Polychlorinated biphenyl exposures differentially regulate hepatic metabolism and pancreatic function: Implications for nonalcoholic steatohepatitis and diabetes

Toxicol Appl Pharmacol. 2019 Jan 15;363:22-33. doi: 10.1016/j.taap.2018.10.011. Epub 2018 Oct 9.

Abstract

The endocrine disrupting chemicals, polychlorinated biphenyls (PCBs), have been associated with nonalcoholic steatohepatitis (NASH) and diabetes. However, an integrative analysis of the effects of PCBs on the liver and pancreas has never been performed for the two major PCB subtypes, dioxin-like (DL) and nondioxin-like (NDL), and a mixture of NDL/DL PCBs. Therefore, male C57BL/6 J mice fed a control synthetic diet were treated with either a NDL PCB mixture, Aroclor 1260 (20 mg/kg); a single DL PCB congener, PCB 126 (20 μg/kg); a NDL/DL mixture, Aroclor 1260 plus PCB 126; or vehicle control for 2 weeks. PCB126 had the greatest impact on hepatic lipid metabolism. It caused steatosis due to increased hepatic lipid import with associated hypolipidemia. However, all PCB exposures impacted expression of hepatic lipid metabolism genes in different manners. The 'NASH gene', Pnpla3, was elevated by Aroclor 1260, but decreased by all other exposures. The expression of hepatokines implicated in metabolic syndrome (Fgf21, Igf1, and betatrophin) were differentially regulated. The NDL/DL PCB mixture had the greatest effects on pancreatic histology, including acinar cell atrophy, mild steatosis, and fibrosis without ductal changes or immune cell infiltration. It decreased expression of insulin and altered the expression of genes regulating islet identity. None of these exposures was associated with altered HOMA-IR or HOMA-B. In summary, PCB exposures differentially regulated liver and pancreas structure and function. Novel mechanisms for PCB-induced endocrine/metabolic disruption included altered hepatokines and Pnpla3 as well as 'PCB pancreatopathy' that was associated with altered expression of pancreatic islet identity factors. More research is required to understand fully these findings in the context of human NASH and diabetes.

Keywords: AhR; FGF21; Islet Identity; PCB; Pnpla3.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Aroclors / toxicity*
  • Diabetes Mellitus / chemically induced
  • Diabetes Mellitus / pathology*
  • Disease Models, Animal
  • Endocrine Disruptors / toxicity*
  • Fibrosis
  • Humans
  • Lipid Metabolism / drug effects
  • Liver / drug effects
  • Liver / metabolism
  • Liver / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Non-alcoholic Fatty Liver Disease / chemically induced
  • Non-alcoholic Fatty Liver Disease / pathology*
  • Pancreas / drug effects
  • Pancreas / pathology
  • Phospholipases A2, Calcium-Independent / metabolism
  • Polychlorinated Biphenyls / toxicity*

Substances

  • Aroclors
  • Endocrine Disruptors
  • aroclor 1260
  • Polychlorinated Biphenyls
  • PNPLA3 protein, mouse
  • Phospholipases A2, Calcium-Independent
  • 3,4,5,3',4'-pentachlorobiphenyl