DNA sequence analysis ofhprt mutants persisting in peripheral blood of cynomolgus monkeys more than two years after ENU treatment

Harbach, P.R.; Mattano, Susan Szabo; Zimmer, David M.; Filipunas, A.L.; Wang, Y.; Aaron, C.S.

doi:10.1002/(sici)1098-2280(1999)33:1<42::aid-em5>3.0.co;2-p

Cited by 6 publications

(1 citation statement)

References 32 publications

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“…Although the HPRT mutation assay was developed originally for use in humans, animal studies are necessary to investigate the impact of genotoxic agents on the biological processes governing T‐cell development, kinetics, and mutation (Crippen & Jones, 1989; Walker et al, 1999, 2009; Walker & Meng, 2000). Thus, mutation assays based upon the cloning of Hprt ‐negative (6‐thioguanine resistant) T‐cells have been adapted to the mouse, rat, and monkey, with studies directed at defining quantitative aspects of mutation induction and expression time as well as qualitative characteristics like mutational spectra in both mice and rats (Aidoo et al, 1991, 1993, 1997; Casciano et al, 1999; Harback et al, 1999; Jones et al, 1985; Jones, Burkhart‐Schultz, & Crippen, 1987; Jones, Burkhart‐Schultz, Strout, & Crippen, 1987; Meng et al, 2004; Skopek et al, 1992; Tates et al, 1994; Walker et al, 1999; Zimmer et al, 1991).…”

Section: Introductionmentioning

confidence: 99%

Clonality, trafficking, and molecular alterations among Hprt mutant T lymphocytes isolated from control mice versus mice treated with N‐ethyl‐N‐nitrosourea

Judice,

Sussman,

Walker

et al. 2023

Environ and Mol Mutagen

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Mutations in T lymphocytes (T‐cells) are informative quantitative markers for environmental mutagen exposures, but risk extrapolations from rodent models to humans also require an understanding of how T‐cell development and proliferation kinetics impact mutagenic outcomes. Rodent studies have shown that patterns in chemical‐induced mutations in the hypoxanthine‐guanine phosphoribosyltransferase (Hprt) gene of T‐cells differ between lymphoid organs. The current work was performed to obtain knowledge of the relationships between maturation events during T‐cell development and changes in chemical‐induced mutant frequencies over time in differing immune compartments of a mouse model. A novel reverse transcriptase‐polymerase chain reaction based method was developed to determine the specific T‐cell receptor beta (Tcrb) gene mRNA expressed in mouse T‐cell isolates, enabling sequence analysis of the PCR product that then identifies the specific hypervariable CDR3 junctional region of the expressed Tcrb gene for individual isolates. Characterization of spontaneous Hprt mutant isolates from the thymus, spleen, and lymph nodes of control mice for their Tcrb gene expression found evidence of in vivo clonal amplifications of Hprt mutants and their trafficking between tissues in the same animal. Concurrent analyses of Hprt mutations and Tcrb gene rearrangements in different lymphoid tissues of control versus N‐ethyl‐N‐nitrosourea‐exposed mice permitted elucidation of the localization and timing of mutational events in T‐cells, establishing that mutagenesis occurs primarily in the pre‐rearrangement replicative period in pre‐thymic/thymic populations. These findings demonstrate that chemical‐induced mutagenic burden is determined by the combination of mutagenesis and T‐cell clonal expansion, processes with roles in immune function and in the pathogenesis of autoimmune disease and cancer.

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Section: Introductionmentioning

confidence: 99%

Clonality, trafficking, and molecular alterations among Hprt mutant T lymphocytes isolated from control mice versus mice treated with N‐ethyl‐N‐nitrosourea

Judice,

Sussman,

Walker

et al. 2023

Environ and Mol Mutagen

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An ENU-induced mutation in the lymphotoxin α gene impairs organogenesis of lymphoid tissues in C57BL/6 mice

Wang

Feng

et al. 2008

Biochemical and Biophysical Research Communications

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The TNF family is critical for development of lymphoid organs and plays significant roles in regulation of innate and adoptive immune responses. Here we describe a novel N-ethyl-N-nitrosourea (ENU)-induced mutant strain, HLB382, with a point mutation in the Lta gene, which encodes lymphotoxin (LT) α, a member of the TNF family. Mutant mice had no lymph nodes and no Peyer's patches. Microscopically, the spleens had disordered follicles and no germinal centers or discernible marginal zones (MZ). While the development of T cells and follicular B cells was normal, the numbers of NK and MZ B cells were significantly reduced. Genomic DNA sequences revealed a single base pair insertion in the coding region of Lta resulting in a frame shift and a premature stop codon. This new strain provides opportunities for understanding the full range of Lta gene function on a pure C57BL/6 background.

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Evaluation of Macaca mulatta as a model for genotoxicity studies

Dobrovolsky

Shaddock

Mittelstaedt

et al. 2009

Mutation Research/Genetic Toxicology and Environmental Mutagene

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DNA sequence analysis ofhprt mutants persisting in peripheral blood of cynomolgus monkeys more than two years after ENU treatment

Cited by 6 publications

References 32 publications

Clonality, trafficking, and molecular alterations among Hprt mutant T lymphocytes isolated from control mice versus mice treated with N‐ethyl‐N‐nitrosourea

Clonality, trafficking, and molecular alterations among Hprt mutant T lymphocytes isolated from control mice versus mice treated with N‐ethyl‐N‐nitrosourea

An ENU-induced mutation in the lymphotoxin α gene impairs organogenesis of lymphoid tissues in C57BL/6 mice

Evaluation of Macaca mulatta as a model for genotoxicity studies

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