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Sex-Dependent Effects of Neonatal Hyperoxia on Prefrontal Cortex Development

ABSTRACT: Premature infants often require oxygen therapy, which increases the risk of bronchopulmonary dysplasia and long-term cognitive impairment. The prefrontal cortex (PFC), essential for higher-order cognition, may be particularly vulnerable to neonatal hyperoxia, yet the cellular and molecular effects remain unclear. We exposed C57Bl/6 mouse pups to hyperoxia (85% O₂) or normoxia from postnatal days 1–14 and performed single nucleus RNA and ATAC sequencing of the PFC, complemented by oligodendrocyte progenitor cell assays and validation in mouse and human brain tissues. Hyperoxia reduced L4/5 intratelencephalic projecting glutamatergic neurons in females and mature oligodendrocytes in males, accompanied by consistent repression of myelination genes proteolipid protein 1 (Plp1) and myelin basic protein (Mbp) and altered chromatin accessibility. Oligodendrocyte transcription factor 2 (Olig2) was induced in both sexes, whereas lysine demethylase 3A (Kdm3a) activation was female specific. Hyperoxia activated Netrin-1 signaling in males and disrupted tumor protein p53 (TP53)-regulated metabolic pathways in females. Oligodendrocyte progenitor cell proliferation and differentiation were inhibited in vitro, and human bronchopulmonary dysplasia PFC samples recapitulated these core alterations. Together, these findings demonstrate that neonatal hyperoxia disrupts PFC development through sex-dependent effects on neuronal differentiation, oligodendrocyte maturation, and transcriptional regulation. Concordant mouse-human myelination deficits highlight the pathological relevance of oxygen exposure and underscore the importance of considering sex as a biological variable in preterm brain injury.

ORGANISM(S): Mus musculus

PROVIDER: GSE331357 | GEO | 2026/07/15

REPOSITORIES: GEO

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Project description:Background: Metabolic dysregulation has been implicated in bronchopulmonary dysplasia development. Taurine is an essential amino acid for neonates and is critically involved in glucose and fatty acid metabolism. Neonatal tissue obtains taurine mainly through the taurine transporter. The biological role of taurine in neonatal lung development has never been explored. As glucose metabolism mechanistically modulates angiogenesis and angiogenesis is the central player for neonatal lung development, we hypothesize that taurine depletion contributes to bronchopulmonary dysplasia development. Results: Although most genes and proteins for oxidative phosphorylation were enriched in hyperoxia pup lungs, the complex-1 activity decreased. The decrease in taurine-dependent complex-1 core subunits, ND5 and ND6, in hyperoxia lungs reasonably explained the discrepancy. Metabolomics analysis demonstrated decreased lung taurine with increased blood taurine of hyperoxia pups, compatible with the decreased taurine transporter expression. Decreased glycosylation and increased degradation explained the decreased taurine transporter expression. The results of the complementary study using tunicamycin and tauroursodeoxycholic acid studies supported that endoplasmic reticulum stress contributes to decreased taurine transporter expression in hyperoxia lungs. The effect of taurine treatment on reducing endoplasmic reticulum stress, increasing ND5 and ND6 expression, angiogenesis, and, most importantly, the alveolar formation is beneficial to hyperoxia rat pups. Conclusion: Hyperoxia exposure causes endoplasmic reticulum stress, increases taurine transporter degradation, and leads to taurine depletion in the neonatal lungs with subsequent metabolic dysregulation, resulting in poor alveolar formation of the neonatal lungs. We provide evidence of the never-being-reported protective role of taurine in neonatal lung development. The fact that taurine attenuates the severity of bronchopulmonary dysplasia by reducing hyperoxia-induced endoplasmic reticulum stress and mitochondrial dysfunction indicates its therapeutic potential for treating bronchopulmonary dysplasia.

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Sex-Dependent Effects of Neonatal Hyperoxia on Prefrontal Cortex Development

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