The chromosome-based challenge assay using fluorescence in situ hybridization: a possible test for increased cancer susceptibility

The challenge assay is a cytogenetic approach to measure the repair compete nce of cells. For in vitro studies, human lymphocytes are exposed to differ ent substances and are irradiated simultaneously. To investigate subjects e xposed occupationally or environmentally, untreated blood samples are direc tly irradiated without any further treatment. Certain substances like heavy metals reveal carcinogenic potential without well defined mechanism of act ion. While they are not mutagenic they may have an effect on DNA repair cap acity, The challenge assay was successfully applied in vitro experiments wi th cadmium to detect an interaction of this heavy metal with the repair of X-ray-induced chromosome breaks. CdCl2 alone had no effect on the formation of chromosome aberrations (CA), not even in the cytotoxic concentration (5 0 mu M). However, cadmium showed an effect on the number of chromosomal rea rrangements (CR) after X-ray challenge. For 0.5 mu M CdCl2, CA frequencies were significantly elevated compared to the rates for X-rays alone. For the two higher concentrations the rates showed a slight additional increase. H ence, the challenge assay appears suitable to test for chromosomal sensitiv ity induced by toxicants. Subsequently, a study of styrene exposed workers was initiated to address the question whether styrene exposure has an influ ence on the DNA repair. In addition, we investigated whether a polymorphism of genes coding for phase II detoxifying enzymes glutathione-S-transferase s GSTM1 and GSTT1 had an influence on chromosomal sensitivity. First and pr eliminary data are presented. While there is a correlation of the rate of C R with cumulative lifetime exposure of styrene, the most recent styrene exp osure had no effect. 'At risk' genotypes with higher incidence of CA could not be identified at this stage of the ongoing study. Conclusion: the chall enge assay is able to detect enhanced susceptibility for CR caused by genet ic predisposition for DNA repair deficiency. Our data indicate that environ mental or occupational exposure to certain substances can interfere with DN A repair processes. As the process of induction of CR is associated with ca rcinogenesis, the challenge assay may provide a valuable biomarker for canc er epidemiology studies. (C) 1999 Elsevier Science B.V. All rights reserved .