Association between genetic polymorphisms and biomarkers in styrene-exposed workers.
A comprehensive approach to evaluate genotoxic effects induced by styrene exposure was employed in 44 hand-lamination workers in comparison with 18 unexposed controls. The acquired data on single-strand breaks in DNA (SSBs), frequency of chromosomal aberrations and HPRT mutant frequency in peripheral blood lymphocytes were compared to the results on genotyping of some of the xenobiotic-metabolising enzymes (CYP1A1, CYP2E1, epoxide hydrolase and GSTM1, GSTP1 and GSTT1). Multifactorial regression analysis indicated that SSB in DNA were significantly associated with styrene exposure and with heterozygosity in CYP2E1 (5'-flanking region and intron 6; r(2)=0.614). The frequency of chromosomal aberrations (CA), as analysed by linear multiple regression analysis, significantly correlated with years of employment (P=0.004) and with combinations of epoxide hydrolase (EPHX) genotypes (exon 3, Tyr/His and exon 4, His/Arg), where individuals with low and medium activity EPHX genotypes exhibited higher frequencies of CA than those with high activity genotypes (P=0.044, r(2)=0.563). Moderately higher HPRT mutant frequencies were detected in styrene-exposed individuals (20.2 +/- 25.8 x 10(-6)) as compared to controls (13.3 +/- 6.3 x 10(-6)), but this difference was not significant. ANOVA (in the whole set of data) revealed that mutant frequencies at the HPRT gene were significantly associated with years of employment (F=6.9, P=0.0001), styrene in blood (F=10.1, P=0.0001), and heterozygosity in CYP2E1 (intron 6; F=13.5, P=0.0008) and GSTP1 (exon 5; F=3.6, P=0.038). In conclusion, our present data suggest that analysed biomarkers of DNA damage may be modulated by polymorphic CYP2E1, EPHX and GSTP1. In our study, styrene-specific DNA and haemoglobin adducts are under investigation. Completing these data with the results of genotyping of metabolising enzymes may provide a useful tool for individual genotoxic risk assessment.
Vodicka
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P
Institute of Experimental Medicine, Czech Academy of Sciences, Videnska 1083, 14220 Prague 4, Czech Republic. pvodicka@biomed.cas.cz
Soucek
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P
Tates
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AD
Dusinska
M
M
Sarmanova
J
J
Zamecnikova
M
M
Vodickova
L
L
Koskinen
M
M
de Zwart
F A
FA
Natarajan
A T
AT
Hemminki
K
K
D000328:Adult; D015415:Biomarkers; D016022:Case-Control Studies; D002869:Chromosome Aberrations; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics; D004249:DNA Damage / Q000187:drug effects / Q000235:genetics; D004277:DNA, Single-Stranded / Q000187:drug effects; D004798:Enzymes / Q000235:genetics* / Q000378:metabolism; D004851:Epoxide Hydrolases / Q000235:genetics; D005260:Female; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase / Q000235:genetics; D006801:Humans; D007041:Hypoxanthine Phosphoribosyltransferase / Q000187:drug effects / Q000235:genetics; D008658:Inactivation, Metabolic; D007527:Isoenzymes / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009153:Mutagens / Q000009:adverse effects*; D009154:Mutation; D016273:Occupational Exposure; D011110:Polymorphism, Genetic; D020058:Styrene / Q000009:adverse effects* / Q000378:metabolism
D015415:Biomarkers; D019363:Cytochrome P-450 CYP1A1; D019392:Cytochrome P-450 CYP2E1; D004277:DNA, Single-Stranded; D004798:Enzymes; D004851:Epoxide Hydrolases; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase; D007041:Hypoxanthine Phosphoribosyltransferase; D007527:Isoenzymes; D009153:Mutagens; D020058:Styrene; C413545:glutathione S-transferase T1; C496556:GSTP1 protein, human