Rationale: Chronic electronic cigarette (EC) users exhibit a higher susceptibility of LDL (low-density lipoprotein) to undergo oxidation as compared with nonuser controls. However, there is a paucity of data regarding EC effects on lipid peroxidation in the blood and their relationship to cardiovascular risk. Objective: To test the hypothesis that chronic (≥1 year) EC use exerts intermediate effects on plasma lipid peroxidation and/or antioxidant defense compared with chronic tobacco cigarette (TC) smoking. Methods and Results: We enrolled EC-users (n=32), TC-smokers (n=29), and nonusers (n=45), with mean ages of 28.3, 27.8, and 27.4 years, respectively. Plasma concentrations of free polyunsaturated fatty acids and oxidized metabolites were assessed by mass spectrometry. Total antioxidant capacity, concentrations of glutathione, bilirubin, HO-1 (heme oxygenase-1), and functional activity of PON1 (paraoxonase1) were determined by colorimetric and enzymatic assays. Multivariable analysis was performed using classification models for segregating participants based on biomarker profiles. TC-smokers exhibited higher plasma arachidonic acid concentration. Instead, EC-users displayed lower plasma concentrations of both arachidonic acid and linoleic acid as compared to non-users and TC-smokers ( P <0.05). Oxidized linoleic acid metabolites (9- and 13-hydroxyoctadecadienoic acid) were lower in EC-users and TC-smokers as compared with nonusers ( P <0.001). Consistently, total antioxidant capacity and bilirubin were elevated in EC-users and TC-smokers as compared with nonusers ( P <0.05). Of interest, plasma HO-1 concentration was higher in TC-smokers as compared with nonusers ( P =0.01) with intermediate levels in EC-users. Multivariable analysis identified 5 biomarkers (13-hydroxyoctadecadienoic acid, linoleic acid, 9-hydroxyoctadecadienoic acid, 12-hydroxyeicosatetraenoic acid, arachidonic acid) that discriminated EC-users from TC-smokers and nonusers with an accuracy of 73.4%. Conclusions: Chronic use of EC induces common (ie, lower 9- and/or 13-hydroxyoctadecadienoic acids and higher total antioxidant capacity and bilirubin) as well as differential effects (ie, altered arachidonic acid and linoleic acid concentrations) to those induced by TC, along with intermediate plasma HO-1 concentration, suggesting that EC, likewise TC smoke, could impact cardiovascular risk.

Both pro- and antiatherosclerotic effects have been ascribed to dietary peroxidized lipids. Confusion on the role of peroxidized lipids in atherosclerotic cardiovascular disease is punctuated by a lack of understanding regarding the metabolic fate and potential physiological effects of dietary peroxidized lipids and their decomposition products. This study sought to determine the metabolic fate and physiological ramifications of 13-hydroperoxyoctadecadienoic acid (13-HPODE) and 13-HODE (13-hydroxyoctadecadienoic acid) supplementation in intestinal and hepatic cell lines, as well as any effects resulting from 13-HPODE or 13-HODE degradation products. In the presence of Caco-2 cells, 13-HPODE was rapidly reduced to 13-HODE. Upon entering the cell, 13-HODE appears to undergo decomposition, followed by esterification. Moreover, 13-HPODE undergoes autodecomposition to produce aldehydes such as 9-oxononanoic acid (9-ONA). Results indicate that 9-ONA was oxidized to azelaic acid (AzA) rapidly in cell culture media, but AzA was poorly absorbed by intestinal cells and remained detectable in cell culture media for up to 18 h. An increased apolipoprotein A1 (ApoA1) secretion was observed in Caco-2 cells in the presence of 13-HPODE, 9-ONA, and AzA, whereas such induction was not observed in HepG2 cells. However, 13-HPODE treatments suppressed paraoxonase 1 (PON1) activity, suggesting the induction of ApoA1 secretion by 13-HPODE may not represent functional high-density lipoprotein (HDL) capable of reducing oxidative stress. Alternatively, AzA induced both ApoA1 secretion and PON1 activity while suppressing ApoB secretion in differentiated Caco-2 cells but not in HepG2. These results suggest oxidation of 9-ONA to AzA might be an important phenomenon, resulting in the accumulation of potentially beneficial dietary peroxidized lipid-derived aldehydes.

Air pollution exposure enhances the risk of cardiovascular morbidity and mortality. Epidemiological studies provide strong evidence of a link between exposure to ambient particulate matter with aerodynamic diameter< 2.5 µm (PM_2.5) and development of cardiovascular and metabolic disorders. We have shown that inhaled ultrafine particles (UFP) or whole diesel exhaust (DE), enriched in UFP, induce cardiometabolic effects, including dyslipidemia and hepatic steatosis. However, the pathogenic mechanisms remain unknown. We recently demonstrated that exposure to ambient particulate in the ultrafine-size range altered the gut microbiota composition in various animal models, with a potential to induce systemic effects. Thus, we hypothesized that sub-chronic inhalation exposure to DE leads to gut dysbiosis and altered gut-derived metabolites, likely responsible for some of the metabolic effects. Male apolipoprotein E^-/- (ApoE^-/-) mice, exposed to inhaled DE vs. filtered air (FA) (6 h/day, 5 days/week for 16 weeks) displayed alterations in cecal microbiota composition, which associated with elevated plasma cholesterol and triglycerides, as well as hepatic triglycerides and oxidized lipids. DE exposure upregulated hepatic mRNA and protein levels of 12-lipoxygenase (Alox12), together with significantly reduced fecal acetate levels, correlating with changes in lipids and cecal microbiota composition. Metabolic effects were recapitulated in HepG2 cells treated with DE particles, including elevated Alox12 mRNA levels and decreased respiration in isolated mitochondria. Supplementation with gut-derived short chain fatty acid acetate reversed these effects in cells. In conclusion, inhaled DE induced gut microbiome dysbiosis, lipid peroxidation and triglyceride accumulation, likely via mitochondrial dysfunction, which was rescued in cells by acetate supplementation.

Inflammatory bowel disease (IBD) is an immunologically complex disorder involving genetic, microbial, and environmental risk factors. Its global burden has continued to rise since industrialization, with epidemiological studies suggesting that ambient particulate matter (PM) in air pollution could be a contributing factor. Prior animal studies have shown that oral PM₁₀ exposure promotes intestinal inflammation in a genetic IBD model and that PM_2.5 inhalation exposure can increase intestinal levels of pro-inflammatory cytokines. PM₁₀ and PM_2.5 include ultrafine particles (UFP), which have an aerodynamic diameter of <0.10 μm and biophysical and biochemical properties that promote toxicity. UFP inhalation, however, has not been previously studied in the context of murine models of IBD. Here, we demonstrated that ambient PM is toxic to cultured Caco-2 intestinal epithelial cells and examined whether UFP inhalation affected acute colitis induced by dextran sodium sulfate and 2,4,6-trinitrobenzenesulfonic acid. C57BL/6J mice were exposed to filtered air (FA) or various types of ambient PM reaerosolized in the ultrafine size range at ~300 μg/m³, 6 h/day, 3–5 days/week, starting 7–10 days before disease induction. No differences in weight change, clinical disease activity, or histology were observed between the PM and FA-exposed groups. In conclusion, UFP inhalation exposure did not exacerbate intestinal inflammation in acute, chemically-induced colitis models.