Abstract：
Environmental exposures often produce reactive electrophiles in vivo, leading to oxidative stress, which plays a major role in carcinogenesis. These electrophiles frequently form adducts with human albumin, which can be measured to assess in vivo oxidative stress. Here, we aimed to examine the associations between circulatory albumin adducts and acute myeloid leukemia (AML), the most common adult myeloid leukemia that showed consistent associations with environmental exposures. We conducted a nested case-control study of 52 incident AML cases and 103 controls matched on age, sex and race within two prospective cohorts: the CLUE and PLCO studies. We measured 42 untargeted albumin adducts in prediagnostic samples using liquid chromatography-high-resolution mass spectrometry. Circulatory albumin adducts were associated with AML in conditional logistic regression models. For instance, higher levels of Cys34 disulfide adduct of the S-γ-glutamylcysteine, a precursor of the essential antioxidant, glutathione were associated with a lower risk of AML (odds ratios [95% confidence intervals]) for the 1st, 2nd and 3rd tertiles were 1.0, 0.65 (0.31-1.36) and 0.31 (0.12-0.80), respectively (P-trend = .01). These associations were largely driven by effects present among cases diagnosed at or above the median follow-up time of 5.5 years. In conclusion, applying a novel approach to characterize exposures in the prediagnostic samples, we found evidence supporting the notion that oxidative stress may play a role in the pathogenesis of AML. Our findings offer insight into AML etiology and may be relevant in identifying novel therapeutic targets.
摘要：
环境暴露通常会在体内产生反应性亲电子试剂，导致氧化应激，在致癌过程中起着重要作用。这些亲电试剂经常与人白蛋白形成加合物，可以测量以评估体内氧化应激。这里,我们旨在研究循环白蛋白加合物与急性髓细胞性白血病（AML）之间的关联，最常见的成人髓细胞性白血病与环境暴露有一致的关联.我们进行了一项巢式病例对照研究，对52例AML事件病例和103例对照进行了年龄匹配，两个前瞻性队列中的性别和种族：CLUE和PLCO研究。我们使用液相色谱-高分辨率质谱法测量了诊断前样品中的42种非靶向白蛋白加合物。在条件逻辑回归模型中，循环白蛋白加合物与AML相关。例如,S-γ-谷氨酰半胱氨酸的Cys34二硫键加合物水平较高，必需抗氧化剂的前体，谷胱甘肽与AML的风险较低相关（比值比[95%置信区间]），第二和第三三元分别为1.0、0.65(0.31-1.36)和0.31(0.12-0.80)，分别(P趋势=0.01)。这些关联在很大程度上是由在5.5年的中位随访时间或以上诊断出的病例中存在的效应驱动的。总之,应用一种新颖的方法来表征诊断前样本中的暴露，我们发现有证据支持氧化应激可能在AML的发病机制中发挥作用.我们的发现提供了对AML病因的见解，并且可能与确定新的治疗靶标有关。
