Gestational exposure to air pollution increases the risk of autism spectrum disorder and cognitive impairments with unresolved molecular mechanisms. This study exposed C57BL/6J mice throughout gestation to urban-derived nanosized particulate matter (nPM). Young adult male and female offspring were studied for behavioral and metabolic changes using forced swim test, fat gain, glucose tolerance, and hippocampal transcriptome. Gestational nPM exposure caused increased depressive behaviors, decreased neurogenesis in the dentate gyrus, and increased glucose tolerance in adult male offspring. Both sexes gained fat and body weight. Gestational nPM exposure induced 29 differentially expressed genes (DEGs) in adult hippocampus related to cytokine production, IL17a signaling, and dopamine degradation in both sexes. Stratification by sex showed twofold more DEGs in males than females (69 vs 37), as well as male-specific enrichment of DEGs mediating serotonin signaling, endocytosis, Gαi, and cAMP signaling. Gene co-expression analysis (WCGNA) identified a module of 43 genes with divergent responses to nPM between the sexes. Chronic changes in 14 DEGs (e.g., microRNA9-1) were associated with depressive behaviors, adiposity and glucose intolerance. These genes enriched neuroimmune pathways such as HMGB1 and TLR4. Based on cerebral cortex transcriptome data of neonates, we traced the initial nPM responses of HMGB1 pathway. In vitro, mixed glia responded to 24 h nPM with lower HMGB1 protein and increased proinflammatory cytokines. This response was ameliorated by TLR4 knockdown. In sum, we identified transcriptional changes that could be associated with air pollution-mediated behavioral and phenotypic changes. These identified genes merit further mechanistic studies for therapeutic intervention development.

妊娠期暴露于空气污染会增加自闭症谱系障碍和认知障碍的风险，其分子机制尚未解决。本研究将 C57BL/6J 小鼠在整个妊娠期暴露于城市衍生的纳米颗粒物 (nPM)。使用强迫游泳测试、脂肪增加、葡萄糖耐量和海马转录组研究年轻成年雄性和雌性后代的行为和代谢变化。妊娠期 nPM 暴露导致抑郁行为增加，齿状回神经发生减少，成年雄性后代葡萄糖耐量增加。两性都增加了脂肪和体重。妊娠期 nPM 暴露在成年海马中诱导了 29 个差异表达基因 (DEG)，这些基因与两性中的细胞因子产生、IL17a 信号传导和多巴胺降解有关。按性别分层显示，男性的 DEG 比女性多两倍（69 比 37），以及介导血清素信号、内吞作用、Gαi 和 cAMP 信号的男性特异性 DEG 富集。基因共表达分析 (WCGNA) 确定了一个由 43 个基因组成的模块，这些基因在两性之间对 nPM 有不同的反应。14 个 DEG（例如 microRNA9-1）的慢性变化与抑郁行为、肥胖和葡萄糖耐受不良有关。这些基因丰富了 HMGB1 和 TLR4 等神经免疫通路。基于新生儿的大脑皮层转录组数据，我们追踪了 HMGB1 通路的初始 nPM 反应。在体外，混合神经胶质对 24 小时 nPM 的反应具有较低的 HMGB1 蛋白和增加的促炎细胞因子。TLR4 敲低改善了这种反应。总共，我们确定了可能与空气污染介导的行为和表型变化相关的转录变化。这些确定的基因值得进一步的机制研究，以进行治疗干预的发展。