Identifying germ cell mutagens using OECD test guideline 488 (transgenic rodent somatic and germ cell gene mutation assays) and integration with somatic cell testing.

Autor: Marchetti F; Environmental Health Science and Research Bureau, Health Canada, Ottawa, ON, Canada. Electronic address: francesco.marchetti@canada.ca., Aardema MJ; Marilyn Aardema Consulting, LLC, USA., Beevers C; Exponent International Limited, Harrogate, United Kingdom., van Benthem J; National Institute for Public Health and the Environment, Bilthoven, The Netherlands., Godschalk R; Department of Pharmacology and Toxicology, School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, The Netherlands., Williams A; Environmental Health Science and Research Bureau, Health Canada, Ottawa, ON, Canada., Yauk CL; Environmental Health Science and Research Bureau, Health Canada, Ottawa, ON, Canada., Young R; MilliporeSigma, BioReliance(®)Testing Services, Rockville, MD, USA., Douglas GR; Environmental Health Science and Research Bureau, Health Canada, Ottawa, ON, Canada.
Jazyk: angličtina
Zdroj: Mutation research. Genetic toxicology and environmental mutagenesis [Mutat Res Genet Toxicol Environ Mutagen] 2018 Aug; Vol. 832-833, pp. 7-18. Date of Electronic Publication: 2018 May 29.
DOI: 10.1016/j.mrgentox.2018.05.021
Abstrakt: The Organisation for Economic Co-operation and Development Test Guideline 488 (TG 488) provides recommendations for assessing germ cell and somatic cell mutagenicity using transgenic rodent (TGR) models. However, important data gaps exist for selecting an optimal approach for simultaneously evaluating mutagenicity in both cell types. It is uncertain whether analysis of germ cells from seminiferous tubules (hereafter, tubule germ cells) or caudal sperm within the recommended design for somatic tissues (i.e., 28 days of exposure plus three days of fixation time, 28 + 3d) has enough sensitivity to detect an effect as compared with the analysis of sperm within the recommended design for germ cells (i.e., 28 + 49d and 28 + 70d for mouse and rat, respectively). To address these data gaps, the Germ Cell workgroup of the Genetic Toxicology Technical Committee of the Health and Environmental Sciences Institute reviewed the available TGR mutagenicity data in male germ cells, and, characterized the exposure history of tubule germ cells for different sampling times to evaluate its impact on germ cell mutagenicity testing using TG 488. Our analyses suggest that evaluating mutant frequencies in: i) sperm from the cauda epididymis at 28 + 3d does not provide meaningful mutagenicity data; ii), tubule germ cells at 28 + 3d provides reliable mutagenicity data only if the results are positive; and iii) tubule germ cells at 28 + 28d produces reliable positive and negative results in both mice and rats. Thus, the 28 + 28d regimen may provide an approach for simultaneously assessing mutagenicity in somatic tissues and germ cells from the same animals. Further work is required to support the 28 + 28d protocol for tissues other than slowly proliferating tissues as per current TG 488. Finally, recommendations are provided to guide the experimental design for germ cell mutagenicity data for regulatory submission, as well as other possible approaches to increase the reliability of the TGR assay.
(Crown Copyright © 2018. Published by Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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