Effect of sex chromosomes versus hormones in neonatal lung injury.

Sandra L Grimm,Yuhao Zhang,Cristian Coarfa,Xiaoyu Dong,Bhagavatula Moorthy,Krithika Lingappan,Arthur P Arnold,Alexandre F Carisey

doi:10.1172/jci.insight.146863

Abstract

The main mechanisms underlying sexually dimorphic outcomes in neonatal lung injury are unknown. We tested the hypothesis that hormone- or sex chromosome–mediated 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, P1–P4: 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 with 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 who developed bronchopulmonary dysplasia (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.

Highlights

Sex as a biological variable plays a crucial role both during lung development and in modulating recovery from neonatal lung injury
Chromosomal sex had a significant impact on alveolarization after neonatal hyperoxia exposure and not gonadal sex
Chromosomal sex and interaction between chromosomal sex and treatment had a significant effect on both alveolarization and pulmonary vascular development in hyperoxia-exposed neonatal mice

Summary

Introduction

Sex as a biological variable plays a crucial role both during lung development and in modulating recovery from neonatal lung injury. Bronchopulmonary dysplasia (BPD), a lung disease characterized by aberrant alveolar and pulmonary vascular development, causes significant morbidity in preterm neonates. The incidence of this disease is skewed toward the male sex [1]. Male mice have greater alveolar simplification, impaired pulmonary vascular development, and more long-term adverse sequelae compared with female mice [5, 6]

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