A compromised liver alters polychlorinated biphenyl-mediated toxicity

Abstract

Exposure to environmental toxicants namely polychlorinated biphenyls (PCBs) is correlated with multiple health disorders including liver and cardiovascular diseases. The liver is important for both xenobiotic and endobiotic metabolism. However, the responses of an injured liver to subsequent environmental insults has not been investigated. The current study aims to evaluate the role of a compromised liver in PCB-induced toxicity and define the implications on overall body homeostasis. Male C57Bl/6 mice were fed either an amino acid control diet (CD) or a methionine-choline deficient diet (MCD) during the 12-week study. Mice were subsequently exposed to either PCB126 (4.9 mg/kg) or the PCB mixture, Arcolor1260 (20 mg/kg) and analyzed for inflammatory, calorimetry and metabolic parameters. Consistent with the literature, MCD diet-fed mice demonstrated steatosis, indicative of a compromised liver. Mice fed the MCD-diet and subsequently exposed to PCB126 showed observable wasting syndrome leading to mortality. PCB126 and Aroclor1260 exposure worsened hepatic fibrosis exhibited by the MCD groups. Interestingly, PCB126 but not Aroclor1260 induced steatosis and inflammation in CD-fed mice. Mice with liver injury and subsequently exposed to PCBs also manifested metabolic disturbances due to alterations in hepatic gene expression. Furthermore, PCB exposure in MCD-fed mice led to extra-hepatic toxicity such as upregulated circulating inflammatory biomarkers, implicating endothelial cell dysfunction. Taken together, these results indicate that environmental pollution can exacerbate toxicity caused by diet-induced liver injury which may be partially due to dysfunctional energy homeostasis. This is relevant to PCB-exposed human cohorts who suffer from alcohol or diet-induced fatty liver diseases.

Epidermal growth factor receptor (EGFR) inhibition by polychlorinated biphenyls contributes to non-alcoholic fatty liver disease (NAFLD).

“…These data suggest that PCB exposures can promote a fibrotic response through a mechanism involving TGF-β production from hepatocytes and MEF2C upregulation. While histologically liver fibrosis was not increased in this model it has been reported in other PCB exposure models that have either longer periods of PCB exposures and/or certain dietary conditions (3,139). These data suggest that fibrosis in response to PCBs should be reevaluated in other model systems and human subjects as the data suggest PCBs promote the early stages of fibrosis (e.g.…”

“…Based On the proteomic data I conducted pathway analysis and transcription factor analysis to elucidate mechanism for PCB-mediated steatohepatitis. Previously some PCBs have been shown to activate human and murine aryl hydrocarbon receptor (AhR) and some nuclear receptors [e.g., the pregnane x receptor (PXR) and the constitutive androstane receptor (CAR)]; while inhibiting epidermal growth factor receptor (EGFR) signaling (3,36,96,139,140). Knocking out PXR or CAR modulated but did not prevent the steatohepatitis associated with Aroclor 1260 and high fat diet co-exposures, implicating additional mechanisms (18).…”

Hepatic signalling disruption by pollutant Polychlorinated biphenyls in steatohepatitis

“…In addition, PCB-126 can promote liver disease in in vivo [24] and was demonstrated to be the most potent EGFR inhibitor (of the PCB congeners) tested in vitro [1]. PCB-153 worsened steatosis in vivo [25], and was a potent EGFR inhibitor in vitro as well, but less so than PCB-126.…”

Protective influence of healthful nutrition on mechanisms of environmental pollutant toxicity and disease risks

“…It has been demonstrated that compromised health or suboptimal lifestyles may exacerbate the toxicity of environmental pollutants. For example, it has been shown that pollutant toxicity is worsened in animal models with NAFLD . This illustrates the idea that individuals in poor health or with underlying disease conditions may be more susceptible to environmental insult or other chemical or nonchemical stressors.…”

“…For example, it has been shown that pollutant toxicity is worsened in animal models with NAFLD. 37 This illustrates the idea that individuals in poor health or with underlying disease conditions may be more susceptible to environmental insult or other chemical or nonchemical stressors. Additionally, it is now appreciated that events occurring during pregnancy can play a significant role in the future health and disease risk of the offspring.…”