Genomic and Epigenomic Biomarkers of Toxicology and Disease. Группа авторов

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style="font-size:15px;">      21 Woodcock, J. (2009). Chutes and ladders on the critical path: Comparative effectiveness, product value, and the use of biomarkers in drug development. Clin. Pharmacol. Ther. 86 (1): 12–14.

       Gail M. Nelson and Brian N. Chorley

       Center for Computational Toxicology and Exposure, Office of Research and Development, US Environmental Protection Agency, Research Triangle Park, NC 27709

      Introduction

      MicroRNAs (miRNAs) are short, non-coding RNAs whose primary known function is to regulate the transcription and translation of messenger RNA. Targeting occurs through sequence specificity; however, this interaction is not limited to a single gene. Rather, a particular miRNA can regulate hundreds of genes. In addition, a transcript may be targeted by multiple miRNAs. As a result, it is estimated that between 30% and 80% of all transcribed genes in mammals may be regulated by miRNAs, depending on the tissue or cell type (Clark et al. 2014; Gu and Kay 2010; Lu and Clark 2012). Thus, alterations in miRNA amounts, even if minute, could feasibly have a large impact on transcriptional profiles. The consequence is important in terms of biological effect, as well as for the identification of biomarkers of health impact.

      The need for specific and sensitive biomarkers spans research and development, regulatory, safety, and clinical sectors. Biomarkers can indicate exposure, biological effect, and sensitivity. All three areas have important purposes and applications. Those that measure biological effect more directly link to biological function, and thus to the putative adverse health effects that a perturbation may mediate. A biomarker may be a measurable alteration—chemical, biochemical, physiological, behavioral, or of some other kind—within an organism (World Health Organization and International Programme on Chemical Safety 1993). miRNAs have the potential to be good biomarkers of biological effect because they are well defined, chemically uniform, restricted to a manageable number, and stable (not readily degraded). They also get released into extracellular matrices, where they are accessible and measurable. In these biofluids such as blood, urine, and sputum, miRNAs serve as unique biomarkers for a minimally invasive prediction of toxicant exposure. The altered biological pathways that is consequent upon (and due to) miRNA changes can therefore reflect the mechanisms of toxicant-related diseases. Measurements of these miRNAs in biofluids can therefore serve as biomarkers of effect.

      The interest in miRNAs as biomarkers of exposure to environmental toxicants and resultant biological effects is bolstered by their stable detection in extracellular biofluids, where they can be non-invasively sampled. There are a number of mechanisms by which miRNAs are released from the cell into these matrices (Condrat et al. 2020) and, importantly, can be linked to tissue or cell type specificity (or both), as well as to mechanisms of biological perturbation that may relate to stress response, toxicity, and disease. In this chapter we review the promise of these putative biomarkers, together with the technical challenges that lie ahead if we want to establish them in the practice of toxicology and regulatory sciences.

      Mechanisms that Contribute to Extracellular miRNA Release

      When using the miRNAs present in biofluids as biomarkers of tissue perturbation, toxicity, or disease, one must understand the origin of these non-coding RNAs in the extracellular space. Most studies have focused on the miRNAs found in blood and urine, although extracellular miRNA has been noted in sputum, tears, amniotic fluid, cerebrospinal fluid, breast milk, and bronchial lavage fluid, among other sites (Arroyo et al. 2011; Chen et al. 2008; Turchinovich et al. 2011; Valadi et al. 2007; Vickers et al. 2011; Wang et al. 2010a; Weber et al. 2010). Although many miRNAs seem to be ubiquitously present in many characterized biofluids, blood plasma has the highest amount of uniquely present miRNAs (Weber et al. 2010). Blood is a complex liquid “tissue” that interacts with many cell types not accessible to other fluids, including those of hematopoietic residence—predominantly erythrocytes and reticulocytes. The contributions from these cell types are important to characterize, so that they can be separated, if needed, from the signals of other cell types or tissues. For example, in whole blood samples, miRs-486-5p and -451a are highly represented because they are derived from erythrocytes and can complicate or mask the evaluation of other putative biomarker miRNAs of lower abundance in the blood (Juzenas et al. 2020). Mechanistically, these potentially interfering factors can be removed by processing blood into serum or plasma, or, in cases where hemolysis may increase the proportion of erythrocyte-derived miRNAs in serum, blocking steps can reduce the measurement of these miRNAs (LaBelle et al. 2021).

      Packaging into Vesicles and Mechanisms of Release

      Figure 2.1 Tissue-specific miRNAs in mammals. Human tissue-specific miRNAs that were described as part of the human miRNA tissue atlas study (Ludwig et al. 2016) (light grey circle with dotted/dashed line) were cross-referenced with miRNA atlas studies that examine tissue-specific miRNAs in mouse (medium grey circle with dashed line) and rat (dark grey circle with solid line). Those miRNAs that transverse all three circles are ideal cross-species biomarkers for toxicological

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