Genotoxic thresholds, DNA repair, and susceptibility in human populations

Toxicology
Gareth J S JenkinsShareen H Doak

Abstract

It has been long assumed that DNA damage is induced in a linear manner with respect to the dose of a direct acting genotoxin. Thus, it is implied that direct acting genotoxic agents induce DNA damage at even the lowest of concentrations and that no "safe" dose range exists. The linear (non-threshold) paradigm has led to the one-hit model being developed. This "one hit" scenario can be interpreted such that a single DNA damaging event in a cell has the capability to induce a single point mutation in that cell which could (if positioned in a key growth controlling gene) lead to increased proliferation, leading ultimately to the formation of a tumour. There are many groups (including our own) who, for a decade or more, have argued, that low dose exposures to direct acting genotoxins may be tolerated by cells through homeostatic mechanisms such as DNA repair. This argument stems from the existence of evolutionary adaptive mechanisms that allow organisms to adapt to low levels of exogenous sources of genotoxins. We have been particularly interested in the genotoxic effects of known mutagens at low dose exposures in human cells and have identified for the first time, in vitro genotoxic thresholds for several mutagenic alkylating agen...Continue Reading

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Citations

Mar 29, 2014·Toxicological Sciences : an Official Journal of the Society of Toxicology·Katja BrüsehaferGareth James Scott Jenkins
Aug 5, 2014·Marine Drugs·Alessandra Mirtes Marques Neves GonçalvesGustavo Henrique Ribeiro Viana
Jan 9, 2015·International Journal of Molecular Sciences·Ting ZhouVivienne I Rebel
Feb 21, 2014·Clinical and Experimental Pharmacology & Physiology·Marilise F de SouzaHelena M T Barros
Jan 1, 2012·Dose-response : a Publication of International Hormesis Society·A BelchiorP Vaz
Oct 30, 2018·Toxicological Research·Takehiko Nohmi
Oct 11, 2019·Environmental and Molecular Mutagenesis·Robert H HeflichPaul A White
Jun 17, 2020·Archives of Toxicology·Andrea HartwigGerhard Eisenbrand
Sep 21, 2020·Environmental and Molecular Mutagenesis·John NicoletteMeredith Crosby
Jan 12, 2021·Ecotoxicology and Environmental Safety·Helene InderbergÅse Krøkje
Jan 14, 2022·Nanotoxicology·Salma AchawiBruno Feneon

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