title: Diet-induced obesity increases the frequency of Pig-a mutant erythrocytes in male C57BL/6J mice.
abstract: Obesity increases the risk of a number of chronic diseases in humans including several cancers. Biological mechanisms responsible for such increased risks are not well understood at present. Increases in systemic inflammation and oxidative stress, endogenous production of mutagenic metabolites, altered signaling in proliferative pathways, and increased sensitivity to exogenous mutagens and carcinogens are some of the potential contributing factors. We hypothesize that obesity creates an endogenously mutagenic environment in addition to increasing the sensitivity to environmental mutagens. To test this hypothesis, we examined two in vivo genotoxicity endpoints. Pig-a mutant frequencies and micronucleus frequencies were determined in blood cells in two independent experiments in 30-week old male mice reared on either a high-fat diet (60% calories from fat) that exhibit an obese phenotype or a normal-fat diet (10% calories from fat) that do not exhibit an obese phenotype. Mice were assayed again at 52 weeks of age in one of the experiments. N-ethyl-N-nitrosourea (ENU) was used as a positive mutation control in one experiment. ENU induced a robust Pig-a mutant and micronucleus response in both phenotypes. Obese, otherwise untreated mice, did not differ from non-obese mice with respect to Pig-a mutant frequencies in reticulocytes or micronucleus frequencies. However, such mice, had significantly higher and sustained Pig-a mutant frequencies (increased 2.5-3.7-fold, p < 0.02) in erythrocytes as compared to non-obese mice (based on measurements collected at 30 weeks or 30 and 52 weeks of age). This suggests that obesity, in the absence of exposure to an exogenous mutagen, is itself mutagenic. Environ. Mol. Mutagen. 57:668-677, 2016. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Department of Global Environmental Health Sciences, School of Public Health and Tropical Medicine, Tulane University, New Orleans, Louisiana, 70112.
authors.forename: Jeffrey K
authors.initials: JK
authors.lastname: Wickliffe
authors.affiliation: Litron Laboratories, 3500 Winton Place, Rochester, New York, 14623.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Dertinger
authors.affiliation: Litron Laboratories, 3500 Winton Place, Rochester, New York, 14623.
authors.forename: Dorothea K
authors.initials: DK
authors.lastname: Torous
authors.affiliation: Litron Laboratories, 3500 Winton Place, Rochester, New York, 14623.
authors.forename: Svetlana L
authors.initials: SL
authors.lastname: Avlasevich
authors.affiliation: Department of Global Environmental Health Sciences, School of Public Health and Tropical Medicine, Tulane University, New Orleans, Louisiana, 70112.
authors.forename: Bridget R
authors.initials: BR
authors.lastname: Simon-Friedt
authors.affiliation: Department of Global Environmental Health Sciences, School of Public Health and Tropical Medicine, Tulane University, New Orleans, Louisiana, 70112.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Wilson
mesh_terms: D000375:Aging / Q000097:blood / Q000235:genetics; D000818:Animals; D015415:Biomarkers / Q000097:blood; D059305:Diet, High-Fat / Q000009:adverse effects*; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism*; D005038:Ethylnitrosourea / Q000633:toxicity; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008810:Mice, Inbred C57BL; D048629:Micronuclei, Chromosome-Defective / Q000139:chemically induced; D009152:Mutagenicity Tests; D009154:Mutation; D009765:Obesity / Q000097:blood / Q000209:etiology / Q000235:genetics*
chemical_list: D015415:Biomarkers; D008565:Membrane Proteins; C080086:phosphatidylinositol glycan-class A protein; D005038:Ethylnitrosourea
keywords: Pig-a mutant; high-fat diet; micronucleus; obesity