Influence of occupational and environmental metal exposure on DNA-damage and DNA-repair capacity: Comparison of established and new biomarkers as to their predictivity for cancer development

Status:

completed 12/2009

Aims:

For an adequate cancer prevention the development of health-based limits also for carcinogenic metal compounds is desirable. For this purpose, dose-effect relationships between metal exposure and health effects have to be established. Therefore the aim of this study was to apply newly developed biomarkers for genotoxicity and to determine their association with exposure values in a low-dose range. In a second later phase of the study the role of these biomarkers in molecular ageing and development of cancer will be clarified.

Activities/Methods:

SALIA (Study on the influence of Air pollution on Lung function, Inflammation and Ageing) is a cohort study in elderly women from the urban Ruhr-area and the Münsterland, a rural district located north of the Ruhr-area. The baseline investigation was performed between 1985 and 1991 and included the evaluation of external and internal metal exposure data. 402 women of this cohort were reinvestigated in 2007/2008, their actual internal metal exposure values were measured and three newly developed biomarkers of genotoxicity were applied. These biomarkers were "number of FPG-sensitive sites per 10*6 base pairs" as measure for oxidative DNA-damage and as measure for DNA-repair capacity the parameters "PARPactivity" and "incision-capacity". Furthermore, eight single nucleotide polymorphisms (SNP) with known associations with DNA-repair genes were analysed. Dose-effect relationships between exposure parameters and the markers of genotoxicity, as well as possible gene-environment interactions were investigated by multiple regression analyses.

Results:

Most striking effects on biomarkers of genotoxicity were found for exposure values measured 20 years ago (1985-1990). Especially, elevated lead and copper burden were significantly associated with more oxidative DNA-damages and less DNA-repair capacities. Additionally, iron and nickel, measured 1985-1990, as well as vehicle-derived particles (2000) and soot (2002/2003) exhibited significant effects. Exposure values during baseline investigation were much higher than those recorded in the present investigation. Metals as lead and cadmium can accumulate in liver and kidney, and internal metal exposure measured 20 years ago, probably still contributes to the actual internal exposure.
The association between exposure parameters and biomarkers of genotoxicity was modulated by some allele combinations of DNA-repair genes. These gene-environment interactions provide supporting evidence for possibly causal relationships.
From the evaluation of the subproject SALIA 2008 it can be concluded, that the applied methods are appropriate to quantify genotoxic effects triggered by environmental metal exposure.

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