Department of Medicinal Chemistry and Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455, United States.
Department of Veterinary Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas 77843, United States.
Chem Res Toxicol. 2021 Nov 15;34(11):2375-2383. doi: 10.1021/acs.chemrestox.1c00291. Epub 2021 Nov 2.
1,3-Butadiene is a known carcinogen primarily targeting lymphoid tissues, lung, and liver. Cytochrome P450 activates butadiene to epoxides which form covalent DNA adducts that are thought to be a key mechanistic event in cancer. Previous studies suggested that inter-species, -tissue, and -individual susceptibility to adverse health effects of butadiene exposure may be due to differences in metabolism and other mechanisms. In this study, we aimed to examine the extent of inter-individual and inter-species variability in the urinary N7-(1-hydroxy-3-buten-2-yl)guanine (EB-GII) DNA adduct, a well-known biomarker of exposure to butadiene. For a population variability study in mice, we used the collaborative cross model. Female and male mice from five strains were exposed to filtered air or butadiene (590 ppm, 6 h/day, 5 days/week for 2 weeks) by inhalation. Urine samples were collected, and the metabolic activation of butadiene by DNA-reactive species was quantified as urinary EB-GII adducts. We quantified the degree of EB-GII variation across mouse strains and sexes; then, we compared this variation with the data from rats (exposed to 62.5 or 200 ppm butadiene) and humans (0.004-2.2 ppm butadiene). We show that sex and strain are significant contributors to the variability in urinary EB-GII levels in mice. In addition, we find that the degree of variability in urinary EB-GII in collaborative cross mice, when expressed as an uncertainty factor for the inter-individual variability (UF), is relatively modest (≤threefold) possibly due to metabolic saturation. By contrast, the variability in urinary EB-GII (adjusted for exposure) observed in humans, while larger than the default value of 10-fold, is largely consistent with UF estimates for other chemicals based on human data for non-cancer endpoints. Overall, these data demonstrate that urinary EB-GII levels, particularly from human studies, may be useful for quantitative characterization of human variability in cancer risks to butadiene.
1,3-丁二烯是一种主要针对淋巴组织、肺和肝脏的已知致癌物质。细胞色素 P450 将丁二烯激活为环氧化物，这些环氧化物形成与 DNA 结合的加合物，被认为是癌症的关键机制事件。先前的研究表明，种间、组织间和个体间对丁二烯暴露的不良健康影响的易感性可能是由于代谢和其他机制的差异。在这项研究中，我们旨在检查个体间和种间在尿 N7-(1-羟基-3-丁烯-2-基)鸟嘌呤 (EB-GII) DNA 加合物水平上的个体间和种间可变性的程度，这是丁二烯暴露的一个众所周知的生物标志物。为了在小鼠中进行人群变异性研究，我们使用了协作交叉模型。来自五个品系的雌性和雄性小鼠通过吸入暴露于过滤空气或丁二烯（590ppm，6 小时/天，每周 5 天）。收集尿液样本，并通过 DNA 反应性物质来量化丁二烯的代谢活化，以测定尿 EB-GII 加合物。我们量化了不同品系和性别的小鼠中 EB-GII 的变异程度；然后，我们将这种变异性与大鼠（暴露于 62.5 或 200ppm 丁二烯）和人类（0.004-2.2ppm 丁二烯）的数据进行了比较。结果表明，性别和品系是影响小鼠尿 EB-GII 水平变异性的重要因素。此外，我们发现，协作交叉小鼠尿 EB-GII 的变异性程度，当表示为个体间变异性的不确定性因子（UF）时，相对适中（≤三倍），可能是由于代谢饱和。相比之下，人类尿 EB-GII 的变异性（根据暴露进行调整）虽然大于默认值的 10 倍，但与基于非癌症终点的人类数据的其他化学物质的 UF 估计值基本一致。总的来说，这些数据表明，尿 EB-GII 水平，特别是来自人类研究的数据，可能有助于定量描述人类对丁二烯致癌风险的变异性。
