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Importantly, all circulating miRNAs associated with metal exposure are currently in stages of discovery and development and have not yet been validated; nor are they considered biomarkers. Biomarkers must be validated in accordance with well-established protocols that involve multiple independent qualitative and quantitative steps, before they can be employed for diagnosis or monitoring (Califf 2018). Consequently, there is a significant knowledge gap when it comes to identifying a circulating miRNA that can be used consistently or can be used as a unique biomarker for heavy metal exposure or for disease outcome(s) of such exposure. Therefore future studies should first find out whether there are differences between heavy metal exposures for the circulating miRNAs summarized in Figure 4.3. Furthermore, the assessment of these candidate biomarkers and of other circulating miRNAs should be validated in other fluids that do not rely on blood draw and contain high levels of miRNAs, for instance sweat, tears, saliva, semen, or breast milk (Barcelo et al. 2019; Karvinen et al. 2020; Rubio et al. 2018; Setti et al. 2020; Weber et al. 2010).

Other areas that need to be addressed are things such as limited sample sizes and the inclusion of geographically restricted populations. Both factors need to be taken into account when suggesting the use of a circulating miRNA as a putative biomarker. Ideally, future studies should be performed with these candidate circulating miRNAs across larger populations from numerous geographic regions. This approach will ultimately enable multiple stratifications across biological and socioeconomic parameters in order to investigate whether initial patterns discovered for circulating miRNAs are both consistent and associated with these additional factors.

Although causality is not a required criterion for a biomarker, it would be important and interesting to examine whether any of these dysregulated miRNAs plays a causal role in the etiology of any metal exposure-induced diseases. A few studies have been conducted in this direction. As consistent with human studies, miR-21 was increased in immortalized human keratinocytes (HaCaT) exposed to 500 nM arsenite for four weeks (Gonzalez et al. 2015) and in human umbilical vein endothelial cells (HUVEC) exposed to 20 μM arsenite for twenty-four hours (Li et al. 2012). A recent systematic review and meta-analysis suggests that arsenic-induced miR-21 expression suppresses phosphatase and tensin homolog (PTEN) and protein sprouty homolog 1 (Spry1) levels, leading to epithelial–mesenchymal transition (EMT) and malignant transformation (Liu et al. 2018). miR-21 is a well-conserved miRNA, frequently found upregulated in numerous types of cancer (Feng and Tsao 2016). Furthermore, in cadmium-exposed individuals, miR-21 was associated with renal dysfunction, characterized by increased excretion of the low molecular weight protein N-Acetyl-beta-(D)-glucosaminidase in urine (Lei et al. 2019). Thus it is important to consider circulating miR-21 as a potential biomarker for heavy metal exposure and to investigate its potential mechanistic role in heavy metal exposure-induced disease outcomes. Similarly, upregulation of miR-92a-3p and miR-486-5p after mercury exposure has been recapitulated in vitro by exposing HEK-293 and HUVEC human cell lines to mercuric chloride (Ding et al. 2017).