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et al. 2015; Song et al. 2016; Wang et al. 2009). In combination with the liver injury biomarkers cytokeratin-18 and glutamate dehydrogenase, miR-122 outperformed individual biomarkers and had a higher than 0.92 correlation with alanine aminotransferase (ALT) in a validation cohort of individuals with acetominophen overdose (Llewellyn et al. 2021). In pre-clinical settings, miR-122 did mildly improve the diagnosis of DILI (4% increase in predictive accuracy using a multiparameter approach) and was highly correlated with necrosis, vacuolization, and hepatocellular hypertrophy (Sharapova et al. 2016), which indicated its usefulness as a leakage biomarker. However, the use of miR-122 has been hampered by a notably high baseline variability in human samples (> 100-fold interval; Vogt et al. 2019). This was likely due to differences in ethnic backgrounds (Church et al. 2019), undiagnosed states such as milder pathologies of non-alcoholic fatty liver disease (Cermelli et al. 2011), and short circulatory half-life (Thulin et al. 2017).

      In addition to liver and kidney injury, circulating miRNAs are being investigated as mechanistic biomarkers of diseases such as cancer (Dutta et al. 2019; Jin et al. 2019; Lin et al. 2019; Pascut et al. 2019; Wang et al. 2018), cardiovascular disease (Zhou et al. 2018), metabolic syndrome (Huang et al. 2018), neurodegenerative disease (Juzwik et al. 2019; Sharma and Lu 2018), and chronic obstructive pulmonary disease (COPD) (Finicelli et al. 2020), all diseases whose etiology can include environmental toxicant exposure. Several recent reviews examine the dysregulation of miRNAs by environmental contaminants related to human health (Balasubramanian et al. 2020; Harrill et al. 2016; Qiao et al. 2019; Sollome et al. 2016; Tumolo et al. 2020; Wallace et al. 2020). Vrijens et al. (2015) summarized some of the miRNAs that respond to environmental exposure and their roles in human disease. The current knowledge linking cancer and neurodegenerative diseases to dysregulation of miRNAs after pesticide exposure was reviewed by Costa et al. (2020). A comprehensive literature review by Sima et al. 2011 (twenty-seven studies between 2012 and 2020) focused on miRNA expression in humans exposed to various air pollutants. Because air pollution is a factor in the development of lung cancer, they reported miRNAs commonly deregulated by both conditions, identifying twenty-five miRNAs that could serve as biomarkers of exposure to harmful pollutants that potentially contribute to lung cancer development. Several miRNAs were deregulated in multiple studies and may therefore be the most promising candidates: miRs-222, -21, -126-3p, -155 and -425.

Exposure Sample type miRNAs Related Disease References
Air Pollution various biofluids multiple, in particular miR-222, miR-21, miR-126-3p, miR-155 and miR-425 lung cancer (Sima et al. 2021)
PM2.5, black carbon, organic carbon, sulfate leukocytes miR-126, miR-135a, miR-146a, miR-155, miR-9 ↓ (Fossati et al. 2014)
Coal fumes (miners) blood lymphocytes SNPs in pre-miRNA genes of miR-149 pneumoconiosus (Wang et al. 2010b)
Black carbon and coal dust (urban traffic PM) blood let-7 g, miR-29, miR-146, miR-421 ↑ (Motta et al. 2013)
Air pollution PM10 plasma MV miR-126 ↑ (Motta et al. 2013)
Metal rich fumes in steel industry (PM10) blood leukocytes miR-21 and miR-222 ↑ (Bollati et al. 2010)
Metal rich fumes in steel industry (PM10) blood leukocytes miR-146 ↓ (Bollati et al. 2010)
Metal rich PM plasma miR-128, miR-302c ↑ (Tumolo et al. 2020), (Bollati et al. 2015)
PM blood miR-21-5p, miR-223-3p ↓ (Tumolo et al. 2020), (Louwies et al. 2016)
PM serum miR-15a-5p, -19b-3p, -23a-3p, -93-5p, -126-3p, -130-3p, -142-3p, -146a-5p, -150-5p, -191-5p, -223-3p, let-7a-5p, let-7g-5p ↑ (Tumolo et al. 2020), (Rodosthenous et al. 2016)
PM

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