Cytogenetic biomarkers.

Abstract

Cytogenetic biomarkers in peripheral blood lymphocytes such as chromosomal aberrations, sister chromatid exchanges and micronuclei have long been applied in surveillance of human genotoxic exposure and early effects of genotoxic carcinogens. The use of these biomarker assays is based on the fact that most established human carcinogens are genotoxic in short-term tests and capable of inducing chromosomal damage. The relevance of chromosomal aberrations as a biomarker has been further emphasized by epidemiological studies suggesting that a high frequency of chromosomal aberrations is predictive of an increased risk of cancer. Structural and numerical chromosomal aberrations are typical of cancer cells, probably as a manifestation of genetic instability of such cells, but may also represent mechanisms leading to such instability. The frequency of all three biomarkers increases with age, and this effect is particularly clear for micronuclei in women. Tobacco smoking is known to increase the level of sister chromatid exchanges and chromosomal aberrations, but its effect on micronuclei is unclear. Several studies have recently examined the influence of genetic polymorphisms of xenobiotic metabolizing enzymes on cytogenetic biomarkers. The lack of glutathione S-transferase M1 (GSTM1 null genotype) appears to be associated with increased sensitivity to genotoxicity of tobacco smoking. N-Acetyltransferase (NAT2) slow acetylation genotypes seem to elevate baseline level of chromosomal aberrations, whereas deletion of glutathione S-transferase T1 gene (GSTT1 null genotype) has been found to yield an increase in baseline sister chromatid exchange frequency. These findings may be explained by reduced detoxification capacity rendered by the altered gene and may be linked with exposure to, for example, heterocyclic amines in the case of NAT2 and endogenously formed ethylene oxide in the case of GSTT1. Recently discovered polymorphisms affecting DNA repair may be expected to be of special importance in modulating genotoxic effects, but, as yet, there is very little information about the significance of these polymorphisms or about their impact on cytogenetic biomarkers.