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Genetics, genetic toxicology

We have demonstrated that deoxyribonucleic acid (DNA) repair is heterogeneous in cells of different organs and organisms and a function of the chromosome structure and nuclear organization. It has been shown that the process of transcription of active genes is closely associated with nucleotide excision repair, and evidence has been obtained that differences in the organization of DNA repair may have a profound influence on mutation induction and transformation of cells from various species, organs ad tissues. Evidence of the involvement of DNA repair in the aetiology of cancer has been obtained via the isolation of defected human repair genes from patients with genetic disorders such as xeroderma pigmentosum, ataxia telangiectasia and cockayne's syndrome. Detailed information about the relation between repair functions and tumour formation is expected to be obtained from the recent generation of knockout transgenic mice lacking the rodent homologues of known human repair genes. Technology to measure biological endpoints in man allows its application for biomonitoring purposes. Various endpoints have been tested such as chromosomal aberrations, sister chromatid exchanges (SCE), micronuclei and the induction of hypoxanthine phosphoribosyltransferase (hprt) mutations in blood cells in humans exposed to chemicals and ionizing radiation. In decreasing order the sensitivity of these biomarkers for practical use turned out to be: chromosomal aberrations, then SCEs, then micronuclei followed by hprt mutations. Cytogenetic techniques have been very successfully applied in victims accidently exposed to ionizing radiation. In these studies it has been possible to estimate absorbed radiation dose in different situations such as, for instance, partial body exposure and acute versus chronic exposures. Finally, the concept that, in principle, all electrophilic agents can react with DNA in cells assigns those agents to potential carcinogens and makes current strategies for hazard and risk assessment an extremely difficult task. It is estimated that humans in average daily life are challenged with a least a million different electrophiles, be it in vastly different exposure levels. So far regulatory measures are primarily based on ad hoc risk assessment of individual genotoxic agents without taking into account the prevalence of carcinogens in our environment. New models are under development that will allow the prioritizing and ranking of potentially genotoxic agents for practical purposes.

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LUMC - Leiden University
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2333 AL Leiden
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