Circulating MicroRNAs, Polychlorinated Biphenyls, and Environmental Liver Disease in the Anniston Community Health Survey

Abstract

Background: Polychlorinated biphenyl (PCB) exposures have been associated with liver injury in human cohorts, and steatohepatitis with liver necrosis in model systems. MicroRNAs (miRs) maintain cellular homeostasis and may regulate the response to environmental stress. Objectives: We tested the hypothesis that specific miRs are associated with liver disease and PCB exposures in a residential cohort. Methods: Sixty-eight targeted hepatotoxicity miRs were measured in archived serum from 734 PCB-exposed participants in the cross-sectional Anniston Community Health Survey. Necrotic and other liver disease categories were defined by serum keratin 18 (K18) biomarkers. Associations were determined between exposure biomarkers (35 ortho-substituted PCB congeners) and disease biomarkers (highly expressed miRs or previously measured cytokines), and Ingenuity Pathway Analysis was performed. Results: The necrotic liver disease category was associated with four up-regulated miRs (miR-99a-5p, miR-122-5p, miR-192-5p, and miR-320a) and five down-regulated miRs (let-7d-5p, miR-17-5p, miR-24-3p, miR-197-3p, and miR-221-3p). Twenty-two miRs were associated with the other liver disease category or with K18 measurements. Eleven miRs were associated with 24 PCBs, most commonly congeners with anti-estrogenic activities. Most of the exposure-associated miRs were associated with at least one serum hepatocyte death, pro-inflammatory cytokine or insulin resistance bioarker, or with both. Within each biomarker category, associations were strongest for the liver-specific miR-122-5p. Pathways of liver toxicity that were identified included inflammation/hepatitis, hyperplasia/hyperproliferation, cirrhosis, and hepatocellular carcinoma. Tumor protein p53 and tumor necrosis factor were well integrated within the top identified networks. Discussion: These results support the human hepatotoxicity of environmental PCB exposures while elucidating potential modes of PCB action. The MiR-derived liquid liver biopsy represents a promising new technique for environmental hepatology cohort studies. https://doi.org/10.1289/EHP9467

The environmental pollutant, polychlorinated biphenyl 126, alters liver function in a rodent model of alcohol‐associated liver disease

“…These environmental chemicals include distinct categories of contaminants such as persistent organic pollutants (POPs) like polychlorinated biphenyls (PCBs). Using epidemiologic data and experimental animal models, several studies have demonstrated that exposure to PCBs is associated with liver injury, steatohepatitis, and obesity (Cave et al, 2022; Clair et al, 2018; Deng et al, 2019). Irrespective of etiology, each subtype of FLD can further progress to more severe pathological states, which are dictated by other factors including sex, diet, alcohol or tobacco use, and genetic susceptibility (Crabb et al, 2020; Younossi et al, 2018).…”

Investigating the effects of long-term Aroclor 1260 exposure on fatty liver disease in a diet-induced obesity mouse model

“…Nonetheless, PCB exposures have been associated with human hepatocellular carcinoma development (46,50). Intriguingly, pathway enrichment analysis and liquid liver biopsy generated from the differentially expressed circulating microRNAs associated with PCB exposures in the ACHS population demonstrated activation of hepatocellular carcinoma-associated pathways involving the tumor suppressor P53 (3). Overall, the mechanisms responsible for the observed PCB-associated hepatocellular carcinoma development in the current study, particularly focusing on carcinogenic pathways, are currently being investigated and findings will be disseminated in a separate publication.…”

“…Polychlorinated biphenyls (PCBs) are environmental toxicants associated with numerous health effects such as cardiovascular complications and metabolic diseases in exposed populations (1)(2)(3). Categorized as persistent organic pollutants (POPs), PCBs continue to threaten public health due to their resistance to degradation and bioaccumulation in living organisms (4).…”

Differential expression of microRNA in the serum of patients with polycystic ovary syndrome with insulin resistance

“…One study found that in PCOS ovarian granulosa cells, inhibition of long noncoding RNA (lncRNA) plasmacytoma variant translocation 1 (PVT1) and overexpression of miR-17-5p resulted in the downregulation of phosphatase and tensin homolog (PTEN) and promoted cell proliferation, thereby inhibiting the apoptosis of ovarian granulosa cells (38). In addition, the downregulation of miR-99a expression in patients with PCOS may be closely related to insulin resistance and hyperinsulinemia (39). miR-99a can inhibit the proliferation of human glomerular basement membrane cells and promote their apoptosis by targeting insulin-like growth factor 1 receptor (IGF-1R), which may be part of the cause of abnormal PCOS follicles (40).…”