Abstract
DNA adducts are considered an integrate measure of carcinogen exposure and the initial step of carcinogenesis. Their levels in more accessible peripheral blood lymphocytes (PBLs) mirror that in the bladder tissue. In this study we explore whether the formation of PBL DNA adducts may be associated with bladder cancer (BC) risk, and how this relationship is modulated by genetic polymorphisms, environmental and occupational risk factors for BC. These complex interrelationships, including direct and indirect effects of each variable, were appraised using the structural equation modeling (SEM) analysis. Within the framework of a hospital-based case/control study, study population included 199 BC cases and 213 non-cancer controls, all Caucasian males. Data were collected on lifetime smoking, coffee drinking, dietary habits and lifetime occupation, with particular reference to exposure to aromatic amines (AAs) and polycyclic aromatic hydrocarbons (PAHs). No indirect paths were found, disproving hypothesis on association between PBL DNA adducts and BC risk. DNA adducts were instead positively associated with occupational cumulative exposure to AAs (p = 0.028), whereas XRCC1 Arg 399 (p<0.006) was related with a decreased adduct levels, but with no impact on BC risk. Previous findings on increased BC risk by packyears (p<0.001), coffee (p<0.001), cumulative AAs exposure (p = 0.041) and MnSOD (p = 0.009) and a decreased risk by MPO (p<0.008) were also confirmed by SEM analysis. Our results for the first time make evident an association between occupational cumulative exposure to AAs with DNA adducts and BC risk, strengthening the central role of AAs in bladder carcinogenesis. However the lack of an association between PBL DNA adducts and BC risk advises that these snapshot measurements are not representative of relevant exposures. This would envisage new scenarios for biomarker discovery and new challenges such as repeated measurements at different critical life stages.
Highlights
Tobacco smoking and occupational exposures to aromatic amines (AAs) and polycyclic aromatic hydrocarbons (PAHs) are the major risk factors for bladder cancer (BC) [1,2]
The aim of this study was twofold: to investigate the extent to which peripheral blood lymphocytes (PBLs) DNA adducts and BC risk were separately affected by genetic polymorphisms, environmental and occupational exposures; and to explore whether the formation of DNA adducts involved an additional increase in BC risk
No significant differences between cases and controls were found for other demographic variables and putative risk factors of BC
Summary
Tobacco smoking and occupational exposures to aromatic amines (AAs) and polycyclic aromatic hydrocarbons (PAHs) are the major risk factors for bladder cancer (BC) [1,2]. The formation of reactive metabolites of AAs and PAHs and their binding to DNA to give unrepaired/stable adducts, all modulated by genetic polymorphisms of metabolic and DNA repair enzymes, are considered critical events alongside the theoretical pathway that links exposure to BC [5]. Some DNA modifications induced by aromatic compounds in the bladder are found to mirror those in the peripheral blood lymphocytes (PBLs) [11,12]. This has addressed the possibility of measuring such biomarker in accessible tissues which can be and non-invasively obtained from humans
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