Effect of sex chromosomes versus hormones in neonatal lung injury

Abstract

The main mechanisms underlying sexually dimorphic outcomes in neonatal lung injury are unknown. We tested the hypothesis that hormonal-or sex chromosomemediated mechanisms interact with hyperoxia exposure to impact injury and repair in the neonatal lung. To distinguish sex differences caused by gonadal hormones versus sex chromosome complement (XX versus XY), we used the four core genotypes (FCG) mice and exposed them to hyperoxia (95% FiO2, PND1-4: saccular stage) or room air. This model generates XX and XY mice that each have either testes (with Sry, XXM or XYM) or ovaries (without Sry, XXF or XYF). Lung alveolarization and vascular development were more severely impacted in XYM and XYF compared to XXF and XXM mice. Cell cycle related pathways were enriched in the gonadal or chromosomal females, while muscle related pathways were enriched in the gonadal males, and immune-response related pathways were enriched in chromosomal males. Female gene signatures showed a negative correlation with human patients that developed BPD or needed oxygen therapy at 28 days. These results demonstrate that, chromosomal sex and not gonadal sex impacted the response to neonatal hyperoxia exposure. The female sex chromosomal complement was protective and could mediate sex-specific differences in the neonatal lung injury.

Neonatal hyperoxia induces sex-dependent pulmonary cellular and transcriptomic changes in an experimental mouse model of bronchopulmonary dysplasia

“…We undertook a single cell survey in a hyperoxia model of experimental BPD to address these key questions. Strikingly, female preterm neonates are less susceptible to BPD in comparison with gestational age matched male preterm infants 16,17 . We also explored the mechanisms associated with decreased hyperoxia-induced lung injury in female neonatal mice at single cell resolution [18][19][20][21] .…”

Microvascular Sex- and Age- Dependent Phosphodiesterase Expression

“…It is worth noting the complexity of teasing out the contribution of gonadal hormones to sex differences. In the simplest paradigm, sexual dimorphisms between juvenile males and females stems from two components: 1) increased gonadal hormone levels during embryonic gonadal organ differentiation, although following the first days of life, circulating gonadal hormone levels are low and comparable between juvenile males and females; 2) sex chromosome complements (XY or XX) ( Arnold and Burgoyne, 2004 ; Grimm et al, 2021 ). Obviously, the roles for sex steroid production and its change with age, and the contribution of the myriad of sex hormone isoforms are beyond the scope of the present work and require much closer inspection.…”

MicroRNA-mRNA networks are dysregulated in opioid use disorder postmortem brain: further evidence for opioid-induced neurovascular alterations

“…A methodology used frequently to assess the interaction between gene signatures in human cohorts is the correlation of gene signature scores; this approach has been utilized both in cancer (32-34) and non-cancer systems (35-37). We downloaded data for 425 control bulk BA9 brain tissues collected by the Genotype-Tissue Expression (GTEx) project (38), using the GTEx data portal.…”