title: Cytogenetic biomarkers and genetic polymorphisms.
abstract: Cytogenetic biomarkers have long been applied in surveillance of human genotoxic exposure and early effects of genotoxic carcinogens. Due to their wide use, it has been possible to evaluate, in international collaborative studies, if a high level of these biomarkers in peripheral lymphocytes is predictive of cancer risk. Thus far, such an association has been observed for chromosomal aberrations (CAs), but not for sister chromatid exchanges (SCEs) or micronuclei (MN). The cancer risk predictivity of CAs was not dependent on the time between CA analysis and cancer detection and did not appear to be explained by tobacco smoking or occupational exposure to carcinogens but was seen in unexposed non-smokers as well. This suggests a role for individual susceptibility factors. Genetic polymorphisms of various xenobiotic-metabolising enzymes, influencing the metabolic activation and detoxification of carcinogens, have been associated with cancer risk, and some of them also appear to affect cytogenetic biomarkers. The lack of glutathione S-transferase M1 (GSTM1 null genotype) is associated with increased sensitivity to genotoxicity of tobacco smoke, and GSTM1 null smokers also show an increased frequency of CAs and SCEs. N-Acetyltransferase (NAT2) slow acetylation genotype and glutathione S-transferase T1 (GSTT1) null genotype seem to elevate the baseline level of CAs and SCEs and CAs, respectively--possibly because of reduced capacity to detoxify some wide-spread or endogenous genotoxins. For some chemicals, in vitro cytogenetic studies with lymphocyte donors representing different genotypes have been able to predict a differential in vivo response. For instance, in vitro SCE induction by styrene and by epoxide metabolites of 1,3-butadiene is modified by GSTM1 and GSTT1 genotypes--which also influence the excretion of specific mercapturic acids in humans exposed to butadiene and styrene. Polymorphisms of DNA repair and folate metabolism are expected to be of special importance in modulating genotoxic effects. Some evidence exists for the effects of X-ray cross complementation group 1 (XRCC1) codon 280 and (in smokers) Xeroderma pigmentosum group D (XPD) codon 23 polymorphisms on baseline CAs, for XRCC1 codon 399 polymorphism on SCEs in smokers, and for methylene tetrahydrofolate reductase (MTHFR) codon 677 and methionine synthase reductase (MTRR) polymorphisms on spontaneous MN.
authors.affiliation: Laboratory of Molecular and Cellular Toxicology, Department of Industrial Hygiene and Toxicology, Finnish Institute of Occupational Health, FIN-00250 Helsinki, Finland. hannu.norppa@ttl.fi
authors.forename: Hannu
authors.initials: H
authors.lastname: Norppa
mesh_terms: D000818:Animals; D020732:Cytogenetic Analysis; D004260:DNA Repair / Q000187:drug effects; D004781:Environmental Exposure / Q000009:adverse effects; D004785:Environmental Pollutants / Q000633:toxicity*; D005492:Folic Acid / Q000378:metabolism; D005819:Genetic Markers; D006801:Humans; D011110:Polymorphism, Genetic / Q000187:drug effects*; D012907:Smoking / Q000235:genetics / Q000378:metabolism; D015262:Xenobiotics / Q000378:metabolism
chemical_list: D004785:Environmental Pollutants; D005819:Genetic Markers; D015262:Xenobiotics; D005492:Folic Acid