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

Autor:	Judice SA; Genetic Toxicology Laboratory, University of Vermont, Burlington, Vermont, USA.; EnviroLogix, Portland, Maine, USA., Sussman HE; School of Public Health, University at Albany - SUNY, Albany, New York, USA.; New York State Department of Health, Wadsworth Center, Albany, New York, USA.; Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, USA., Walker DM; Experimental Pathology Laboratories, Sterling, Virginia, USA.; The Burlington HC Research group, Inc., Jericho, Vermont, USA., O'Neill JP; Genetic Toxicology Laboratory, University of Vermont, Burlington, Vermont, USA., Albertini RJ; Genetic Toxicology Laboratory, University of Vermont, Burlington, Vermont, USA.; Department of Pathology and Laboratory Medicine, Larner College of Medicine, University of Vermont, Burlington, Vermont, USA., Walker VE; New York State Department of Health, Wadsworth Center, Albany, New York, USA.; Department of Pathology and Laboratory Medicine, Larner College of Medicine, University of Vermont, Burlington, Vermont, USA.
Jazyk:	angličtina
Zdroj:	Environmental and molecular mutagenesis [Environ Mol Mutagen] 2023 Oct-Nov; Vol. 64 (8-9), pp. 432-457. Date of Electronic Publication: 2023 Nov 30.
DOI:	10.1002/em.22579
Abstrakt:	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. (© 2023 The Authors. Environmental and Molecular Mutagenesis published by Wiley Periodicals LLC on behalf of Environmental Mutagenesis and Genomics Society.)
Databáze:	MEDLINE
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