Abstract
BackgroundEarly-life exposure to nitrogen dioxide (NO2) is associated with an increased risk of developing a neurodevelopmental disorder during childhood or later in life. ObjectivesWe 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. MethodsPregnant 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). ResultsPrenatal 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. ConclusionsPrenatal 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.
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