Exploring the Impact of Polychlorinated Biphenyls (PCBs) on the Development of MASLD: A Comprehensive Review

Highlights: Experimental, epidemiological, and mechanistic evidence links polychlorinated bi-phenyl (PCB) exposure to liver injury, steatosis/steatohepatitis, fibrosis, and hepato-carcinogenesis, with a focus on congener profiles and susceptibility factors (e.g., sex, metabolic comorbidities). PCB-driven molecular pathways in hepatocytes and hepatic non-parenchymal cells, specifically in aryl hydrocarbon receptor (AhR), constitutive androstane receptor (CAR), and pregnane X receptor (PXR) signaling, oxidative stress, mitochondrial dysfunction, lipid metabolism reprogramming, inflammatory/immune responses, have implications for liver disease progression. What are the main findings? Chronic PCB exposure is consistently associated with liver dysfunction and MASLD phenotypes in both humans and experimental models. PCBs disrupt hepatic homeostasis by converging on a limited set of pathways (AhR, CAR/PXR), inducing oxidative and ER stress, mitochondrial impairment, and the dysregulation of lipid and glucose metabolism. What are the implications of the main findings? There is an impact on public health and clinical practice. We suggestcandidate biomarkers and therapeutic targets. Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), is becoming the most common liver disease, affecting between 30 and 40% of the global population. MASLD is a multifaceted disease spectrum that is closely associated with obesity, insulin resistance, type 2 diabetes mellitus and, more broadly, metabolic syndrome. All these conditions increase the risk of liver-related mortality, which explains the intense research efforts in recent years to better elucidate its pathogenesis. The crucial impact of environmental pollutants on the development of MASLD is now well recognized. Polychlorinated biphenyls (PCBs) are environmental contaminants that act as endocrine disruptors. Recently, they have been associated with the development of diabetes, obesity, MASLD, and cancer. The association between liver diseases, namely toxicant-associated steatotic liver disease and steatohepatitis (TASLD and TASH, respectively), and occupational exposure to PCBs and other industrial chemicals has been documented by several lines of evidence, whereas the potential role of low-level environmental pollution in liver disease and in MASLD remains incompletely understood. Previous studies on animal models have shown that PCB exposure is associated with steatosis/steatohepatitis, fibrosis, cirrhosis, hepatocellular carcinoma (HCC), altered liver enzymes, and mortality in exposed populations. This review investigates the mechanisms underlying hepatic steatogenesis in preclinical and animal models and analyzes the existing literature on the possible role of PCBs, together with the other conventional risk factors, in the development of MASLD in humans.