Background: Maternal asthma during pregnancy is associated with low birth weight. In these pregnancies, female but not male birth weight is negatively correlated with cord blood cortisol. The actions of glucocorticoids (GCs) are mediated through the glucocorticoid receptor (GR); a number of isoforms exist, including GRα, GRβ, GRγ, GR-A and GR-P. Further, different isoforms of GRα have been described. Tissue specific expression of these isoforms is associated with distinct regulatory patterns and responses to GCs. We hypothesise that the sexually dimorphic fetal growth in asthmatic pregnancies is due to differences in sensitivity to GCs, mediated by differential expression of placental GR isoforms.
Methods: Cytosolic and nuclear protein fractions were prepared from frozen placental tissue (Asthma: male n=27, female n=26; Control: male n=19, female n=25). Western blotting was performed using anti-GR total, anti-GRα and anti-GRβ antibodies. The different GR isoforms were determined based on their expected molecular weights. The relative expression of different GR isoforms was calculated using densitometry.
Results: The presence of a 94kDa (GRα) and a 90kDa (GRβ) isoform were identified. Bands corresponding to 75kDa, 69 kDa, 65kDa and 50kDa were also detected, potentially relating to GRα-A, GRα-B, GRα-C, GR-P and GRα-D. In male but not female placenta from asthmatic pregnancies, the intensity of GRα in the nucleus, the expression of cytosolic GRβ and 65kDa (GR-A) were decreased relative to control (p<0.05 in each case). Decreased expression of nuclear 50kDa (GRα-D) and cytosolic 38kDa were also noted in male placenta with asthma compared to controls.
Conclusion: The identified changes in GRβ, GR-A and GRα-D protein expression may result in an altered functional response of GRα, leading to glucocorticoid resistance in the male feto-placental unit. This may contribute to the sexually dimorphic fetal growth strategies in response to asthma, with relevance to other maternal complications of pregnancy where sex differences in growth are also described.