Environmental and Molecular Mutagenesis (EMM) Editor's Choice - June 2014
The Editor's Choice for June is "Quantitative Dose-Response Analysis of Ethyl Methanesulfonate Genotoxicity in Adult gpt-delta Transgenic Mice” by Xuefei Cao, Roberta A. Mittelstaedt, Mason G. Pearce, Bruce C. Allen, Lya G. Soeteman-Hernández, George E. Johnson, C. Anita H. Bigger, and Robert H. Heflich.
Few studies attempt to assess the ability of carcinogens to induce mutations at low doses, which is not surprising given the technical challenge of observing small magnitude effects. The work by Cao et al. was based on a previous study by Gocke and Müller [Mutation Research (2009) 678:101-107], which treated mice with ethyl methanesulfonate (EMS) and reported the level of EMS that produced a level of lacZ mutation that could not be distinguished from spontaneous mutation. Cao et al. investigated whether a different result would be obtained using mutation detection assays that had lower background levels of spontaneous mutation. The strength of this work lies in its remarkably thorough experimental strategy. Cao et al. analyzed a large range of doses (5 to 100 mg/kg EMS), analyzed mutation induction at the gpt locus of multiple solid tissues of transgenic mice, and coupled that analysis with measurements of micronucleus frequency and analysis of mutation in the Pig-a gene of blood cells. In addition, they evaluated three different modeling methods in terms of their ability to distinguish EMS-induced effects from spontaneous events. Importantly, they observed significant effects at lower doses than those reported by Gocke and Müller and concluded that the magnitude and shape of the mutagenicity dose responses caused by EMS differ between mouse models, with smaller effects of treatment measureable using mutation assays with a low background of spontaneous events. This important publication, therefore, provides a template for how to accurately measure predicted low-dose effects of mutagenic carcinogens. Environ. Mol. Mutagen. 55:385-399, 2014. © Wiley Periodicals, Inc.