Evaluation of the genotoxicity of PM2.5 collected by a high-volume air sampler with impactor

Abstract Background The harmful effects of fine particles with an aerodynamic diameter less than 2.5 μm (PM2.5) on respiratory organs are emphasized in pollution studies because PM2.5 have high deposition rates in the respiratory organs and contain various hazardous compounds. In this study, a sampling method combining a high-volume air sampler (HV) with a PM2.5 impactor was developed for collecting large quantities of PM2.5. The concentrations of elemental carbon (EC), organic carbon (OC), inorganic ions, and polycyclic aromatic hydrocarbons (PAHs) were measured in PM2.5 collected by the high-and low-volume air samplers (LV). Results Similar results were obtained from the HV and LV methods, with respect to inorganic carbon, organic carbon, sodium ions, ammonium ions, and PAHs with more than four rings. Because of the much larger amount of PM2.5 could be collected by the HV method, the trace constituents, that were difficult to detect by the conventional LV method, were readily detected by the HV method. Furthermore, when the microsuspension method that was modified more sensitive Ames mutagenicity test, was used to test the PM2.5 samples at four sites, mutagenic activities were detected by strains TA100 and TA98. Most of the mutagenic activity was associated with the PM2.5 fraction and mutagenic activity in winter was greater than that in summer. Conclusions The HV method produced results similar to those from the conventional LV method with respect to the PM2.5 components present in the atmosphere in relatively high concentrations, but its 40-fold greater flow rate enabled the detection of mutagenic compounds present in only trace concentrations

Enterohepatic Transcription Factor CREB3L3 Protects Atherosclerosis via SREBP Competitive Inhibition

動脈硬化発症を制御する転写因子の相互作用を発見. 京都大学プレスリリース. 2020-12-09.Background and Aims: cAMP responsive element-binding protein 3 like 3 (CREB3L3) is a membrane-bound transcription factor involved in the maintenance of lipid metabolism in the liver and small intestine. CREB3L3 controls hepatic triglyceride and glucose metabolism by activating plasma fibroblast growth factor 21 (FGF21) and lipoprotein lipase. In this study, we intended to clarify its effect on atherosclerosis. Methods: CREB3L3-deficifient, liver-specific CREB3L3 knockout, intestine-specific CREB3L3 knockout, both liver- and intestine-specific CREB3L3 knockout, and liver CREB3L3 transgenic mice were crossed with LDLR−/− mice. These mice were fed with a Western diet to develop atherosclerosis. Results: CREB3L3 ablation in LDLR−/− mice exacerbated hyperlipidemia with accumulation of remnant APOB-containing lipoprotein. This led to the development of enhanced aortic atheroma formation, the extent of which was additive between liver- and intestine-specific deletion. Conversely, hepatic nuclear CREB3L3 overexpression markedly suppressed atherosclerosis with amelioration of hyperlipidemia. CREB3L3 directly upregulates anti-atherogenic FGF21 and APOA4. In contrast, it antagonizes hepatic sterol regulatory element-binding protein (SREBP)-mediated lipogenic and cholesterogenic genes, and regulates intestinal liver X receptor-regulated genes involved in the transport of cholesterol. CREB3L3 deficiency results in the accumulation of nuclear SREBP proteins. Because both transcriptional factors share the cleavage system for nuclear transactivation, full-length CREB3L3 and SREBPs in the endoplasmic reticulum (ER) functionally inhibit each other. CREB3L3 promotes the formation of the SREBP-insulin induced gene 1 (SREBP-INSIG1) complex to suppress SREBPs for ER-Golgi transport, resulting in ER retention and inhibition of proteolytic activation at the Golgi, and vice versa. Conclusions: CREB3L3 has multi-potent protective effects against atherosclerosis owing to new mechanistic interaction between CREB3L3 and SREBPs under atherogenic conditions