Transcriptome sequencing analysis reveals a potential role of lncRNA NONMMUT058932.2 and NONMMUT029203.2 in abnormal myelin development of male offspring following prenatal PM exposure.

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.