A Northern Contaminant Mixture Impairs Pancreas Function in Obese and Lean JCR Rats and Inhibits Insulin Secretion in MIN6 Cells

Toxicology. 2015 Aug 6;334:81-93. doi: 10.1016/j.tox.2015.06.001. Epub 2015 Jun 9.

Abstract

Rates of obesity and diabetes mellitus of Arctic populations are increasing due to multiple reasons including a departure from traditional lifestyles and alcohol consumption patterns. These populations are also exposed to a variety of anthropogenic contaminants through consumption of contaminated country foods. We have previously shown that a Northern contaminant mixture (NCM), containing 22 organic and inorganic contaminants found in the blood of Canadian Arctic populations, induces endothelial cell dysfunction and exacerbates development of non-alcoholic fatty liver disease in experimental models. In order to determine if these contaminants affect pancreas function and physiology and if obesity and alcohol can influence contaminant toxicity and the development of diabetes, lean and obese JCR rats were orally treated with NCM at 0 (vehicle), 1.6 or 16mg/kg BW for four weeks in the presence or absence of 10% (v/v) alcohol. NCM treatment altered islet morphology, increased iron deposit in pancreas, and reduced circulating and pancreatic insulin levels and circulating glucagon levels as a result of direct islet injury with β and α cell loss with or without exposure to alcohol. Studies conducted with cultured mouse insulin-secreting (MIN6) β cells further demonstrated that NCM inhibited insulin release and induced cell death through oxidative stress and mitochondrial dysfunction. 2,3,4,6-Tetrabromophenol, a minor component of the NCM, alone also inhibited insulin release from MIN6 cells after 10min of exposure. These results suggest that Northern contaminants may contribute to pancreatic dysfunction, and possibly development of diabetes, in some of the highly exposed Arctic populations. The implications and relevance of these findings to Northern populations remains to be confirmed through epidemiological studies.

Keywords: Insulin; MIN6 cells; Northern contaminant mixture; Obese and lean JCR rats; Pancreas; β cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alcohol Drinking / adverse effects
  • Animals
  • Cell Death / drug effects
  • Cell Line, Tumor
  • Complex Mixtures / toxicity*
  • Diabetes Mellitus / blood
  • Diabetes Mellitus / chemically induced*
  • Diabetes Mellitus / pathology
  • Diabetes Mellitus / physiopathology
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Environmental Pollutants / toxicity*
  • Glucagon / blood
  • Insulin / blood
  • Insulin / metabolism*
  • Insulin Secretion
  • Insulinoma / metabolism*
  • Islets of Langerhans / drug effects*
  • Islets of Langerhans / metabolism
  • Islets of Langerhans / physiopathology
  • Male
  • Mice
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Mitochondria / pathology
  • Obesity / blood
  • Obesity / complications*
  • Obesity / pathology
  • Obesity / physiopathology
  • Oxidative Stress / drug effects
  • Pancreatic Neoplasms / metabolism*
  • Rats
  • Risk Assessment
  • Thinness / blood
  • Thinness / complications*
  • Thinness / pathology
  • Thinness / physiopathology

Substances

  • Complex Mixtures
  • Environmental Pollutants
  • Insulin
  • Glucagon