Maternal genotype is an important determinant of the outcome of antenatal glucocorticoid treatment in GR+/+ and GR+/− foetal mice

Glucocorticoids are routinely administered to pregnant women at risk of pre-term delivery to mature foetal organs and improve neonatal survival. Previous work in glucocorticoid receptor (GR)-deficient mice showed that GR activation is essential for maturation of the foetal heart. Here, we tested the hypotheses that i) antenatal glucocorticoid exposure, prior to the normal increase in glucocorticoid levels, will advance foetal heart maturation and ii) this would depend on maternal GR genotype. Female GR+/− and GR+/+ mice were crossed with male GR+/− mice to generate GR+/+, GR+/− and, from GR+/− intercrosses only, GR−/− (glucocorticoid-resistant controls) littermate foetuses. Dexamethasone (100 μg/kg per day) or vehicle was administered in the drinking water of pregnant dams from E12.5 (n=3–6/group). In utero high frequency ultrasound was performed at E15.5. Myocardial performance index (MPI), a measure of combined systolic and diastolic function, did not differ between GR+/− and GR+/+ littermates in vehicle-treated GR+/+ or GR+/− dams. Dexamethasone treatment of GR+/+ dams did not affect MPI in either GR+/− or GR+/+ foetuses. However, compared to vehicle, dexamethasone treatment of GR+/− dams decreased MPI (indicating improved cardiac function) in their GR+/− foetuses (mean±S.E.M.:vehicle=0.746±0.020, dex=0.620±0.028; P<0.01, n=13–16) whilst having no effect on MPI in their GR+/+ foetuses (Mean±S.E.M.:vehicle=0.713±0.044, dex=0.687±0.082, n=4–7). Examination of the influence of maternal genotype showed MPI in GR+/+ foetuses was higher in GR+/− dams than GR+/+ and was unaffected by dexamethasone treatment. Importantly, whilst MPI was elevated in GR+/− foetuses in GR+/− dams compared to GR+/+ dams (Mean±S.E.M.:GR+/− dams=0.769±0.027, GR+/+ dams=0.585±0.075, n=4), this was reversed by dexamethasone treatment (two-way ANOVA interaction P≤0.01). Precocious GR activation therefore improves foetal heart function, but only in GR+/− foetuses from GR+/− dams, suggesting foetal heart maturation is dependent on both foetal and maternal factors. Foetal factors could include reduced GR density in GR+/− mice and maternal factors may include the higher circulating plasma levels of glucocorticoid in GR+/− mice.