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miRNA expression profiling has demonstrated dysregulation of miRNA expression in a wide range of human diseases (Bonneau et al. 2019). Dysregulated miRNA expression has been shown to affect a large variety of cellular processes, for example transcription, signal transduction, cellular proliferation, differentiation, apoptosis, and epithelial-mesenchymal transition (Aleckovic and Kang 2015). Alterations in miRNA expression signatures offer great potential for use as clinical biomarkers, because miRNAs are stable in biological samples, including formalin fixed paraffin sections (FFPE) and plasma (Amini et al. 2017; Aryani and Denecke 2015; Heneghan et al. 2010; Kotorashvili et al. 2012; Wimmer et al. 2018). Additionally, miRNAs can be reliably detected in multiple bodily fluids such as blood, serum, amniotic fluid, breast milk, bronchial lavage, cerebrospinal fluid, colostrum, peritoneal fluid, plasma, pleural fluid, saliva, seminal fluid, tears, and urine (De Guire et al. 2013; Hammond 2015; Lawrie et al. 2008; Weber et al. 2010). But the total RNA concentration and the total number of distinct miRNAs can differ vastly between various body fluids (Weber et al. 2010). Likewise, specific circulating miRNAs can be enriched within specific fluids.

Circulating miRNAs are released into circulation in one of two forms: they are either bound to specific RNA-binding proteins (Ago; high density lipoprotein, HDL; or low-density lipoprotein, LDL) or encapsulated in microvesicles along with proteins, lipids, and other nucleic acids (Aleckovic and Kang 2015; Cui et al. 2019; Mori et al. 2019; see Figure 4.2). The release mechanisms of protein- or lipid-bound miRNAs is largely unknown, whereas exosomal miRNAs are known to be selectively recruited and actively secreted in a regulated manner (Aleckovic and Kang 2015). When injected intravenously, the exosomes can remain in the circulation for up to two hours, which implies a large range in the bioavailability of circulating miRNAs (Mori et al. 2019).

The potential use of circulating miRNAs as non-invasive diagnostic and prognostic biomarkers for disease status in biological fluids was first realized in the field of cancer biology because cancer diagnosis and prognosis rely on invasive tissue biopsies (Correia et al. 2017; Iorio and Croce 2012). More recently, changes in circulating miRNA profiles upon heavy metal exposure have been described. In consequence, this chapter strives to provide a comprehensive resource, which will highlight studies that have identified circulating miRNAs as a result of heavy metal exposure and assist with rigor and reproducibility in future studies. We have chosen to limit our focus to the five metals (arsenic, lead, mercury, cadmium, chromium) ranked currently at the top of the ASTDR substance priority list on the basis of their significant toxicity and of the high potential for human exposure to them.