Maternal exposure to ambient PM2.5 perturbs the metabolic homeostasis of maternal serum and placenta in mice.

Epidemiological and animal studies have shown that maternal fine particulate matters (PM2.5) exposure correlates with various adverse pregnancy outcomes such as low birth weight (LBW) of offspring. However, the underlying biological mechanisms have not been fully understood. In this study, female C57Bl/6 J mice were exposed to filtered air (FA) or concentrated ambient PM2.5 (CAP) during pregestational and gestational periods, and metabolomics was performed to analyze the metabolic features in maternal serum and placenta by liquid chromatography-mass spectrometry (LC-MS). The partial least squares discriminate analysis (PLS-DA) displayed evident clustering of FA- and CAP-exposed samples for both maternal serum and placenta. In addition, pathway analysis identified that vitamin digestion and absorption was perturbed in maternal serum, while metabolic pathways including arachidonic acid metabolism, serotonergic synapse, 2-oxocarboxylic acid metabolism and cAMP signaling pathway were perturbed in placenta. Further analysis indicated that CAP exposure influenced the nutrient transportation capacity of placenta, by not only changing the ratios of some critical metabolites in placenta to maternal serum but also significantly altering the expressions of nutrition transporters in placenta. These findings reaffirm the importance of protecting women from PM2.5 exposure, and also advance our understanding of the toxic actions of ambient PM2.5.

Deficiency of interleukin-6 receptor ameliorates PM2.5 exposure-induced pulmonary dysfunction and inflammation but not abnormalities in glucose homeostasis.

BACKGROUND: Ambient fine particulate matter (PM2.5) exposure increases local and systemic interleukin-6 (IL-6). However, the pathogenic role of IL-6 signalling following PM2.5 exposure, particularly in the development of pulmonary dysfunction and abnormal glucose homeostasis, has hardly been investigated. RESULTS: In the study, IL-6 receptor (IL-6R)-deficient (IL-6R-/-) and wildtype littermate (IL-6R+/+) mice were exposed to concentrated ambient PM2.5 (CAP) or filtered air (FA), and their pulmonary and metabolic responses to these exposures were analyzed. Our results demonstrated that IL-6R deficiency markedly alleviated PM2.5 exposure-induced increases in lung inflammatory markers including the inflammation score of histological analysis, the number of macrophages in bronchoalveolar lavage fluid (BALF), and mRNA expressions of TNFα, IL-1ß and IL-6 and abnormalities in lung function test. However, IL-6R deficiency did not reduce the hepatic insulin resistance nor systemic glucose intolerance and insulin resistance induced by PM2.5 exposure. CONCLUSION: Our findings support the crucial role of IL-6 signalling in the development of pulmonary inflammation and dysfunction due to PM2.5 exposure but question the putative central role of pulmonary inflammation for the extra-pulmonary dysfunctions following PM2.5 exposure, providing a deep mechanistic insight into the pathogenesis caused by PM2.5 exposure.

Differential Roles of Water-Insoluble and Water-Soluble Fractions of Diesel Exhaust Particles in the Development of Adverse Health Effects Due to Chronic Instillation of Diesel Exhaust Particles.

Ambient fine particulate matter (PM2.5) has a marked temporospatial variation in chemical composition, but how the composition of PM2.5 influences its toxicity remains elusive. To explore the roles of individual PM2.5 components in the pathogenesis following PM2.5 exposure, we prepared water-soluble (WS-DEP) and water-insoluble (WIS-DEP) fractions of diesel exhaust particles (DEP) and performed 15-week intratracheal instillation on C57Bl/6J mice using these fractions. Their effects on pulmonary and systemic inflammation, hepatic steatosis and insulin resistance, systemic glucose homeostasis, and gut microbiota were then assessed. Compared to control, instillation of DEP or WIS-DEP, but not WS-DEP, significantly increased pulmonary inflammatory scores and expression of inflammatory markers, bronchoalveolar lavage fluid cell number, and circulating pro-inflammatory cytokines. Consistently, DEP- or WIS-DEP-instilled but not WS-DEP-instilled mice versus control had significant hepatic steatosis and insulin resistance and systemic glucose intolerance. In contrast, instillation of WS-DEP versus instillation of WIS-DEP had effects on the gut microbiota more comparable to that of instillations of DEP. The pulmonary and systemic inflammation, hepatic steatosis and insulin resistance, and systemic glucose intolerance following chronic DEP instillation are all attributable to the WIS-DEP, suggesting that PM2.5 may have a solubility-dependent basal toxicity.

Gut microbiota mediates ambient PM2.5 exposure-induced abnormal glucose metabolism via short-chain fatty acids.

PM2.5 exposure has been found to cause gut dysbiosis and impair glucose homeostasis in human and animals, yet their underlying biological connection remain unclear. In the present study, we aim to investigate the biological significance of gut microbiota in PM2.5-induced glucose metabolic abnormalities. Our results showed that microbiota depletion by antibiotics treatment significantly alleviated PM2.5-induced glucose intolerance and insulin resistance, as indicated by the intraperitoneal glucose tolerance test, glucose-induced insulin secretion, insulin tolerance test, insulin-induced phosphorylation levels of Akt and GSK-3ß in insulin sensitive tissues. In addition, faecal microbiota transplantation (FMT) from PM2.5-exposed donor mice successfully remodeled the glucose metabolism abnormalities in recipient mice, while the transplantation of autoclaved faecal materials did not. Faecal microbiota analysis demonstrated that the composition and alpha diversity of the gut bacterial community were altered by PM2.5 exposure and in FMT recipient mice. Furthermore, short-chain fatty acids levels analysis showed that the circulating acetate was significantly decreased in PM2.5-exposed donor and FMT recipient mice, and supplementation of sodium acetate for 3 months successfully improved the glucose metabolism abnormalities induced by PM2.5 exposure. These results indicate that manipulating gut microbiota or its metabolites could be a potential strategy for preventing the adverse health effects of ambient PM2.5.

Cholinergic anti-inflammatory pathway mediates diesel exhaust PM2.5-induced pulmonary and systemic inflammation.

Previous research has indicated that the cholinergic anti-inflammatory pathway (CAP) can regulate the duration and intensity of inflammatory responses. A wide range of research has demonstrated that PM2.5 exposure may induce various negative health effects via pulmonary and systemic inflammations. To study the potential role of the CAP in mediating PM2.5-induced effects, mice were treated with vagus nerve electrical stimulation (VNS) to activate the CAP before diesel exhaust PM2.5 (DEP) instillation. Analysis of pulmonary and systemic inflammations in mice demonstrated that VNS significantly reduced the inflammatory responses triggered by DEP. Meanwhile, inhibition of the CAP by vagotomy aggravated DEP-induced pulmonary inflammation. The flow cytometry results showed that DEP influenced the CAP by altering the Th cell balance and macrophage polarization in spleen, and in vitro cell co-culture experiments indicated that this DEP-induced change on macrophage polarization may act via the splenic CD4+ T cells. To further confirm the effect of alpha7 nicotinic acetylcholine receptor (α7nAChR) in this pathway, mice were then treated with α7nAChR inhibitor (α-BGT) or agonist (PNU282987). Our results demonstrated that specific activation of α7nAChR with PNU282987 effectively alleviated DEP-induced pulmonary inflammation, while specific inhibition of α7nAChR with α-BGT exacerbated the inflammatory markers. The present study suggests that PM2.5 have an impact on the CAP, and CAP may play a critical function in mediating PM2.5 exposure-induced inflammatory response. AVAILABILITY OF DATA AND MATERIALS: The datasets used and/or analyzed during the present study are available from the corresponding author on reasonable request.