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Sublinear response in lacZ mutant frequency of Muta(™)Mouse spermatogonial stem cells after low dose subchronic exposure to N‐ethyl‐N‐nitrosourea
The transgenic rodent mutation assay was used to compare the dose–response relationship of lacZ mutant frequency (MF) in spermatogonial stem cells exposed acutely or subchronically to N‐ethyl‐N‐nitrosourea (ENU). Muta(™)Mouse males were exposed orally to 0, 25, 50, or 100 mg/kg ENU for acute exposur...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6680333/ https://www.ncbi.nlm.nih.gov/pubmed/25598316 http://dx.doi.org/10.1002/em.21932 |
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author | O'Brien, Jason M. Walker, Mike Sivathayalan, Ahalya Douglas, George R. Yauk, Carole L. Marchetti, Francesco |
author_facet | O'Brien, Jason M. Walker, Mike Sivathayalan, Ahalya Douglas, George R. Yauk, Carole L. Marchetti, Francesco |
author_sort | O'Brien, Jason M. |
collection | PubMed |
description | The transgenic rodent mutation assay was used to compare the dose–response relationship of lacZ mutant frequency (MF) in spermatogonial stem cells exposed acutely or subchronically to N‐ethyl‐N‐nitrosourea (ENU). Muta(™)Mouse males were exposed orally to 0, 25, 50, or 100 mg/kg ENU for acute exposures and 0, 1, 2, or 5 mg/(kg day) for 28‐day subchronic exposures. LacZ MF was measured in sperm collected 70 days post‐exposure to target spermatogonial stem cells. Dose–response data were fit to linear, quadratic, exponential, or power models. Acute exposure resulted in a dose‐dependent increase in MF that was significant (P < 0.05) at all doses tested and was best described by a quadratic dose–response model that was linear in the low dose range. In contrast, similar total doses fragmented over a 28‐day subchronic exposure only resulted in a significant increase in lacZ MF at the highest dose tested. Therefore, the subchronic no observable genotoxic effect level (NOGEL) was 2 mg/(kg day) (or 56 mg/kg total dose). The subchronic dose–response was best described by the exponential and power models, which were sublinear in the low dose range. Benchmark dose lower confidence limits (BMDLs) for acute and subchronic exposure were 3.0 and 1.0 mg/(kg day) (or 27.4 mg/kg total dose), respectively. These findings are supportive of a saturable DNA repair mechanism as the mutagenic mode of action for ENU in spermatogonia and imply that sufficiently low exposures would not cause appreciable genotoxic effects over background. This may have important implications for the quantitative risk assessment of germ cell mutagens. Environ. Mol. Mutagen. 56:347–355, 2015. © 2015 The Authors. Environmental and Molecular Mutagenesis Published by Wiley Periodicals, Inc. |
format | Online Article Text |
id | pubmed-6680333 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-66803332019-08-09 Sublinear response in lacZ mutant frequency of Muta(™)Mouse spermatogonial stem cells after low dose subchronic exposure to N‐ethyl‐N‐nitrosourea O'Brien, Jason M. Walker, Mike Sivathayalan, Ahalya Douglas, George R. Yauk, Carole L. Marchetti, Francesco Environ Mol Mutagen Research Articles The transgenic rodent mutation assay was used to compare the dose–response relationship of lacZ mutant frequency (MF) in spermatogonial stem cells exposed acutely or subchronically to N‐ethyl‐N‐nitrosourea (ENU). Muta(™)Mouse males were exposed orally to 0, 25, 50, or 100 mg/kg ENU for acute exposures and 0, 1, 2, or 5 mg/(kg day) for 28‐day subchronic exposures. LacZ MF was measured in sperm collected 70 days post‐exposure to target spermatogonial stem cells. Dose–response data were fit to linear, quadratic, exponential, or power models. Acute exposure resulted in a dose‐dependent increase in MF that was significant (P < 0.05) at all doses tested and was best described by a quadratic dose–response model that was linear in the low dose range. In contrast, similar total doses fragmented over a 28‐day subchronic exposure only resulted in a significant increase in lacZ MF at the highest dose tested. Therefore, the subchronic no observable genotoxic effect level (NOGEL) was 2 mg/(kg day) (or 56 mg/kg total dose). The subchronic dose–response was best described by the exponential and power models, which were sublinear in the low dose range. Benchmark dose lower confidence limits (BMDLs) for acute and subchronic exposure were 3.0 and 1.0 mg/(kg day) (or 27.4 mg/kg total dose), respectively. These findings are supportive of a saturable DNA repair mechanism as the mutagenic mode of action for ENU in spermatogonia and imply that sufficiently low exposures would not cause appreciable genotoxic effects over background. This may have important implications for the quantitative risk assessment of germ cell mutagens. Environ. Mol. Mutagen. 56:347–355, 2015. © 2015 The Authors. Environmental and Molecular Mutagenesis Published by Wiley Periodicals, Inc. John Wiley and Sons Inc. 2015-01-17 2015-05 /pmc/articles/PMC6680333/ /pubmed/25598316 http://dx.doi.org/10.1002/em.21932 Text en © 2015 The Authors. Environmental and Molecular Mutagenesis Published by Wiley Periodicals, Inc. This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made. |
spellingShingle | Research Articles O'Brien, Jason M. Walker, Mike Sivathayalan, Ahalya Douglas, George R. Yauk, Carole L. Marchetti, Francesco Sublinear response in lacZ mutant frequency of Muta(™)Mouse spermatogonial stem cells after low dose subchronic exposure to N‐ethyl‐N‐nitrosourea |
title | Sublinear response in lacZ mutant frequency of Muta(™)Mouse spermatogonial stem cells after low dose subchronic exposure to N‐ethyl‐N‐nitrosourea |
title_full | Sublinear response in lacZ mutant frequency of Muta(™)Mouse spermatogonial stem cells after low dose subchronic exposure to N‐ethyl‐N‐nitrosourea |
title_fullStr | Sublinear response in lacZ mutant frequency of Muta(™)Mouse spermatogonial stem cells after low dose subchronic exposure to N‐ethyl‐N‐nitrosourea |
title_full_unstemmed | Sublinear response in lacZ mutant frequency of Muta(™)Mouse spermatogonial stem cells after low dose subchronic exposure to N‐ethyl‐N‐nitrosourea |
title_short | Sublinear response in lacZ mutant frequency of Muta(™)Mouse spermatogonial stem cells after low dose subchronic exposure to N‐ethyl‐N‐nitrosourea |
title_sort | sublinear response in lacz mutant frequency of muta(™)mouse spermatogonial stem cells after low dose subchronic exposure to n‐ethyl‐n‐nitrosourea |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6680333/ https://www.ncbi.nlm.nih.gov/pubmed/25598316 http://dx.doi.org/10.1002/em.21932 |
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