A guide for mutagenicity testing using the dominant lethal assay

Green, Sídney; Lavappa, K. S.; Manandhar, Madhu; Sheu, C.W.; Whorton, Elbert B.; Springer, Janet A.

doi:10.1016/0165-1218(87)90022-x

Cited by 29 publications

(6 citation statements)

References 4 publications

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“…Extrapolation from animal data has been used in an effort to understand IRinduced germline mutations in humans due to the inherent difficulties in human epidemiological studies involving germ cells [1]. Several rodent assays are capable of detecting germline mutation, including the specific locus (SL) test [2], heritable translocation (HT) assay [3], dominant lethal (DL) assay [4], expanded simple tandem repeats (ESTRs) assay [5], and transgenic rodent assays [6,7]. The traditional mutation assays, e.g.…”

Section: Introductionmentioning

confidence: 99%

Recovery of a low mutant frequency after ionizing radiation-induced mutagenesis during spermatogenesis

Intano

McCarrey

et al. 2008

Mutation Research/Genetic Toxicology and Environmental Mutagene

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Humans are exposed to ionizing radiation (IR) under various circumstances, e.g. cosmic radiation, diagnostic X-rays and radiotherapy for cancer. It has been shown that IR can impair spermatogenesis and can cause mutations in germ cells. However, the mutagenic responses of germ cells exposed to IR at different stages of testicular maturation have not been examined by directly assessing the mutant frequency in defined spermatogenic cell types. This study was performed to address whether preadult exposure to IR can increase mutations in adult germ cells that could in turn have a major impact on adult reproductive function and the health of ensuing offspring. Male Lac I transgenic mice were irradiated with a single dose of 2.5 Gy of γ-ray at different ages before adulthood, reflecting different stages of testicular maturation, and then mutant frequency (MF) was determined directly in spermatogenic cell types emanating from the irradiated precursor cells. The results showed that (1) preadult exposure to IR did not significantly increase MF in adult epididymal spermatozoa; (2) spermatogenic stages immediately following the irradiated stage(s) displayed an elevated mutant frequency, but (3) the mutant frequency was restored to unirradiated levels in later stages of spermatogenesis. These findings provide evidence that there is a mechanism(s) to prevent spermatogenic cells with elevated mutant frequencies from progressing through spermatogenesis.

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Section: Introductionmentioning

confidence: 99%

Recovery of a low mutant frequency after ionizing radiation-induced mutagenesis during spermatogenesis

Intano

McCarrey

et al. 2008

Mutation Research/Genetic Toxicology and Environmental Mutagene

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“…However, the data from animal models have clearly demonstrated that effects of the parental radiation exposure are transmitted through the germline to the progeny of the irradiated parent [Morgan, 2003a,b,c]. Early studies of these transgeneration effects used various tests such as the specific locus, dominant lethal, and heritable translocation assays [Generoso et al, 1980;Russell and Kelly, 1982;Green et al, 1987;Russell et al, 1998]. Other studies focused on heritable alterations in cancer incidence and teratogenesis following the parental preconception irradiation [Mohr et al, 1999;Pils et al, 1999;Nomura, 2003;Nomura et al, 2004;Dasenbrock et al, 2005].…”

Section: Transgeneration Radiation-induced Effectsmentioning

confidence: 99%

Epigenetic changes and nontargeted radiation effects—Is there a link?

Kovalchuk

Baulch

2008

Environ and Mol Mutagen

123

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It is now well accepted that the effects of ionizing radiation (IR) exposure can be noticed far beyond the borders of the directly irradiated tissue. IR can affect neighboring cells in the proximity, giving rise to a bystander effect. IR effects can also span several generations and influence the progeny of exposed parents, leading to transgeneration effects. Bystander and transgeneration IR effects are linked to the phenomenon of the IR‐induced genome instability that manifests itself as chromosome aberrations, gene mutations, late cell death, and aneuploidy. While the occurrence of the abovementioned phenomena is well documented, the exact mechanisms that lead to their development have still to be delineated. Evidence suggests that the IR‐induced genome instability, bystander, and transgeneration effects may be epigenetically mediated. The epigenetic changes encompass DNA methylation, histone modification, and RNA‐associated silencing. Recent studies demonstrated that IR exposure alters epigenetic parameters in the directly exposed tissues and in the distant bystander tissues. Transgeneration radiation effects were also proposed to be of an epigenetic nature. We will discuss the role of the epigenetic mechanisms in radiation responses, bystander effects, and transgeneration effects. Environ. Mol. Mutagen., 2008. © 2008 Wiley‐Liss, Inc.

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“…[37]). The workshop participants acknowledged that although the mutational effects are manifest in the offspring, the endpoint cannot be considered heritable because the measured outcome is embryonic death; however, the great majority of chemicals that are positive in the DLT are also positive in the HTT, which does measure an inherited effect [32,33].…”

Section: Dominant Lethal Testmentioning

confidence: 99%

“…The dominant lethal test (DLT) measures genetic changes in germ cells that lead to subsequent embryonic or fetal death (OECD TG 478) [32,33], and has been the most extensively used germ cell mutagenicity test. The assay is conducted in either rats or mice, usually in males.…”

Section: Dominant Lethal Testmentioning

confidence: 99%

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

Yauk

Aardema

Benthem

et al. 2015

Mutation Research/Genetic Toxicology and Environmental Mutagene

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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.

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A guide for mutagenicity testing using the dominant lethal assay

Cited by 29 publications

References 4 publications

Recovery of a low mutant frequency after ionizing radiation-induced mutagenesis during spermatogenesis

Recovery of a low mutant frequency after ionizing radiation-induced mutagenesis during spermatogenesis

Epigenetic changes and nontargeted radiation effects—Is there a link?

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

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