Adult mouse hippocampal transcriptome changes associated with long-term behavioral and metabolic effects of gestational air pollution toxicity

Abstract

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.

The Effects of Chronic Exposure to Ambient Traffic-Related Air Pollution on Alzheimer’s Disease Phenotypes in Wildtype and Genetically Predisposed Male and Female Rats

“…2011 ), nano-sized or ultrafine PM ( Cacciottolo et al. 2020 , 2017 ; Haghani et al. 2020c ; Jew et al.…”

Transcriptomics of single dose and repeated carbon black and ozone inhalation co-exposure highlight progressive pulmonary mitochondrial dysfunction

“…In both newborn [ 28 ] and adult [ 29 ] mice, O 3 exposure is associated with alterations to the pulmonary transcriptome, which contribute to cellular signaling involving cellular proliferation and differentiation. Maternal exposure to CB has been linked to transcriptomic changes in extrapulmonary organs of progeny, such as the hippocampus [ 30 ] and liver [ 31 ]. While these studies demonstrate the evident impact of O 3 and CB on mRNA expression, they are unable to model the interaction of these toxicants in vivo to induce potentially new or more exaggerated cellular responses.…”

Hippocampal transcriptome profiling reveals common disease pathways in chronic hypoperfusion and aging

“…A limitation of this study that warrants future study is the lack of sex-specific analysis of the hippocampal transcriptome as only male mice were used here. Previous studies indicate that sex differences are likely to exist in the hippocampal transcriptome profile [55,56]. Furthermore, as VaD is more prevalent in males than females [57], we postulate sex-specific alterations to be present but less profound in the context of this BCAS model.…”