College of Environment and Resource, Research Center of Environment and Health, Shanxi University, Taiyuan, Shanxi 030006, PR China.
Xuzhou Engineering Research Center of Medical Genetics and Transformation, Key Laboratory of Genetic Foundation and Clinical Application, Department of Genetics, Xuzhou Medical University, Xuzhou, Jiangsu 221004, PR China.
Sci Total Environ. 2023 Oct 15;895:165004. doi: 10.1016/j.scitotenv.2023.165004. Epub 2023 Jun 20.
Numerous epidemiological studies have shown that PM exposure in early life can influence brain development and increase the risk of neurodevelopmental disorders in boys, but the underlying molecular mechanisms remain unclear. In the current study, pregnant C57BL/6 J mice were oropharyngeally administered with PM suspension (3mg/kg/2 days) until the birth of offspring. Based on mRNA expression profiles, two-way analysis of variance (two-way ANOVA) and weighted gene co-expression network analysis (WGCNA) were conducted to explore the most impacted neurodevelopmental processes in male offspring and the most significantly associated gene modules. Gene Ontology (GO) enrichment and Encyclopedia of Genes and Genomes (KEGG) pathway analyses suggested that prenatal PM exposure significantly altered several biological processes (such as substrate adhesion-dependent cell spreading, myelination, and ensheathment of neurons) and KEGG pathways (such as tight junction and axon guidance). We further found that PM exposure significantly changed the expression of myelination-related genes in male offspring during postnatal development and impaired myelin ultrastructure on PNDs 14 and 21, as demonstrated by the decreased thickness of myelin sheaths in the optic nerves, and mild loss of myelin in the corpus callosum. Importantly, lncRNA NONMMUT058932.2 and NONMMUT029203.2 played key roles in abnormal myelination by regulating the expression of several myelination-related genes (Fa2h, Mal, Sh3tc2, Trf and Tppp) through the binding to transcription factor Ctcf. Our work provides genomic evidence for prenatal PM exposure-induced neurodevelopmental disorders in male offspring.
大量的流行病学研究表明，早期生命中 PM 暴露会影响大脑发育，并增加男孩神经发育障碍的风险，但潜在的分子机制尚不清楚。在本研究中，通过口咽给予怀孕的 C57BL/6J 小鼠 PM 混悬液（3mg/kg/2 天），直至后代出生。基于 mRNA 表达谱，进行了双向方差分析（two-way ANOVA）和加权基因共表达网络分析（WGCNA），以探讨雄性后代受影响最严重的神经发育过程和最显著相关的基因模块。基因本体论（GO）富集和基因和基因组百科全书（KEGG）途径分析表明，产前 PM 暴露显著改变了几个生物学过程（如底物附着依赖性细胞扩展、髓鞘形成和神经元包绕）和 KEGG 途径（如紧密连接和轴突导向）。我们进一步发现，PM 暴露在雄性后代出生后发育过程中显著改变了髓鞘形成相关基因的表达，并损害了 PNDs 14 和 21 时的髓鞘超微结构，表现为视神经髓鞘厚度减少，胼胝体髓鞘轻度丢失。重要的是，lncRNA NONMMUT058932.2 和 NONMMUT029203.2 通过与转录因子 Ctcf 结合，调节几个髓鞘形成相关基因（Fa2h、Mal、Sh3tc2、Trf 和 Tppp）的表达，在异常髓鞘形成中发挥关键作用。我们的工作为产前 PM 暴露引起雄性后代神经发育障碍提供了基因组证据。
