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group but not in the exposed groups, which suggested that the disruption of miRNA activity was due to chemical exposure. Messenger RNAs connecting with miR-200a and miR-375 in the control network only were enriched for the mammary gland development and gland morphogenesis pathways, and the effects of chemical exposure on these two miRNAs were confirmed in human breast cancer cell lines.

      Song and Ryu (2015) identified characteristic miRNA profiles of human whole blood in workers exposed to volatile organic compounds (VOCs) and compared their effectiveness to the conventionally used metabolite markers of exposure. They were able to discern each VOC (toluene, xylene, and ethylbenzene) from the control group with higher accuracy, sensitivity, and specificity than the urinary biomarkers. In a recent study, serum miRNAs were associated with polychlorinated biphenyl (PCB) exposures and environmental liver disease in a residential cohort (Cave et al. 2022). This longitudinal cohort study enrolled residents of Anniston, Alabama that exhibited PCB levels twice and three times higher than found in the average population (Pavuk et al. 2014). A miRNA panel for liver toxicity and disease was assessed, and many of the miRNAs correlated with biomarkers of disease toxicity, metabolic changes, and inflammation. In addition, some of the miRNAs also correlated with levels of PCB measured in the serum. These miRNAs included miR-122-5p, -192-5p, and -99a-5p, which have been previously established to have important roles in liver disease and can serve as accessible biomarkers of disease progression (Brunetto et al. 2014; Gjorgjieva et al. 2019; Lopez-Sanchez et al. 2021). While more work needs to be done to establish the causative reasons why miRNAs in blood are correlating with both disease biomarkers and exposure, the indication is that they may serve as biomarkers of environmental pollutant health effects that include liver cell loss, change in function, and inflammatory response.

      Application

      Challenges and Future Focus

      While there is considerable promise in the use of miRNA biomarkers in biofluids, the precise quantification of circulating miRNAs is challenging and the validation of introduced biomarkers is often unsuccessful. This is indicated by a decline in published biofluid-based miRNA biomarker research in the past couple of years, whereas between 2009 and 2015 yearly publications nearly doubled (Chorley et al. 2021a). This downward trajectory is partially attributed to technical obstacles for measuring miRNAs, some of which have been discussed in the preceding sections. Pre-analytical variables such as sample collection, processing, storage, and extraction are potential causes of inconsistency in miRNA measurements. Post-analytical challenges include the normalization of data and the interpretation of miRNA changes observed to be due to perturbation and release into biofluids. These uncertainties and challenges have inhibited full implementation in multiple sectors such as clinical, regulatory, and academic use.

      For pre-analytical steps, the standardization of

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