Xu Huan, Lauer Fredine T, Liu Ke Jian, Hudson Laurie G, Burchiel Scott W
Department of Pharmaceutical Sciences, The University of New Mexico College of Pharmacy, New Mexico 87131.
Department of Pharmaceutical Sciences, The University of New Mexico College of Pharmacy, New Mexico 87131
Toxicol Sci. 2016 Nov;154(1):153-161. doi: 10.1093/toxsci/kfw151. Epub 2016 Aug 7.
Arsenic and polycyclic aromatic hydrocarbon (PAH) exposures affect many people worldwide leading to cancer and other diseases. Arsenite (As) and certain PAHs are known to cause genotoxicity. However, there is limited information on the interactions between As and PAHs at environmentally relevant concentrations. The thymus is the primary immune organ for T cell development in mammals. Our previous studies showed that environmentally relevant concentrations of As induce genotoxicity in mouse thymus cells through Poly(ADP-ribose) polymerase (PARP) inhibition. Certain PAHs, such as the metabolites of benzo(a)pyrene (BaP), are known to cause DNA damage by forming DNA adducts. In the present study, primary mouse thymus cells were examined for DNA damage following 18 hr in vitro treatments with 5 or 50 nM As and 100 nM BaP, benzo[a]pyrene-7,8-dihydrodiol (BP-Diol), or benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide (BPDE). An interactive increase in genotoxicity and apoptosis were observed following treatments with 5 nM As +100 nM BP-diol and 50 nM As +100 nM BPDE. We attribute the increase in DNA damage to inhibition of PARP inhibition leading to decreased DNA repair. To further support this hypothesis, we found that a PARP inhibitor, 3,4-dihydro-5[4-(1-piperindinyl) butoxyl]-1(2H)-isoquinoline (DPQ), also interacted with BP-diol to produce an increase in DNA damage. Interestingly, we also found that As and BP-diol increased CYP1A1 and CYP1B1 expression, suggesting that increased PAH metabolism may also contribute to genotoxicity. In summary, these results show that the suppression of PARP activity and induction of CYP1A1/CYP1B1 may act together to increase DNA damage produced by As and PAHs.
砷和多环芳烃（PAH）暴露影响着全球许多人，会导致癌症和其他疾病。已知亚砷酸盐（As）和某些多环芳烃会引起基因毒性。然而，关于环境相关浓度下砷与多环芳烃之间相互作用的信息有限。胸腺是哺乳动物中T细胞发育的主要免疫器官。我们之前的研究表明，环境相关浓度的砷通过抑制聚（ADP - 核糖）聚合酶（PARP）在小鼠胸腺细胞中诱导基因毒性。某些多环芳烃，如苯并（a）芘（BaP）的代谢产物，已知会通过形成DNA加合物导致DNA损伤。在本研究中，对原代小鼠胸腺细胞进行体外处理18小时，分别用5或50 nM的As以及100 nM的BaP、苯并[a]芘 - 7,8 - 二氢二醇（BP - Diol）或苯并[a]芘 - 7,8 - 二氢二醇 - 9,10 - 环氧化物（BPDE）处理，检测DNA损伤情况。在用5 nM As + 100 nM BP - Diol和50 nM As + 100 nM BPDE处理后，观察到基因毒性和细胞凋亡的交互增加。我们将DNA损伤的增加归因于PARP抑制导致DNA修复减少。为了进一步支持这一假设，我们发现一种PARP抑制剂3,4 - 二氢 - 5[4 - （1 - 哌啶基）丁氧基] - 1（2H） - 异喹啉（DPQ）也与BP - Diol相互作用，导致DNA损伤增加。有趣的是，我们还发现As和BP - Diol增加了CYP1A1和CYP1B1的表达，这表明多环芳烃代谢增加也可能导致基因毒性。总之，这些结果表明PARP活性的抑制和CYP1A1/CYP1B1的诱导可能共同作用，增加砷和多环芳烃产生的DNA损伤。
