Differential Roles of Water–Insoluble and –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.