin in fetal programming in compromised pregnancies, focusing on its involvement in redox and epigenetic mechanisms.

Alterations in NADPH oxidase expression and blood-brain barrier in bile duct ligation-treated young rats: effects of melatonin.

Bile duct ligation (BDL)-treated rats exhibit cholestasis and increased systemic and brain oxidative stress. Activation of NADPH (nicotinamide adenine dinucleotide phosphate) oxidase and disruption of the blood-brain barrier (BBB) are implicated as the pathogenetic mechanisms of brain dysfunction in BDL-treated adult rats. Young rats underwent sham ligation or BDL at day 17 for 2 or 4weeks. Treatment group rats were administered melatonin between day 17 and 45. We found a progressive increase in prefrontal cortex NADPH-dependent superoxide anion (O(2)(-)) production and increased expression of NADPH oxidase subunits in either the prefrontal cortex or the hippocampus in BDL-treated young rats. In addition, expression of intercellular adhesion molecule-1 (ICAM) and tissue plasminogen activator (t-PA) genes were increased in either the prefrontal cortex or the hippocampus. Prefrontal cortex capillary junctional complex proteins expressions including occludin, claudin-5, platelet endothelial cell adhesion molecule-1 and vascular endothelial cadherin were not altered. Melatonin lowered the prefrontal cortex NADPH-dependent O(2)(-) production and t-PA gene expression. We conclude that alterations in NADPH oxidase expression and BBB are involved in brain dysfunction in BDL-treated young rats. In addition, melatonin regulates NADPH oxidase activity and t-PA gene expression.