Porru Stefano, Pavanello Sofia, Carta Angela, Arici Cecilia, Simeone Claudio, Izzotti Alberto, Mastrangelo Giuseppe
Department of Medical-Surgical Specialties, Radiological Sciences and Public Health, Section of Public Health and Human Sciences, University of Brescia, Brescia, Italy.
Department of Cardiac, Thoracic, and Vascular Sciences, Unit of Occupational Medicine, University of Padova, Padova, Italy.
PLoS One. 2014 Apr 10;9(4):e94566. doi: 10.1371/journal.pone.0094566. eCollection 2014.
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.
DNA加合物被认为是致癌物暴露的综合指标以及致癌作用的起始步骤。它们在更容易获取的外周血淋巴细胞（PBL）中的水平反映了膀胱组织中的水平。在本研究中，我们探讨了PBL DNA加合物的形成是否可能与膀胱癌（BC）风险相关，以及这种关系如何受到基因多态性、BC的环境和职业风险因素的调节。使用结构方程模型（SEM）分析评估了这些复杂的相互关系，包括每个变量的直接和间接影响。在一项基于医院的病例/对照研究框架内，研究人群包括199例BC病例和213例非癌症对照，均为白种男性。收集了关于终生吸烟、咖啡饮用、饮食习惯和终生职业的数据，特别提及了芳香胺（AAs）和多环芳烃（PAHs）的暴露情况。未发现间接路径，这否定了关于PBL DNA加合物与BC风险之间关联的假设。相反，DNA加合物与职业性累积暴露于AAs呈正相关（p = 0.028），而XRCC1 Arg 399（p<0.006）与加合物水平降低相关，但对BC风险无影响。SEM分析还证实了先前关于每包年（p<0.001）、咖啡（p<0.001）、累积AAs暴露（p = 0.041）和MnSOD（p = 0.009）使BC风险增加以及MPO（p<0.008）使风险降低的研究结果。我们的结果首次明确了职业性累积暴露于AAs与DNA加合物和BC风险之间的关联，强化了AAs在膀胱癌发生中的核心作用。然而，PBL DNA加合物与BC风险之间缺乏关联表明这些即时测量结果并不代表相关暴露情况。这将设想生物标志物发现的新场景以及新的挑战，例如在不同关键生命阶段进行重复测量。
