title: A Northern contaminant mixture impairs pancreas function in obese and lean JCR rats and inhibits insulin secretion in MIN6 cells.
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.
authors.affiliation: Regulatory Toxicology Research Division, Bureau of Chemical Safety, Food Directorate, Health Canada, 251 Sir Frederick Banting Driveway, Ottawa, Ontario K1A 0K9, Canada; Institute of Biochemistry, Department of Biology, Carleton University, 1125 Colonel By Drive, Ottawa, Ontario K1S 5B6, Canada.
authors.forename: Ryan
authors.initials: R
authors.lastname: Mailloux
authors.affiliation: Regulatory Toxicology Research Division, Bureau of Chemical Safety, Food Directorate, Health Canada, 251 Sir Frederick Banting Driveway, Ottawa, Ontario K1A 0K9, Canada; Institute of Biochemistry, Department of Biology, Carleton University, 1125 Colonel By Drive, Ottawa, Ontario K1S 5B6, Canada.
authors.forename: Accalia
authors.initials: A
authors.lastname: Fu
authors.affiliation: Regulatory Toxicology Research Division, Bureau of Chemical Safety, Food Directorate, Health Canada, 251 Sir Frederick Banting Driveway, Ottawa, Ontario K1A 0K9, Canada; Institute of Biochemistry, Department of Biology, Carleton University, 1125 Colonel By Drive, Ottawa, Ontario K1S 5B6, Canada.
authors.forename: Maria
authors.initials: M
authors.lastname: Florian
authors.affiliation: Regulatory Toxicology Research Division, Bureau of Chemical Safety, Food Directorate, Health Canada, 251 Sir Frederick Banting Driveway, Ottawa, Ontario K1A 0K9, Canada.
authors.forename: Ivan
authors.initials: I
authors.lastname: Petrov
authors.affiliation: Regulatory Toxicology Research Division, Bureau of Chemical Safety, Food Directorate, Health Canada, 251 Sir Frederick Banting Driveway, Ottawa, Ontario K1A 0K9, Canada.
authors.forename: Qixuan
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Regulatory Toxicology Research Division, Bureau of Chemical Safety, Food Directorate, Health Canada, 251 Sir Frederick Banting Driveway, Ottawa, Ontario K1A 0K9, Canada.
authors.forename: Melanie C
authors.initials: MC
authors.lastname: Coughlan
authors.affiliation: Regulatory Toxicology Research Division, Bureau of Chemical Safety, Food Directorate, Health Canada, 251 Sir Frederick Banting Driveway, Ottawa, Ontario K1A 0K9, Canada; Institute of Biochemistry, Department of Biology, Carleton University, 1125 Colonel By Drive, Ottawa, Ontario K1S 5B6, Canada.
authors.forename: Mahemuti
authors.initials: M
authors.lastname: Laziyan
authors.affiliation: Regulatory Toxicology Research Division, Bureau of Chemical Safety, Food Directorate, Health Canada, 251 Sir Frederick Banting Driveway, Ottawa, Ontario K1A 0K9, Canada.
authors.forename: Jin
authors.initials: J
authors.lastname: Yan
authors.affiliation: Scientific Services Division, Bureau of Chemical Safety, Food Directorate, Health Canada, 251 Sir Frederick Banting Driveway, Ottawa, K1A 0K9 Ontario, Canada.
authors.forename: Don
authors.initials: D
authors.lastname: Caldwell
authors.affiliation: Scientific Services Division, Bureau of Chemical Safety, Food Directorate, Health Canada, 251 Sir Frederick Banting Driveway, Ottawa, K1A 0K9 Ontario, Canada.
authors.forename: Dominique
authors.initials: D
authors.lastname: Patry
authors.affiliation: Scientific Services Division, Bureau of Chemical Safety, Food Directorate, Health Canada, 251 Sir Frederick Banting Driveway, Ottawa, K1A 0K9 Ontario, Canada.
authors.forename: Michelle
authors.initials: M
authors.lastname: Lalande
authors.affiliation: Scientific Services Division, Bureau of Chemical Safety, Food Directorate, Health Canada, 251 Sir Frederick Banting Driveway, Ottawa, K1A 0K9 Ontario, Canada.
authors.forename: Gen-Sheng
authors.initials: GS
authors.lastname: Wang
authors.affiliation: Institute of Biochemistry, Department of Biology, Carleton University, 1125 Colonel By Drive, Ottawa, Ontario K1S 5B6, Canada.
authors.forename: William
authors.initials: W
authors.lastname: Willmore
authors.affiliation: Regulatory Toxicology Research Division, Bureau of Chemical Safety, Food Directorate, Health Canada, 251 Sir Frederick Banting Driveway, Ottawa, Ontario K1A 0K9, Canada. Electronic address: dawn.jin@hc-sc.gc.ca.
authors.forename: Xiaolei
authors.initials: X
authors.lastname: Jin
mesh_terms: D000428:Alcohol Drinking / Q000009:adverse effects; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D045424:Complex Mixtures / Q000633:toxicity*; D003920:Diabetes Mellitus / Q000097:blood / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004785:Environmental Pollutants / Q000633:toxicity*; D005934:Glucagon / Q000097:blood; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D000078790:Insulin Secretion; D007340:Insulinoma / Q000378:metabolism*; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009765:Obesity / Q000097:blood / Q000150:complications* / Q000473:pathology / Q000503:physiopathology; D018384:Oxidative Stress / Q000187:drug effects; D010190:Pancreatic Neoplasms / Q000378:metabolism*; D051381:Rats; D018570:Risk Assessment; D013851:Thinness / Q000097:blood / Q000150:complications* / Q000473:pathology / Q000503:physiopathology
chemical_list: D045424:Complex Mixtures; D004785:Environmental Pollutants; D007328:Insulin; D005934:Glucagon
keywords: Insulin; MIN6 cells; Northern contaminant mixture; Obese and lean JCR rats; Pancreas; β cells