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Often populations are exposed to a mixture of metals released into the environment either through natural processes or as an outcome of anthropogenic activities (Cory-Slechta 2005). While it is important to understand the effect of each metal on human health individually, this does not adequately elucidate the molecular events operative within the environmental reality of mixed metal exposures (Cory-Slechta 2005). This is particularly important, given that exposure to one metal can affect the uptake, metabolism, disposition, and elimination of other metals and their metabolites (Young et al. 2019).

Recently studies have started analyzing how expression of miRNA(s) are altered by exposure to multimetal mixtures. In a study of welders exposed to mixed metal fumes, plasma miR-21 and miR-155 levels were lower than in matched unexposed control populations (Amrani et al. 2020). Furthermore, miR-21 and miR-155 expression levels were demonstrated to be positively associated with urinary chromium levels, while miR-146a was positively associated with urinary nickel levels (Amrani et al. 2020). In another study on sixty-three healthy male steel plant workers occupationally exposed to mixed metal particulate matter, blood leukocyte expression of miR-222 was positively correlated with lead exposure, while that of miR-146a was negatively correlated with lead and cadmium exposures (Bollati et al. 2010). Importantly, only miR-222 was found to be significantly upregulated in workers at the end of the workweek by comparison with the situation at the beginning of the workweek, after two days’ break from exposure to particulate matter. In a subsequent study from the same group, the leukocyte expression of four upregulated miRNAs (miR-421, miR-146a, miR-29a, and let-7g) was found to regulate the downstream expression of eleven target candidate inflammatory genes in a population of ten steel plant workers exposed to mixed metal particulate matter (Motta et al. 2013). In another study, urinary expression of miR-200c and miR-423 was positively associated with chromium concentration in individuals in the upper tertile of urinary chromium levels, but not with arsenic levels in a cohort of Mexican children (Cardenas-Gonzalez et al. 2016). In a study of healthy male coke oven workers in southern China, decreased plasma expression levels of miR-27a-3p were associated with lead exposure (Deng et al. 2019). In another study, on Hong Kong Chinese adolescents, expressions of urinary miR-21 and miR-221 were found to be negatively correlated both with urinary arsenic and lead (Kong et al. 2012).

Multiple heavy metal exposures often interact in a myriad of ways, modulating toxicity and health outcomes (Wah Chu and Chow 2002; Young et al. 2019). No studies thus far have examined whether there is any additive, synergistic, or antagonistic effect between the different metals in terms of miRNA expression modulation. This lack of investigation represents a considerable knowledge gap in the field—and one that needs to be addressed.