Jenifer Saffi

Genotoxicity, recombinogenicity and cellular preneoplasic transformation induced by Vitamin a supplementation

In spite of being one of the first vitamins to be discovered, the full range of biological activities of Vitamin A remains incomplete. A growing body of evidence has demonstrated an apparent enhancement of carcinogenesis, induced by dietary retinol. Since DNA damage is a well-recognized inducer of carcinogenesis, the aim of this study was to test the possible genotoxic effect of dietary retinol, using different types of bioassays. Retinol caused an increased recombinogenic activity in Drosophila melanogaster larvae as measured by the SMART test. In mammalian cell cultures, retinol supplementation-induced DNA double-strands breaks (DSB) and single-strands breaks (SSB), cell cycle progression and proliferative focus formation in terminal-differentiated rat Sertoli cells and increased DNA fragmentation in Chinese hamster lung fibroblasts (V79 cells), as measured by the comet assay. Altogether, our results suggest that retinol causes DNA damage and chromosomal rearrangements, which may disturbs key physiological processes and lead to cell cycle progression and preneoplasic transformation of terminal-differentiated mammalian cells.

Occupational risk assessment of genotoxicity and oxidative stress in workers handling anti-neoplastic drugs during a working week

Twenty pharmacists and nurses handling anti-neoplastic drugs in a hospital were monitored during a working week, from Monday to Friday, in the morning (only on Monday) and afternoon (all days). Genotoxicity was analysed by the comet assay and the micronucleus (MN) test, while oxidative stress was analysed in serum by thiobarbituric acid reactive substances (TBARS) and by measurements of the antioxidant enzymes superoxide dismutase (Sod) and catalase (Cat). The exposed workers presented increased DNA damage levels by the comet assay as compared to the controls. The comet assay results have also shown significant positive correlation with the day of the week and with alcohol consumption. MN frequency was significantly higher in the exposed workers and presented noteworthy correlation with age and working time. In the oxidative stress parameters, only Cat presented a significant increase in the exposed group, considering all the samplings. However, TBARS data showed interesting results, considering the different sampling times; the exposed group presented a significant correlation with the working days and significantly higher results on Friday as compared to the controls and Monday morning. Monitoring occupational risk during a longer time, e.g. during a working week as done in this study, introduces additional aspects of risk behaviour, which can improve risk management. This study demonstrates the usefulness of evaluating oxidative stress also in genotoxic risk assessment since both events often result from the same factors.

BER gene polymorphisms (OGG1 Ser326Cys and XRCC1 Arg194Trp) and modulation of DNA damage due to pesticides exposure.

The susceptibility of individuals to the genotoxic effect of pesticides can be modulated by genetic variations in the xenobiotic detoxification and DNA repair processes. This study evaluates if the two BER polymorphisms (XRCC1Arg194Trp and OGG1Ser326Cys) or the combined genotypes of these polymorphisms with PON1Gln192Arg could modify individual susceptibility to pesticide exposure in vineyard workers, as measured by micronucleus formation and DNA damage induction in peripheral leukocytes. The study population comprised 108 agricultural workers exposed to pesticides and 65 nonexposed. Our results demonstrate that individuals with the variant allele (OGG1Cys) showed higher DNA damage, detected by the comet assay, in relation to individuals carrying the wild‐type OGG1Ser allele. Considering the combined influence of metabolizing PON1 and the DNA repair OGG1 genes, we observed significantly higher DNA damage in the comet assay in the exposed group when a less efficient OGG1Cys allele was acting independently of the PON1 genotype, reinforcing the importance of the OGG1 repair enzyme in the response to DNA damage by pesticide exposure. The association of the PONGln/Gln genotype with higher MN frequency suggests that the PON1 genotype is a major determinant of genotoxic risk in individuals exposed to pesticides. Analysis of the compared effect of XRCC1 and PON1 genotypes in the exposed group suggested that, among the poorly metabolizing PON1Gln/Gln individuals, the XRCC1Arg/Trp genotype has a protective effect with respect to MN formation. These results indicate that enhanced XRCC1 function may provide some protection from the enhanced genotoxic risk associated with inefficient xenobiotic detoxification in the studied population. Environ. Mol. Mutagen. 52:20–27, 2011.