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Figure 4.3 depicts the candidate circulating miRNA biomarker expression status across different metals (or metal mixtures), stratified by body fluids (plasma, blood, serum and urine). Plasma and blood are by far the most heavily investigated biofluids; and they are followed by urine and serum. However, regardless of the body fluids assessed, very few miRNAs are represented as putative biomarkers across multiple metal exposures. Presently miR-21 seems to be the most promising biomarker candidate and the one with the strongest experimental evidence. Circulating miR-21 is higher in both the plasma and the blood of arsenic-exposed individuals from India and China. Additionally, plasma levels of miR-21 are suppressed in chromium-exposed individuals but induced in cadmium-exposed individuals. Circulating miR-21 has also been detected in the urine of individuals exposed to metal mixtures, although the nature of its expression varied depending on the population (Cardenas-Gonzalez et al. 2016; Kong et al. 2012).

Figure 4.3 Differential expression map of circulating miRNAs dysregulated after heavy metal or mixed metal exposure, stratified by body fluid. Circulating miRNAs dysregulated as a result of heavy metal exposure to arsenic (As), cadmium (Cd), chromium (Cr), mercury (Hg), lead (Pb), and mixed metals (MM) across all studies examined in this chapter are presented within specific biofluids analysed: (A) plasma, (B) whole blood, (C) urine, and (D) serum. Induced circulating miRNAs are represented in blue, suppressed or lower circulating miRNAs are represented in green, miRNAs that were not examined in a particular biofluid for specific metals are represented in white, and miRNAs that showed conflicting results in multiple studies within a biofluid are shown in purple.

Figure 4.4 represents the circulating miRNA biomarker expression status across different body fluids for each metal (or metal mixture) exposure, individually. Even for the same metal exposure, the nature of dysregulated miRNA expression varies considerably within the different body fluids tested so far, with little or no overlap. Furthermore, even if the same miRNA is differentially expressed in multiple body fluids for a particular metal exposure, often the direction of expression change is not consistent across the different fluids. For example, miR-126 is dysregulated upon arsenic exposure in blood, plasma, and serum. However, while it is induced in blood, it is found to be suppressed in both plasma and serum (Figure 9.4), which suggests that the induction is in circulating cells. In summary, despite all the studies, there is still no circulating miRNA that is unequivocally representative of exposure to a specific heavy metal, either across all biofluids or across all heavy metals for any specific biofluid. This inconsistency is possibly due to the fact that the number of studies that are not on arsenic exposure is so limited. Such inconsistencies are further complicated by differences between study designs, some of which employ end points and statistical measures (e.g., point estimates versus interval estimates) that make it difficult to unify all the results and gain a holistic understanding.

Figure 4.4 Differential expression map of circulating miRNAs dysregulated after a specific heavy metal or mixed metal exposure across different body fluids. Circulating miRNAs dysregulated in different biofluids (blood, plasma, serum and urine) upon exposure to (A) arsenic (As), (B) cadmium (Cd), (C) chromium (Cr), (D) mercury (Hg), (E) lead (Pb), and (F) mixed metals (MM). Induced circulating miRNAs are represented in blue, suppressed or lower circulating miRNAs are represented in green, miRNAs that were not examined in a particular biofluid for specific metals are represented in white, and miRNAs that showed conflicting results in multiple studies within a biofluid are shown in purple.