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Investigating Mechanisms for Non-linear Genotoxic Responses, and Analysing Their Effects in Binary Combination

George Johnson Orcid Logo, Zoulikha M Zair, Owen Bodger Orcid Logo, Paul Lewis, Ben J Rees, Jatin R Verma, Adam D Thomas, Shareen H Doak, Gareth Jenkins Orcid Logo

Genes and Environment, Volume: 34, Issue: 4, Pages: 179 - 185

Swansea University Authors: George Johnson Orcid Logo, Owen Bodger Orcid Logo, Paul Lewis, Gareth Jenkins Orcid Logo

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DOI (Published version): 10.3123/jemsge.34.179

Abstract

A recent shift by the scientific and regulatory community, towards accepting the existence of non-linear dose responses for certain DNA reactive genotoxic agents, has unveiled a myriad of questions regarding their biological basis. The mechanisms responsible fogenotoxic tolerance' at low doses...

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Published in: Genes and Environment
ISSN: 1880-7046 1880-7062
Published: 2012
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URI: https://cronfa.swan.ac.uk/Record/cronfa13400
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spelling 2019-06-24T14:14:00.8838847 v2 13400 2012-12-01 Investigating Mechanisms for Non-linear Genotoxic Responses, and Analysing Their Effects in Binary Combination 37d0f121db69fd09f364df89e4405e31 0000-0001-5643-9942 George Johnson George Johnson true false 8096440ab42b60a86e6aba678fe2695a 0000-0002-4022-9964 Owen Bodger Owen Bodger true false 46dfc22d7468f247c390ba0c6cd8fba6 Paul Lewis Paul Lewis true false a44095d26187304e903da7ca778697b6 0000-0002-5437-8389 Gareth Jenkins Gareth Jenkins true false 2012-12-01 MEDS A recent shift by the scientific and regulatory community, towards accepting the existence of non-linear dose responses for certain DNA reactive genotoxic agents, has unveiled a myriad of questions regarding their biological basis. The mechanisms responsible fogenotoxic tolerance' at low doses are wide ranging but poorly understood, yet this information is essential when analysing non-linear dose responses for hazard and risk assessment. For DNA reactive genotoxins, non-linear dose responses can arise from many different biological mechanisms, including DNA repair. Recent work from our group explored the contributory role of DNA repair to nonlinear genotoxic dose responses, in human cells exposed alkylating agents. Here we discuss the involvement of the repair enzymes methylpurine DNA-glycosylase and methyl-guanine methyl-transferase in modulating the non-linear dose responses observed in human cells exposed to ethyl methanesulfonate (EMS) and N-methyl-N-nitrosourea, respectively. We also discuss the exposure of binary mixtures, and how combinations of the dissimilar acting agents Benomyl and EMS at their no observed genotoxic effect levels, induce a significant increase in micronuclei. Journal Article Genes and Environment 34 4 179 185 1880-7046 1880-7062 27 11 2012 2012-11-27 10.3123/jemsge.34.179 Special issue paper: https://www.jstage.jst.go.jp/browse/jemsge/34/4/_contents COLLEGE NANME Medical School COLLEGE CODE MEDS Swansea University 2019-06-24T14:14:00.8838847 2012-12-01T19:36:56.3376126 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine George Johnson 0000-0001-5643-9942 1 Zoulikha M Zair 2 Owen Bodger 0000-0002-4022-9964 3 Paul Lewis 4 Ben J Rees 5 Jatin R Verma 6 Adam D Thomas 7 Shareen H Doak 8 Gareth Jenkins 0000-0002-5437-8389 9 0013400-28112014091428.pdf 2012__Johnson__et__al.pdf 2014-11-28T09:14:28.6830000 Output 476396 application/pdf Version of Record true 2014-11-28T09:14:28.0000000 true
title Investigating Mechanisms for Non-linear Genotoxic Responses, and Analysing Their Effects in Binary Combination
spellingShingle Investigating Mechanisms for Non-linear Genotoxic Responses, and Analysing Their Effects in Binary Combination
George Johnson
Owen Bodger
Paul Lewis
Gareth Jenkins
title_short Investigating Mechanisms for Non-linear Genotoxic Responses, and Analysing Their Effects in Binary Combination
title_full Investigating Mechanisms for Non-linear Genotoxic Responses, and Analysing Their Effects in Binary Combination
title_fullStr Investigating Mechanisms for Non-linear Genotoxic Responses, and Analysing Their Effects in Binary Combination
title_full_unstemmed Investigating Mechanisms for Non-linear Genotoxic Responses, and Analysing Their Effects in Binary Combination
title_sort Investigating Mechanisms for Non-linear Genotoxic Responses, and Analysing Their Effects in Binary Combination
author_id_str_mv 37d0f121db69fd09f364df89e4405e31
8096440ab42b60a86e6aba678fe2695a
46dfc22d7468f247c390ba0c6cd8fba6
a44095d26187304e903da7ca778697b6
author_id_fullname_str_mv 37d0f121db69fd09f364df89e4405e31_***_George Johnson
8096440ab42b60a86e6aba678fe2695a_***_Owen Bodger
46dfc22d7468f247c390ba0c6cd8fba6_***_Paul Lewis
a44095d26187304e903da7ca778697b6_***_Gareth Jenkins
author George Johnson
Owen Bodger
Paul Lewis
Gareth Jenkins
author2 George Johnson
Zoulikha M Zair
Owen Bodger
Paul Lewis
Ben J Rees
Jatin R Verma
Adam D Thomas
Shareen H Doak
Gareth Jenkins
format Journal article
container_title Genes and Environment
container_volume 34
container_issue 4
container_start_page 179
publishDate 2012
institution Swansea University
issn 1880-7046
1880-7062
doi_str_mv 10.3123/jemsge.34.179
college_str Faculty of Medicine, Health and Life Sciences
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hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Medicine{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Medicine
document_store_str 1
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description A recent shift by the scientific and regulatory community, towards accepting the existence of non-linear dose responses for certain DNA reactive genotoxic agents, has unveiled a myriad of questions regarding their biological basis. The mechanisms responsible fogenotoxic tolerance' at low doses are wide ranging but poorly understood, yet this information is essential when analysing non-linear dose responses for hazard and risk assessment. For DNA reactive genotoxins, non-linear dose responses can arise from many different biological mechanisms, including DNA repair. Recent work from our group explored the contributory role of DNA repair to nonlinear genotoxic dose responses, in human cells exposed alkylating agents. Here we discuss the involvement of the repair enzymes methylpurine DNA-glycosylase and methyl-guanine methyl-transferase in modulating the non-linear dose responses observed in human cells exposed to ethyl methanesulfonate (EMS) and N-methyl-N-nitrosourea, respectively. We also discuss the exposure of binary mixtures, and how combinations of the dissimilar acting agents Benomyl and EMS at their no observed genotoxic effect levels, induce a significant increase in micronuclei.
published_date 2012-11-27T06:24:56Z
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