Approaches for identifying germ cell mutagens: Report of the 2013 IWGT workshop on germ cell assays(☆)

Mutat Res Genet Toxicol Environ Mutagen. 2015 May 1:783:36-54. doi: 10.1016/j.mrgentox.2015.01.008. Epub 2015 Jan 24.

Abstract

This workshop reviewed the current science to inform and recommend the best evidence-based approaches on the use of germ cell genotoxicity tests. The workshop questions and key outcomes were as follows. (1) Do genotoxicity and mutagenicity assays in somatic cells predict germ cell effects? Limited data suggest that somatic cell tests detect most germ cell mutagens, but there are strong concerns that dictate caution in drawing conclusions. (2) Should germ cell tests be done, and when? If there is evidence that a chemical or its metabolite(s) will not reach target germ cells or gonadal tissue, it is not necessary to conduct germ cell tests, notwithstanding somatic outcomes. However, it was recommended that negative somatic cell mutagens with clear evidence for gonadal exposure and evidence of toxicity in germ cells could be considered for germ cell mutagenicity testing. For somatic mutagens that are known to reach the gonadal compartments and expose germ cells, the chemical could be assumed to be a germ cell mutagen without further testing. Nevertheless, germ cell mutagenicity testing would be needed for quantitative risk assessment. (3) What new assays should be implemented and how? There is an immediate need for research on the application of whole genome sequencing in heritable mutation analysis in humans and animals, and integration of germ cell assays with somatic cell genotoxicity tests. Focus should be on environmental exposures that can cause de novo mutations, particularly newly recognized types of genomic changes. Mutational events, which may occur by exposure of germ cells during embryonic development, should also be investigated. Finally, where there are indications of germ cell toxicity in repeat dose or reproductive toxicology tests, consideration should be given to leveraging those studies to inform of possible germ cell genotoxicity.

Keywords: Chromosome aberrations; Copy number variants; Gene; Genetic disease; Germ cell mutation; Reproductive health; mutation.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • DNA Mutational Analysis / methods
  • DNA Mutational Analysis / standards
  • Education
  • Genome-Wide Association Study / methods
  • Genome-Wide Association Study / standards
  • Germ Cells* / metabolism
  • Germ Cells* / pathology
  • Germ-Line Mutation*
  • High-Throughput Nucleotide Sequencing / methods
  • High-Throughput Nucleotide Sequencing / standards
  • Humans
  • Mutagenicity Tests / methods
  • Mutagenicity Tests / standards
  • Mutagens / toxicity*
  • Risk Assessment

Substances

  • Mutagens