Departament de Genètica i de Microbiologia, Facultat de Biociències, Grup de Mutagènesi, Universitat Autònoma de Barcelona, 08193 Cerdanyola del Vallès, Bellaterra, Spain.
Arch Toxicol. 2013 Jun;87(6):1001-12. doi: 10.1007/s00204-012-0948-6. Epub 2012 Oct 5.
Inorganic arsenic (i-As) is a naturally occurring toxic metalloid affecting millions of people worldwide. It is known to be carcinogen, liver being a potential target, and related to the prevalence of diabetes in arseniasis-endemic areas. Hepatocyte nuclear factor 1 and 4 alpha (HNF1α and HNF4α) are key members of a transcriptional network essential for normal liver architecture. Changes in HNF1α and HNF4α expression are clearly associated with the development of liver malignancies and diabetes in humans. In this work, hepatic HepG2 cells and golden Syrian hamsters were exposed to sub-toxic, environmentally relevant doses of sodium arsenite (SA; up to 10 μM in vitro, 15 mg/L in vivo) in order to evaluate whether arsenic is able to compromise the expression of hepatocyte nuclear factors. Also, liver histopathological examination was carried out, and several markers of hepatocyte differentiation and glucose metabolism status were determined as a measure of i-As-induced effects. Results show a consistent down-regulation of HNF1α and HNF4α under a scenario of exposure where HepG2 cells (1) gained resistance to arsenic-induced toxicity/apoptosis, (2) attained loss of tissue-specific features (as shown by the observed down-regulation of ALDOB, PEPCK and CYP1A2, triggering of the epithelial-to-mesenchymal transition program and the hypersecretion of matrix metalloproteinase-2 and 9), (3) failed to maintain balanced expression of the "stemness" genes C-MYC, OCT3/4, LIN28 and NOTCH2 and (4) showed glucose metabolism impairment. We conclude that the i-As-induced down-regulation of HNF1α and HNF4α under chronic settings may play a central role in the features of disease and cancer observed both in vivo and in vitro.
无机砷（i-As）是一种天然存在的有毒类金属元素，影响着全球数百万人。它是一种已知的致癌物质，肝脏是其潜在的靶器官，与砷暴露地区糖尿病的流行有关。肝细胞核因子 1 和 4α（HNF1α 和 HNF4α）是正常肝脏结构所必需的转录网络的关键成员。HNF1α 和 HNF4α 表达的变化与人类肝癌和糖尿病的发生明显相关。在这项工作中，肝细胞 HepG2 细胞和金黄地鼠被暴露于亚毒性、环境相关剂量的亚砷酸钠（SA；体外最高 10 μM，体内 15 mg/L），以评估砷是否能够损害肝细胞核因子的表达。此外，还进行了肝脏组织病理学检查，并测定了几种肝细胞分化和葡萄糖代谢状态的标志物，作为评估 i-As 诱导作用的指标。结果表明，在 HepG2 细胞（1）获得对砷诱导的毒性/凋亡的抗性，（2）获得组织特异性特征丧失（如观察到的 ALDOB、PEPCK 和 CYP1A2 下调，上皮-间充质转化程序触发和基质金属蛋白酶-2 和 9 的过度分泌），（3）未能维持“干性”基因 C-MYC、OCT3/4、LIN28 和 NOTCH2 的平衡表达，（4）表现出葡萄糖代谢受损的情况下，HNF1α 和 HNF4α 持续下调。我们得出结论，慢性环境下 i-As 诱导的 HNF1α 和 HNF4α 下调可能在体内和体外观察到的疾病和癌症特征中发挥核心作用。
