Molecular Patterns of Neurodevelopmental Preconditioning: A Study of the Effects of Antenatal Steroid Therapy in a Protein-Restriction Mouse Model

Abstract

Introduction. Prenatal programming secondary to maternal protein restriction renders an inherent susceptibility to neural compromise in neonates and any addition of glucocorticosteroids results in further damage. This is an investigation of consequent global gene activity due to effects of antenatal steroid therapy on a protein restriction mouse model. Methods. C57BL/6N pregnant mice were administered control or protein restricted diets and subjected to either 100 μg/Kg of dexamethasone sodium phosphate with normosaline or normosaline alone during late gestation (E10–E17). Nontreatment groups were also included. Brain samples were collected on embryonic day 17 and analyzed by mRNA microarray analysis. Results. Microarray analyses presented 332 significantly regulated genes. Overall, neurodevelopmental genes were overrepresented and a subset of 8 genes allowed treatment segregation through the hierarchical clustering method. The addition of stress or steroids greatly affected gene regulation through glucocorticoid receptor and stress signaling pathways. Furthermore, differences between dexamethasone-administered treatments implied a harmful effect during conditions of high stress. Microarray analysis was validated using qPCR. Conclusion. The effects of antenatal steroid therapy vary in fetuses according to maternal-fetal factors and environmental stimuli. Defining the key regulatory networks that signal either beneficial or damaging corticosteroid action would result in valuable adjustments to current treatment protocols.

CRH/CRHR1 mediates prenatal synthetic glucocorticoid programming of depression‐like behavior across 2 generations

“…A number of studies have shown the gene expression profile caused by prenatal sGC treatment in rodents, including guinea pig and mice. A study by Kimura's group reported that prenatal exposure to Dex during E10 to -17 results in altered expression of 332 genes in E17 hippocampus of mice (45). Interestingly, Crudo et al (46) found that acute exposure to sGC leads to significant changes in more than 1000 genes in fetal hippocampus, while only 81 genes exhibit altered expression in fetal hippocampus at 14 d after sGC exposure in a guinea pig model.…”

Antenatal glucocorticoids: where are we after forty years?

“…[36][37][38] These observations have raised concern that glucocorticoids may disrupt fetal cardiovascular compensation for placental insufficiency [39][40][41] and increase cerebral oxidative stress and injury. 37,42 While randomized trials have not specifically addressed the use of antenatal glucorticoids in the presence of fetal growth restriction, key trials did include such pregnancies 3 and observational data, though limited, appear reassuring with respect to later neurological outcome. 43 One trial suggested that glucocorticoids may be less effective in reducing respiratory distress syndrome in infants with lower birthweight percentile, 44 but in growth restricted fetal sheep, glucocorticoid-induced pulmonary maturation was similar to that of normally grown animals.…”

Ultrasound Imaging of Mouse Fetal Intracranial Hemorrhage Due to Ischemia/Reperfusion

“…Our recent prenatal programming studies centered on maternal protein restriction illustrate the inherent susceptibility of fetuses and neonates to this type of neural compromise due to intrauterine growth restriction (Velayo et al, 2010 , 2014 ; Dong et al, 2014 , 2015 ). Molecular evidence show both prenatal and postnatal adaptive responses to protein-restricted diets rendering offspring vulnerable to further damage.…”