Prenatal NO2 exposure and neurodevelopmental disorders in offspring mice: Transcriptomics reveals sex-dependent changes in cerebral gene expression

Abstract

Background: Early-life exposure to nitrogen dioxide (NO₂) is associated with an increased risk of developing a neurodevelopmental disorder during childhood or later in life.

Objectives: We investigated whether prenatal NO₂ inhalation causes neurodevelopmental abnormalities and cognitive deficits in weanling offspring without subsequent postnatal NO₂ exposure and how this prenatal exposure contributes to postnatal consequences.

Methods: Pregnant C57BL/6 mice were exposed to air or NO₂ (2.5 ppm, 5 h/day) throughout gestation, and the offspring were sacrificed on postnatal days (PNDs) 1, 7, 14 and 21. We determined the mRNA profiles of different postnatal developmental windows, detected the long noncoding RNA (lncRNA) profiles and cognitive function in weanling offspring, and analyzed the effects of hub lncRNAs on differentially expressed genes (DEGs).

Results: Prenatal NO₂ inhalation significantly impaired cognitive function in the weanling male, but not female, offspring. The male-specific response was coupled with abnormal neuropathologies and transcriptional profiles in the cortex during different postnatal developmental windows. Consistently, Gene Ontology (GO) analysis of the DEGs revealed persistent disruptions in neurodevelopment-associated biological processes and cellular components in the male offspring, and Apolipoprotein E (ApoE) was one of key factors contributing to prenatal exposure-induced male-specific neurological dysfunction. In addition, distinct sex-dependent lncRNA expression was identified in the weanling offspring, and metastasis-associated lung adenocarcinoma transcript 1 (Malat1) acted as a hub lncRNA and was coexpressed with most coding genes in the lncRNA-mRNA coexpressed pairs in the male offspring. Importantly, lncRNA Malat1 expression was elevated, and Malat1 modulated ApoE expression through NF-κB activation during this process.

Conclusions: Prenatal NO₂ exposure is related to sex-dependent neurocognitive deficits and transcriptomic profile changes in the cortices of the prenatally exposed offspring. Male-specific neurological dysfunction is associated with the constant alteration of genes during postnatal neurodevelopment and their transcriptional modulation by hub lncRNAs.

Keywords: Apolipoprotein E (ApoE); Metastasis-associated lung adenocarcinoma transcript 1 (Malat1); Prenatal NO(2) exposure; Spatial learning and memory; mRNA and long noncoding (lncRNA) expression profiles.