The development and prevalidation of anin vitromutagenicity assay based on MutaMouse primary hepatocytes, Part II: Assay performance for the identification of mutagenic chemicals

Abstract

As demonstrated in Part I, cultured MutaMouse primary hepatocytes (PHs) are suitable cells for use in an in vitro gene mutation assay due to their metabolic competence, their “normal” phenotype, and the presence of the MutaMouse transgene for reliable mutation scoring. The performance of these cells in an in vitro gene mutation assay is evaluated in this study, Part II. A panel of 13 mutagenic and nonmutagenic compounds was selected to investigate the performance of the MutaMouse PH in vitro gene mutation assay. The nine mutagens represent a range of classes of chemicals and include mutagens that are both direct‐acting and requiring metabolic activation. All the mutagens tested, except for ICR 191, elicited significant, concentration‐dependent increases in mutant frequency (MF) ranging from 2.6‐ to 14.4‐fold over the control. None of the four nonmutagens, including two misleading, or “false,” positives (i.e., tertiary butylhydroquinone [TBHQ] and eugenol), yielded any significant increases in MF. The benchmark dose covariate approach facilitated ranking of the positive chemicals from most (i.e., 3‐nitrobenzanthrone [3‐NBA], benzo[ a ]pyrene [BaP], and aflatoxin B 1 [AFB1]) to least (i.e., N ‐ethyl‐ N ‐nitrosourea [ENU]) potent. Overall, the results of this preliminary validation study suggest that this assay may serve as a complimentary tool alongside the standard genotoxicity test battery. This study, alongside Part I, illustrates the promise of MutaMouse PHs for use in an in vitro gene mutation assay, particularly for chemicals requiring metabolic activation. Environ. Mol. Mutagen. 60:348–360, 2019. © 2019 The Authors. Environmental and Molecular Mutagenesis published by Wiley Periodicals, Inc. on behalf of Environmental Mutagen Society.

Cellular toxicities of gadolinium‐based contrast agents used in magnetic resonance imaging

“…Genotoxicity tests are used for the examination of the mutagenicity of physical agents, drugs, food additives, nanoparticles, and various environmental pollutants. Some of the commonly applied genotoxicity tests are Ames, the hypoxanthine (guanine) phosphoribosyltransferase (HPRT), chromosome aberrations (CAs), sister chromatid exchanges (SCEs), micronucleus (MN), and comet tests (Ataseven et al, 2016; Cox et al, 2019; Luijten et al, 2016; Mamur et al, 2010; Møller, 2018; Unal et al, 2021; Yilmaz et al, 2008; Yuzbasioglu et al, 2006). The bacterial reverse mutation (Ames) is the most extensively used test to examine the mutagenic potential of exogenous chemicals (Ames, 1974).…”