Liver Disease in a Residential Cohort With Elevated Polychlorinated Biphenyl Exposures

Clair, Heather B.; Pinkston, Christina; Shesh, N.; Pavúk, Marián; Dutton, Nina; Brock, Guy; Prough, Russell A.; Falkner, K. Cameron; McClain, Craig J.; Cave, Matthew C.

doi:10.1093/toxsci/kfy076

Cited by 59 publications

(70 citation statements)

References 49 publications

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“…Secondly, PCBs are endocrine disruptors which have been shown to decrease circulating hormone levels [6]. For example, PCB exposures were associated with reduced insulin and leptin levels in both animal and human studies (ACHS) [6, 15]. This is consistent with decreased insulin and leptin action detected by MetaCore ontologies in this study.…”

Section: Discussionsupporting

confidence: 84%

“…The interaction of a HFD and PCB exposure highlighted liver necrosis pathology which reinforces previous findings [25, 29, 30]. Aroclor was found to affect pathways involving PI3K (phosphoinositide 3-kinase), insulin and LXR (Liver X receptor) that has previously been demonstrated with PCB exposures in the liver [1, 6, 11]. These animals were in the fasted state where hepatic EGFR regulates PI3K activity [31].…”

Section: Discussionsupporting

confidence: 84%

“…Thus, the pathway analysis highlighting insulin and leptin signalling (fed state receptors) as pathways affected by Aroclor exposure was interesting as these receptors all overlap in their regulation of PI3K [32]. Previously elevated PCB body burden in humans was directly correlated to decreases in serum leptin and insulin [6]. This may in part explain the pathway analysis and further contribute to understanding how PCBs disrupt cell signalling through limiting the abundance of metabolic receptor ligands.…”

Section: Discussionmentioning

confidence: 99%

“…Due to homology with other conserved receptor structure, it is possible that PCBs could also inhibit related receptors [35]. Secondly, PCBs are endocrine disruptors which have been shown to decrease circulating hormone levels [6]. For example, PCB exposures were associated with reduced insulin and leptin levels in both animal and human studies (ACHS) [6, 15].…”

Section: Discussionmentioning

confidence: 99%

“…The Anniston Community Health Survey (ACHS) is a highly exposed cohort of residents living near a former PCB manufacturing plant in Alabama. Elevated PCB body burden in this cohort was positively associated with suspected TASH and the liver necrosis marker cytokeratin 18 (KRT18) M65 [6]. In animal models that mimic these human exposures, the development of PCB-mediated TASH was contingent upon both the exposure and the feeding of a high fat diet (HFD).…”

Section: Introductionmentioning

confidence: 99%

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Hepatic signalling disruption by pollutant Polychlorinated biphenyls in steatohepatitis

Hardesty

Wahlang

Falkner

et al. 2019

Cellular Signalling

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Background: Polychlorinated biphenyl-mediated steatohepatitis has been shown to be due in part to inhibition of epidermal growth factor receptor (EGFR) signalling. EGFR signalling regulates many facets of hepatocyte function, but it is unclear which other kinases and pathways are involved in the development of toxicant-associated steatohepatitis (TASH). Methods: Comparative hepatic phosphoproteomic analysis was used to identify which kinases were affected by either PCB exposure (Aroclor 1260 mixture), high fat diet (HFD), or their interaction in a chronic exposure model of TASH. Cellular assays and western blot analysis were used to validate the phosphoproteomic findings. Results: 1760 unique phosphorylated peptides were identified and of those 588 were significantly different. PCB exposure and dietary interaction promoted a near 25% reduction of hepatic phospho-peptides. Leptin and insulin signalling were pathways highly affected by PCB exposure and liver necrosis was a pathologic ontology over represented due to interaction between PCBs and a HFD. Casein kinase 2 (CK2), Extracellular regulated kinase (ERK), Protein kinase B (AKT), and Cyclin dependent kinase (CDK) activity were demonstrated to be downregulated after PCB exposure and this downregulation was exacerbated with a HFD. PCB exposure led to a loss of hepatic CK2 subunit expression limiting CK2 kinase activity and negatively regulating caspase-3 (CASP3). PCBs promoted secondary necrosis in vitro validating the latter observation. The loss of hepatic phosphoprotein signalling appeared to be due to decreased signal transduction rather than phosphatase upregulation. Conclusions: PCBs are signal disrupting chemicals that promote secondary necrosis through affecting a myriad of liver processes including metabolism and cellular maintenance. PCB exposure, particularly with interaction with a HFD greatly down- regulates the hepatic kinome. More data are needed on signalling disruption and its impact on liver health.

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Section: Discussionsupporting

confidence: 84%

Section: Discussionsupporting

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Hepatic signalling disruption by pollutant Polychlorinated biphenyls in steatohepatitis

Hardesty

Wahlang

Falkner

et al. 2019

Cellular Signalling

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Hepatic STAMP2 alleviates polychlorinated biphenyl‐induced steatosis and hepatic iron overload in NAFLD models

Kim

Park

et al. 2022

Environmental Toxicology

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Polychlorinated biphenyls (PCBs) have been associated with neurotoxicity, hepatoxicity, oncogenicity, and endocrine-disrupting effects. Although the recent studies have demonstrated that PCB exposure leads to nonalcoholic fatty liver disease (NAFLD), the underlying mechanism has remained unsolved. In this study, we examined the hepatic effects of a PCB mixture, Aroclor 1260, whose composition mimics human bioaccumulation patterns, and PCB 126 in C57BL/6 mice. Male C57Bl/6 mice were fed a standard diet or a 60% high-fat diet and exposed to Aroclor 1260 (10 mg/kg or 20 mg/kg) or PCB 126 (1 mg/kg or 5 mg/kg) by intraperitoneal injection for a total of four injections (2, 3, 4, and 5 weeks) for 6 weeks. In mice, both Aroclor 1260 and PCB 126-induced liver damage, hepatic steatosis and inflammation. We also observed that PCB exposure-induced hepatic iron overload (HIO). We previously demonstrated that hepatic six transmembrane protein of prostate 2 (STAMP2) may represent a suitable therapeutic target for NAFLD patients. Thus, we further examined whether hepatic STAMP2 is involved in PCB-induced NAFLD. We observed that hepatic STAMP2 was significantly decreased in PCB-induced NAFLD models in vivo and in vitro. Furthermore, overexpression of hepatic STAMP2 using an adenoviral delivery system resulted in improvement of PCB-induced steatosis and HIO in vivo and in vitro. Our findings indicate that enhancing hepatic STAMP2 expression represents a potential therapeutic avenue for the treatment of PCB exposure-induced NAFLD.

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Source and Risk Assessment of Polychlorinated Biphenyls (PCBs) in Ambient Air and Its Human Health Implications

Mohankumar,

Salavath,

Karunamoorthy

et al. 2024

Aerosol Optical Depth and Precipitation

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Liver Disease in a Residential Cohort With Elevated Polychlorinated Biphenyl Exposures

Cited by 59 publications

References 49 publications

Hepatic signalling disruption by pollutant Polychlorinated biphenyls in steatohepatitis

Hepatic signalling disruption by pollutant Polychlorinated biphenyls in steatohepatitis

Hepatic STAMP2 alleviates polychlorinated biphenyl‐induced steatosis and hepatic iron overload in NAFLD models

Source and Risk Assessment of Polychlorinated Biphenyls (PCBs) in Ambient Air and Its Human Health Implications

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