Department of Internal Medicine, Division of Epidemiology, Biostatistics and Preventive Medicine, University of New Mexico, Albuquerque, New Mexico 87131-00001, USA.
Environ Mol Mutagen. 2013 Mar;54(2):82-98. doi: 10.1002/em.21749. Epub 2012 Nov 29.
Gene expression changes in primary human uroepithelial cells exposed to arsenite and its methylated metabolites were evaluated to identify cell signaling pathway perturbations potentially associated with bladder carcinogenicity. Cells were treated with mixtures of inorganic arsenic and its pentavalent or trivalent metabolites for 24 hr at total arsenic concentrations ranging from 0.06 μM to 18 μM. One series (five samples) was conducted with arsenite and pentavalent metabolites and a second (10 samples) with arsenite and trivalent metabolites. Similar gene expression responses were obtained for pentavalent or trivalent metabolites. A suite of eight gene changes was consistently identified across individuals that reflect effects on key signaling pathways: oxidative stress, protein folding, growth regulation, metallothionine regulation, DNA damage sensing, thioredoxin regulation, and immune response. No statistical significance of trend (NOSTASOT) analysis of these common genes identified lowest observed effect levels (LOELs) from 0.6 to 6.0 μM total arsenic and no observed effect levels (NOELs) from 0.18 to 1.8 μM total arsenic. For the trivalent arsenical mixture, benchmark doses (BMDs) ranged from 0.13 to 0.92 μM total arsenic; benchmark dose lower 95% confidence limits (BMDLs) ranged from 0.09 to 0.58 μM total arsenic. BMDs ranged from 0.53 to 2.7 μM and BMDLs from 0.35 to 1.7 μM for the pentavalent arsenical mixture. Both endpoints varied by a factor of 3 across individuals. Thisstudy is the first to examine gene expression response in primary uroepithelial cells from multiple individuals and to identify no effect levels for arsenical-induced cell signaling perturbations in normal human cells exposed to a biologically plausible concentration range.
评估人原代尿路上皮细胞暴露于亚砷酸盐及其甲基化代谢物后基因表达的变化，以鉴定可能与膀胱癌发生相关的细胞信号通路扰动。将细胞用总砷浓度范围为 0.06 μM 至 18 μM 的无机砷及其五价或三价代谢物混合物处理 24 小时。一组（五个样本）用亚砷酸盐和五价代谢物进行，另一组（十个样本）用亚砷酸盐和三价代谢物进行。五价或三价代谢物得到了相似的基因表达反应。在个体之间一致鉴定出了一组八个基因变化，反映了对关键信号通路的影响：氧化应激、蛋白质折叠、生长调节、金属硫蛋白调节、DNA 损伤感应、硫氧还蛋白调节和免疫反应。对这些常见基因的趋势（NOSTASOT）分析没有统计学意义，确定了总砷浓度为 0.6 至 6.0 μM 的最低观察到的效应水平（LOEL）和总砷浓度为 0.18 至 1.8 μM 的无观察到的效应水平（NOEL）。对于三价砷混合物，基准剂量（BMD）范围为 0.13 至 0.92 μM 总砷；基准剂量下限 95%置信区间（BMDL）范围为 0.09 至 0.58 μM 总砷。对于五价砷混合物，BMD 范围为 0.53 至 2.7 μM，BMDL 范围为 0.35 至 1.7 μM。这两个终点在个体之间变化了 3 倍。这项研究首次检查了来自多个个体的原代尿路上皮细胞的基因表达反应，并确定了在暴露于生物学上合理的浓度范围内的正常人类细胞中，砷诱导的细胞信号扰动的无效应水平。
