The common current assumption is that there is an essentially linear relationship between exposure to genotoxic chemicals, DNA lesion formation and the induction of mutagenic changes. A number of studies of DNA adduct induction indicate that such a linear relationship between DNA modifications and exposure does exist (van Sittert et al, 2000). However, mutations are not produced directly by DNA adducts and there are a range of factors (such as DNA repair activity) that potentially limits the proportion of adducts processed into mutational changes. The aim of the project is to determine the quantitative and qualitative relationships between exposure, DNA adducts and gene and chromosome mutations initially using an in vitro model in cultured human cells. The study will characterise, using mass spectrometry, the dose response relationships of chemicals producing both minor adduct modifications and bulky adducts. Co-incident exposure experiments will be performed for the mutation and chromosome aberration studies. The influence of DNA repair activity upon dose response relationships will also be determined. The data generated from this project will help answer the questions related to the biological significance of low-dose exposures to DNA adduct forming chemicals.
Johnson G.E., Doak S.H., Griffiths S.M., Quick E.L., Skibinski D.O.F., Zaïr Z.M. and Jenkins G.J. (2009). Non-linear dose–response of DNA-reactive genotoxins: Recommendations for data analysis. Mutation Research.
Jenkins G.J.S., Zoulikha Zaïr Z., Johnson G.E. and Doak S.H. (2009). Genotoxic thresholds, DNA repair, and susceptibility in human populations. Toxicology.
SH Doak, GJS Jenkins, GE Johnson, E Quick, EM Parry, JM Parry, Mechanistic influences for mutation induction curves after exposure to DNA-reactive carcinogens, Cancer Research 2007, 67, 3904-3911.
GJS Jenkins, SH Doak, GE Johnson, E Quick, EM Waters, JM Parry, Do dose response thresholds exist for genotoxic alkylating agents?, Mutagenesis 2005, 20, 389-398.
Parry J.M., Parry E.M., Johnson G., Quick E. and Waters E.M. (2005). The detection of genotoxic activity and the quantitative and qualitative assessment of the consequences of exposures. Experimental and Toxicologic Pathology. 57, 205–212.