Diversity Outbred Mice Identify Population-Based Exposure Thresholds and Genetic Factors that Influence Benzene-Induced Genotoxicity

• Published in: Environmental health perspectives Vol. 123; no. 3; p. 237
• Main Authors: French, John E, Gatti, Daniel M, Morgan, Daniel L, Kissling, Grace E, Shockley, Keith R, Knudsen, Gabriel A, Shepard, Kim G, Price, Herman C, King, Deborah, Witt, Kristine L, Pedersen, Lars C, Munger, Steven C, Svenson, Karen L, Churchill, Gary A
• Format: Journal Article
• Language: English
• Published: United States National Institute of Environmental Health Sciences 01.03.2015; NLM-Export
• Subjects: Animal welfare; Animals; Animals, Outbred Strains; Benzene; Benzene - toxicity; Blood diseases; Bone marrow; Bone Marrow Cells - drug effects; Carcinogens; Chromosome aberrations; Chromosomes; DNA Damage - drug effects; DNA Damage - genetics; Dose-Response Relationship, Drug; Environmental aspects; Estimates; Exposure; Flow cytometry; Gene expression; Genetic aspects; Genetic diversity; Genetic factors; Genetic Linkage - drug effects; Genetics; Genotoxicity; Hazardous Substances - toxicity; Health aspects; Human populations; Hydrocarbons; Inhalation; Inhalation Exposure; Laboratory animals; Mathematical models; Metabolism; Metabolites; Mice; Micronucleus Tests; Occupational exposure; Phenols; Population; Reticulocytes - drug effects; Risk Assessment; Risk factors; Studies; Sulfotransferases - genetics; Thresholds; Toxicity; Toxicology; Variance analysis; United States
• ISSN: 0091-6765; 1552-9924
• DOI: 10.1289/ehp.1408202

Inhalation of benzene at levels below the current exposure limit values leads to hematotoxicity in occupationally exposed workers. We sought to evaluate Diversity Outbred (DO) mice as a tool for exposure threshold assessment and to identify genetic factors that influence benzene-induced genotoxicity. We exposed male DO mice to benzene (0, 1, 10, or 100 ppm; 75 mice/exposure group) via inhalation for 28 days (6 hr/day for 5 days/week). The study was repeated using two independent cohorts of 300 animals each. We measured micronuclei frequency in reticulocytes from peripheral blood and bone marrow and applied benchmark concentration modeling to estimate exposure thresholds. We genotyped the mice and performed linkage analysis. We observed a dose-dependent increase in benzene-induced chromosomal damage and estimated a benchmark concentration limit of 0.205 ppm benzene using DO mice. This estimate is an order of magnitude below the value estimated using B6C3F1 mice. We identified a locus on Chr 10 (31.87 Mb) that contained a pair of overexpressed sulfotransferases that were inversely correlated with genotoxicity. The genetically diverse DO mice provided a reproducible response to benzene exposure. The DO mice display interindividual variation in toxicity response and, as such, may more accurately reflect the range of response that is observed in human populations. Studies using DO mice can localize genetic associations with high precision. The identification of sulfotransferases as candidate genes suggests that DO mice may provide additional insight into benzene-induced genotoxicity.