Sex as a Biological Variable in Bronchopulmonary Dysplasia

Abstract

The incidence of bronchopulmonary dysplasia (BPD) is higher among premature male neonates even after adjusting for other confounders. Despite the well‐established sex‐specific differences in the incidence of BPD and impaired lung function in males, the molecular mechanism(s) behind this are poorly understood. Mammalian cells have intrinsic differences based on sex and respond differently to stressors irrespective of the past or current concentrations of sex hormones. Our research investigates the effect of sex on neonatal hyperoxic lung injury and the mechanisms underlying these differences. Alveolarization and angiogenesis is preserved in female neonatal mice exposed to hyperoxia compared to males. Differences in the lung transcriptome and the epigenome may contribute to these sex‐specific differences. We have shown that differential expression of miRNA (miR‐30a) and their downstream targets have also been shown to modulate this process. Sex‐specific differences at the cellular level in the pulmonary endothelial cells and fibroblasts will also be discussed. To distinguish sex differences caused by gonadal hormones versus sex chromosome complement (XX versus XY), we used the four Core Genotype mice (FCG). The FCG model can discriminate between sex differences determined by gonadal type (versus those determined by the effects of sex chromosomes). Sex‐specific transcriptomic changes were observed in numerous genes for each genotype at in room air and after hyperoxia exposure. Sex‐hormones and sex chromosomes may cause sex‐specific differences in the pathogenesis of BPD in premature neonates. The presentation will address knowledge gaps in the molecular mechanisms behind the sexually divergent incidence of BPD and will discuss novel molecular pathways for future therapeutic interventional strategies to combat BPD.Support or Funding InformationThis work was supported by grants from NIH: K08‐HL127103; R03‐HL141572 and R01‐HL14775 to KL.