Journal Article

Reduced nucleotide excision repair and <i>GSTM1</i>-null genotypes influence <i>anti</i>-B[<i>a</i>]PDE–DNA adduct levels in mononuclear white blood cells of highly PAH-exposed coke oven workers

Sofia Pavanello, Alessandra Pulliero, Ewa Siwinska, Danuta Mielzynska and Erminio Clonfero

in Carcinogenesis

Volume 26, issue 1, pages 169-175
Published in print January 2005 | ISSN: 0143-3334
Published online January 2005 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgh303
Reduced nucleotide excision repair and GSTM1-null genotypes influence anti-B[a]PDE–DNA adduct levels in mononuclear white blood cells of highly PAH-exposed coke oven workers

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It is important to identify the potential genetic-susceptible factors that are able to modulate individual responses to exposure to carcinogenic polycyclic aromatic hydrocarbons (PAHs). In the present study we evaluated the influence of four polymorphisms of nucleotide excision repair (NER) genes [xeroderma pigmentosum-C (XPC)-PAT +/−, xeroderma pigmentosum-A (XPA) 5′ non-coding region-A23G, XPD-exon 23 A35931C Lys751Gln, xeroderma pigmentosum-D (XPD)-exon 10 G23591A Asp312Asn] and that of glutathione S-transferase μ1 (GSTM1-active or -null) on benzo[a]pyrene diol epoxide (B[a]PDE)–DNA adduct levels from the lympho-monocyte fraction (LMF) of highly PAH benzo[a]pyrene (B[a]P)-exposed Polish coke oven workers (n = 67, 67% current smokers) with individual urinary post-shift excretion of 1-pyrenol exceeding the proposed biological exposure index (BEI) (2.28 µmol/mol creatinine). The bulky (±)-r-7,t-8-dihydroxy-t-9,10-oxy-7,8,9,10-tetrahydrobenzo[a]pyrene (anti-B[a]PDE)–DNA adduct levels were detected by high-performance liquid chromatography (HPLC)/fluorescence analysis and genotypes by polymerase chain reaction. We found that workers with the low DNA repair capacity of XPC-PAT+/+ and XPA-A23A genotypes had significantly increased anti-B[a]PDE–DNA adduct levels (Mann–Whitney U-test, z = 2.24, P = 0.02 and z = 2.65, P = 0.01). Moreover, DNA adducts were also raised in workers without GSTM1 activity (GSTM1-null genotype) (Mann–Whitney U-test, z = 2.25, P = 0.0246). Workers with unfavourable XPC-PAT+/+ and XPA-A23A NER genotypes, alone (∼65% of workers) or combined with GSTM1-null genotype (∼75% of workers) were in the tertile with the highest adduct level, i.e. >4.11 adducts/108 nt (χ2 = 5.85, P = 0.0156 and χ2 = 5.40, P = 0.01). The increase in anti-B[a]PDE–DNA adduct levels (ln values) was significantly related in a multiple linear regression analysis to PAH exposure (i.e. urinary post-shift excretion of 1-pyrenol) (t = 2.61, P = 0.0115), lack of GSTM1 activity (t = 2.41, P = 0.0192) and to low DNA repair capacity of the XPC-PAT+/+ genotype (t = 2.34, P = 0.0226). The influence of the XPA-A23A genotype was not evident in this statistical analysis, and no associations with XPD polymorphisms, dietary habits or tobacco smoking were found. The modulation of anti-B[a]PDE–DNA adducts in the LMF by GSTM1-null and some low-activity NER genotypes may be considered as a potential genetic susceptibility factor capable of modulating individual responses to PAH (B[a]P) genotoxic exposure and the consequent risk of cancer in coke oven workers.

Keywords: anti-B[a]PDE, (±)-r-7,t-8-dihydroxy-t-9,10-oxy-7,8,9,10-tetrahydrobenzo[a]pyrene; B[a]P, benzo[a]pyrene; B[a]P-tetrol I-1, r-7,c-10,t-8,t-9-tetrahydroxy-7,8,9,10-tetrahydrobenzo[a]pyrene; GSTM1, glutathione S-transferase μ 1; HPLC, high-performance liquid chromatography; LMF, lymphocyte plus monocyte fraction; NER, nucleotide excision repair, PAHs, polycyclic aromatic hydrocarbons; PCR, polymerase chain reaction; XPA, xeroderma pigmentosum-A; XPC, xeroderma pigmentosum-C; XPD, xeroderma pigmentosum-D

Journal Article.  5624 words. 

Subjects: Clinical Cytogenetics and Molecular Genetics

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