MicroRNA Expression in Response to Controlled Exposure to Diesel Exhaust: Attenuation by the Antioxidant N -Acetylcysteine in a Randomized Crossover Study

Abstract

Background: Adverse health effects associated with diesel exhaust (DE) are thought to be mediated in part by oxidative stress, but the detailed mechanisms are largely unknown. MicroRNAs (miRNAs) regulate gene expression post-transcriptionally and may respond to exposures such as DE.Objectives: We profiled peripheral blood cellular miRNAs in participants with mild asthma who were exposed to controlled DE with and without antioxidant supplementation.Methods: Thirteen participants with asthma underwent controlled inhalation of filtered air and DE in a double-blinded, randomized crossover study of three conditions: a) DE plus placebo (DEP), b) filtered air plus placebo (FAP), or c) DE with N-acetylcysteine supplementation (DEN). Total cellular RNA was extracted from blood drawn before exposure and 6 hr after exposure for miRNA profiling by the NanoString nCounter assay. MiRNAs significantly associated with DEP exposure and a predicted target [nuclear factor (erythroid-derived 2)-like 2 (NRF2)] as well as antioxidant enzyme genes were assessed by reverse transcription–quantitative polymerase chain reaction (RT-qPCR) for validation, and we also assessed the ability of N-acetylcysteine supplementation to block the effect of DE on these specific miRNAs. 8-hydroxy-2´-deoxyguanosine (8-OHdG) was measured in plasma as a systemic oxidative stress marker.Results: Expression of miR-21, miR-30e, miR-215, and miR-144 was significantly associated with DEP. The change in miR-144 was validated by RT-qPCR. NRF2 and its downstream antioxidant genes [glutamate cysteine ligase catalytic subunit (GCLC) and NAD(P)H:quinone oxidoreductase 1 (NQO1)] were negatively associated with miR-144 levels. Increases in miR-144 and miR-21 were associated with plasma 8-hydroxydeoxyguanosine 8-OHdG level and were blunted by antioxidant (i.e, DEN).Conclusions: Systemic miRNAs with plausible biological function are altered by acute moderate-dose DE exposure. Oxidative stress appears to mediate DE-associated changes in miR-144.

In utero exposure to second‐hand smoke activates pro‐asthmatic and oncogenic miRNAs in adult asthmatic mice

“…Dysregulation of miRNA expression has been implicated in diverse diseases, including inflammatory lung disease [Oglesby et al, 2010], cardiovascular disease [Small et al, 2010], and cancer [Melo and Esteller, 2011;Chen et al, 2012]. In recent years, an increasing body of literature has reported dysregulated miRNA expression profiles resulting from direct exposures to various environmental pollutants, including metal-rich particulate matter [Bollati et al, 2010], diesel exhaust particles [Jardim et al, 2009;Yamamoto et al, 2013], and tobacco smoke [Izzotti et al, 2009;Schembri et al, 2009]. Among these studies, metal-rich particulate matter and diesel exhaust particle exposures were reported to aggravate systemic oxidative stress and to up-regulate expression of miRNAs, particularly of miR-21 [Bollati et al, 2010;Yamamoto et al, 2013]; whereas cigarette smoke exposures, both in vitro with human primary bronchial epithelial cells [Schembri et al, 2009] and in vivo with rat lungs [Izzotti et al, 2009], down-regulate expression of miRNAs.…”

“…In recent years, an increasing body of literature has reported dysregulated miRNA expression profiles resulting from direct exposures to various environmental pollutants, including metal-rich particulate matter [Bollati et al, 2010], diesel exhaust particles [Jardim et al, 2009;Yamamoto et al, 2013], and tobacco smoke [Izzotti et al, 2009;Schembri et al, 2009]. Among these studies, metal-rich particulate matter and diesel exhaust particle exposures were reported to aggravate systemic oxidative stress and to up-regulate expression of miRNAs, particularly of miR-21 [Bollati et al, 2010;Yamamoto et al, 2013]; whereas cigarette smoke exposures, both in vitro with human primary bronchial epithelial cells [Schembri et al, 2009] and in vivo with rat lungs [Izzotti et al, 2009], down-regulate expression of miRNAs. Although those dysregulated miRNA expression profiles were clearly detectable immediately after exposures to the environmental pollutants ended, whether the influence of the pollutants on miRNA expression is retained long after the exposures end has not yet been adequately investigated.…”

miR-3940-5p associated with genetic damage in workers exposed to hexavalent chromium

“…Although many studies have showed relationships between environmental chemicals and miRNAs, most of them were conducted via in vitro tests (Jardim et al, 2009), and few focused on examining miRNA expression related to chemicals on human, especially genotoxic chemicals (Bollati et al, 2010;Yamamoto et al, 2013). Here, we screened miRNAs sensitive to Cr(VI) exposure, and validated their target genes related to genetic damage using bioinformatic methods and ELISA.…”

Expression of aromatase in the embryonic brain of the olive ridley sea turtle (Lepidochelys olivacea), and the effect of bisphenol-A in sexually differentiated embryos

“…One and two way ANOVAs coupled to the Holm-Sidak test for multiple comparisons were performed using SigmaPlot v11 and STATISTICA v7 in order to find statistical differences in aromatase relative expression levels (P<0.05). Normalized data (log 2) were plotted according to Yamamoto et al, (2013).…”