The quantitation of TK−/− and HGPRT− mutants of L5178Y/TK+/− mouse lymphoma cells at varying times post‐treatment

Moore, Martha M.; Clive, D.

doi:10.1002/em.2860040409

Cited by 48 publications

(10 citation statements)

References 28 publications

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“…A higher mutability at the Tk locus than at the Hprt locus has also been observed by Clive et al (9) and Moore and Clive (27) situated on a hemizygous chromosomal region (e.g., the Hprt locus on the X chromosome). In contrast, a high recovery of multilocus LY-S mutants is obtained at the Tk locus because of the presence of active copies of the linked essential genes on the homologous chromosome 11.…”

Section: Resultssupporting

confidence: 64%

Locus specificity in the mutability of L5178Y mouse lymphoma cells: the role of multilocus lesions.

Evans¹,

Mencl²,

Horng³

et al. 1986

Proc. Natl. Acad. Sci. U.S.A.

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Mouse L5178Y strain LY-S and its parental strain LY-R differ in their comparative sensitivities to the cytotoxic effects of various mutagenic agents-i.e., strain LY-S has been found to be more sensitive, less sensitive, or similarly sensitive to individual agents in comparison to strain LY-R. Nevertheless, strain LY-S has been found to be uniformly less mutable than strain LY-R at the hypoxanthine (guanine) phosphoribosyltransferase (Hprt) locus following treatment with x-radiation, UV radiation, or alkylating agents. In the present work we have isolated subclones of strains LY-R and LY-S that are heterozygous at the thymidine kinase (Tk) locus (chromosome 11). We have found that a heterozygous LY-S Tk+/Tk-strain shows as high or higher mutability at the Tk locus than do heterozygous LY-R strains following treatment with x-radiation, UV radiation, or ethyl methanesulfonate.Mutability of all heterozygous strains at the Tk locus is much higher than at the Hprt locus following treatment with these mutagenic agents, with the exception ofone heterozygous LY-R strain that possesses only one chromosome 11 and that is poorly mutable at the Tk locus by x-radiation. On the basis of these results, we have suggested that (i) because of a repair deficiency, multilocus lesions are formed in the DNA of LY-S strains following treatment with radiation or alkylating agents; (ii) multilocus lesions lead to poor recovery of viable mutants when the target locus is closely linked to essential genes and situated on a hemizygous chromosomal region (e.g., the Hprt locus on the X chromosome or the Tk locus in strains monosomic for chromosome 11); and (iii) x-radiation is a relatively poor mutagen at loci situated on hemizygous chromosomal regions, in repair-efficient and repair-deficient cells, because of its tendency to form multilocus lesions.Mouse lymphoma strain L-5178Y-S (LY-S) was first isolated by Alexander and Mikulski (1) following a spontaneous increase in the x-radiation sensitivity ofL5178Y cells growing in vitro. The parental strain was named L5178Y-R (LY-R) to differentiate it from the newly isolated sensitive strain. In spite of the greater sensitivity of strain LY-S to the cytotoxic effects of x-radiation and alkylating agents (2-5), strain LY-S is less mutable than strain LY-R by UV radiation and x-radiation and by alkylating agents at the hypoxanthine (guanine) phosphoribosyltransferase (Hprt) and Na+,K+-ATPase loci (4-6). In the present work we have compared the mutability of the two strains at the thymidine kinase (Tk) locus situated on chromosome 11 (7, 8) using heterozygous Tk+/Tk-strains of LY-R and LY-S. We have found the mutability of the heterozygous LY-S strain (LY-Si) to be as high or higher than that of LY-R heterozygous strains (LY-R16 and LY-R83) at the Tk locus following treatment with x-radiation, UV radiation, or ethyl methanesulfonate (EtMes). Mutant frequencies are much higher at the Tk locus than at the Hprt and Na',K+-ATPase loci for LY-S and LY-R heterozygous strains treated with these age...

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Section: Resultssupporting

confidence: 64%

Locus specificity in the mutability of L5178Y mouse lymphoma cells: the role of multilocus lesions.

Evans¹,

Mencl²,

Horng³

et al. 1986

Proc. Natl. Acad. Sci. U.S.A.

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“…A higher mutability for the autosomal Tk gene than for the hemizygous Hprt gene has been observed in mouse lymphoma cells, Chinese hamster ovary cells, and the human B-lymphoblastoid cell line TK6 [Clive et al, 1979;Moore and Clive, 1982;Coppinger et al, 1984;Yandell et al, 1986;Kronenberg et al, 1989;Moore et al, 1989]. The hypothesis explaining this difference in sensitivity between the two genes has been that the hemizygous nature of the Hprt gene permits recovery only of mutations primarily affecting the function of a single gene, whereas the heterozygous nature of the Tk locus permits recovery of both single gene and chromosomal mutations [Moore et al, 1987].…”

Section: Discussionmentioning

confidence: 99%

Mutant frequency and mutational spectra in the Tk and Hprt genes of N‐ethyl‐N‐nitrosourea‐treated mouse lymphoma cells†

Chen

Harrington‐Brock

Moore

2002

Environ and Mol Mutagen

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The mouse lymphoma assay (MLA) utilizing the Tk gene is widely used to identify chemical mutagens. The autosomal location of the Tk gene allows for the detection of a wide range of mutational events, from point mutations to chromosome alterations. However, chemically induced point mutation spectra in the Tk gene of mouse lymphoma cells have not been characterized. In this study, we determined and compared the mutagenicity and mutational spectra of N-ethyl-N-nitrosourea (ENU) in the Tk and Hprt genes of mouse lymphoma cells. Treatment of L5178Y mouse lymphoma cells with 100 microg/ml ENU induced a Tk mutant frequency of 756 x 10(-6) and an Hprt mutant frequency of 311 x 10(-6). Sequence analysis of Tk and Hprt mutant cDNAs showed a similar overall mutation pattern in the two genes with base-pair substitutions accounting for 83% of non-loss of heterozygosity mutations in the Tk gene and 75% of all mutations in the Hprt gene. The most common point mutation induced by ENU was G:C --> A:T transition (36 and 28% of independent mutations detected in the Tk and Hprt genes, respectively). The mutation spectra induced by ENU in both the Tk and Hprt genes were different from the respective patterns produced in mutants from untreated cells. About 9% of Tk and 7% of Hprt mutations from control cells were in-frame deletions, whereas no such mutations were found among the ENU-induced Tk and Hprt mutations. Our results indicate that ENU produces a chemical-specific point mutational profile in the Tk gene of mouse lymphoma cells that is remarkably similar to that found in the X-linked Hprt gene. This study provides evidence that the MLA can be used not only to detect point mutagens but also for analysis of mutational spectra.

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“…Iodomethane has been tested in a variety of mammalian cell test systems; some systems examined mutagenicity and others examined clastogenic potential. These include two modern GLP studies (Gudi & Brown, 2001;San & Clarke, 2001) and nine earlier published studies (Pienta et al, 1977;Clive et al, 1979;Oshiro et al, 1981;Moore & Clive, 1982;Amacher & Zelljadt, 1984;Amacher & Dunn, 1985;Moore et al, 1985aMoore et al, , 1985b (Table 8). The iodomethane studies conducted on mammalian cells in vitro indicate that iodomethane may cause clastogenic effects in cell culture but is not mutagenic.…”

Section: Thyroid Tumor Evaluationmentioning

confidence: 99%

Iodomethane human health risk characterization

Mileson¹,

Sweeney

Gargas

et al. 2009

Inhalation Toxicology

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Iodomethane is a new pre-plant soil fumigant approved in the United States. Human exposure may occur via inhalation due to the high vapor pressure of iodomethane. A quantitative human health risk assessment was conducted for inhalation exposure. The critical effects of acute duration iodomethane exposure are: (1) fetal losses in rabbits, (2) lesions in rat nasal epithelium, and (3) transient neurotoxicity in rats. Chronic exposure of rats resulted in increased thyroid follicular cell tumors from sustained perturbation of thyroid hormone homeostasis. A physiologically based pharmacokinetic (PBPK) model for iodomethane was developed to characterize potential human health effects from iodomethane exposure. The model enabled calculation of human equivalent concentrations (HECs) to the animal no-observed-adverse-effect levels (NOAELs) using chemical-specific parameters to determine the internal dose instead of default assumptions. Iodomethane HECs for workers and bystanders were derived using the PBPK model and NOAELs for acute exposure endpoints of concern. The developmental endpoint NOAEL was 10 ppm and corresponding bystander HEC was 7.4 ppm. The nasal endpoint NOAEL was 21 ppm and the HEC was 4.5 ppm. The transient neurotoxicity endpoint NOAEL was 27 ppm and the HEC was10 ppm. Data demonstrated that humans are less sensitive to the effect that causes developmental toxicity in rabbits and the PBPK model incorporated this information, resulting in a higher HEC for the developmental endpoint than for the nasal endpoint. Nasal olfactory degeneration is the primary endpoint for risk assessment of acute exposure to iodomethane.

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The quantitation of TK^−/− and HGPRT⁻ mutants of L5178Y/TK^+/− mouse lymphoma cells at varying times post‐treatment

Cited by 48 publications

References 28 publications

Locus specificity in the mutability of L5178Y mouse lymphoma cells: the role of multilocus lesions.

Locus specificity in the mutability of L5178Y mouse lymphoma cells: the role of multilocus lesions.

Mutant frequency and mutational spectra in the Tk and Hprt genes of N‐ethyl‐N‐nitrosourea‐treated mouse lymphoma cells†

Iodomethane human health risk characterization

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