College of Environment and Resource, Research Center of Environment and Health, Shanxi University, Taiyuan, Shanxi 030006, China.
College of Environment and Resource, Research Center of Environment and Health, Shanxi University, Taiyuan, Shanxi 030006, China.
Environ Int. 2020 May;138:105659. doi: 10.1016/j.envint.2020.105659. Epub 2020 Mar 20.
Early-life exposure to nitrogen dioxide (NO) is associated with an increased risk of developing a neurodevelopmental disorder during childhood or later in life.
We investigated whether prenatal NO inhalation causes neurodevelopmental abnormalities and cognitive deficits in weanling offspring without subsequent postnatal NO exposure and how this prenatal exposure contributes to postnatal consequences.
Pregnant C57BL/6 mice were exposed to air or NO (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).
Prenatal NO 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.
Prenatal NO 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.
儿童期或生命后期早期接触二氧化氮（NO）会增加患神经发育障碍的风险。
我们研究了在没有随后的产后 NO 暴露的情况下，产前吸入 NO 是否会导致断乳后代出现神经发育异常和认知缺陷，以及这种产前暴露如何导致产后后果。
将怀孕的 C57BL/6 小鼠暴露于空气或 NO（2.5 ppm，每天 5 小时）中，直至分娩，并在产后第 1、7、14 和 21 天处死后代。我们确定了不同产后发育窗口的 mRNA 谱，检测了断乳后代的长非编码 RNA（lncRNA）谱和认知功能，并分析了 hub lncRNA 对差异表达基因（DEG）的影响。
产前吸入 NO 显著损害了断乳雄性，而不是雌性，后代的认知功能。这种雄性特异性反应与不同产后发育窗口的皮质中异常的神经病理学和转录谱有关。一致地，差异表达基因的基因本体论（GO）分析表明，雄性后代的神经发育相关生物过程和细胞成分持续受到破坏，载脂蛋白 E（ApoE）是导致产前暴露引起的雄性特异性神经功能障碍的关键因素之一。此外，在断乳后代中鉴定出了不同的性别依赖性 lncRNA 表达，并且转移相关肺腺癌转录本 1（Malat1）作为 hub lncRNA，与雄性后代的 lncRNA-mRNA 共表达对中的大多数编码基因共表达。重要的是，lncRNA Malat1 的表达增加，并且 Malat1 通过 NF-κB 激活调节 ApoE 表达。
产前 NO 暴露与产前暴露后代皮质中性别依赖性神经认知缺陷和转录组谱变化有关。雄性特异性神经功能障碍与产后神经发育过程中基因的持续改变以及 hub lncRNA 对其转录调节有关。
