Investigating mechanisms for non-linear genotoxic responses, and analysing their effects in binary combination

Za�r, Zoulikha M.; Bodger, Owen G.; Lewis, Paul D.; Rees, Ben J.; Verma, Jatin R.; Thomas, Adam D.; Doak, Shareen H.; Jenkins, Gareth J S; Johnson, George E.

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 for 'genotoxic 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. © The Japanese Environmental Mutagen Society.

• Journal Article Type: Review
• Acceptance Date: Sep 20, 2012
• Publication Date: Dec 1, 2012
• Journal: Genes and Environment
• Electronic ISSN: 1880-7062
• Publisher: BioMed Central
• Peer Reviewed: Peer Reviewed
• Volume: 34
• Issue: 4
• Pages: 179-185
• DOI: https://doi.org/10.3123/jemsge.34.179
• Public URL: https://uwe-repository.worktribe.com/output/953940
• Publisher URL: https://doi.org/10.3123/jemsge.34.179