Cartularo Laura, Laulicht Freda, Sun Hong, Kluz Thomas, Freedman Jonathan H, Costa Max
Department of Environmental Medicine, New York University School of Medicine, New York, NY, United States.
Department of Pharmacology and Toxicology, University of Louisville Health Sciences Center, Louisville, KY, United States.
Toxicol Appl Pharmacol. 2015 Nov 1;288(3):399-408. doi: 10.1016/j.taap.2015.08.011. Epub 2015 Aug 24.
Cadmium (Cd) is a toxic and carcinogenic metal naturally occurring in the Earth's crust. A common route of human exposure is via diet and cadmium accumulates in the liver. The effects of Cd exposure on gene expression in human hepatocellular carcinoma (HepG2) cells were examined in this study. HepG2 cells were acutely-treated with 0.1, 0.5, or 1.0 μM Cd for 24h; or chronically-treated with 0.01, 0.05, or 0.1 μM Cd for three weeks and gene expression analysis was performed using Affymetrix GeneChip® Human Gene 1.0 ST Arrays. Acute and chronic exposures significantly altered the expression of 333 and 181 genes, respectively. The genes most upregulated by acute exposure included several metallothioneins. Downregulated genes included the monooxygenase CYP3A7, involved in drug and lipid metabolism. In contrast, CYP3A7 was upregulated by chronic Cd exposure, as was DNAJB9, an anti-apoptotic J protein. Genes downregulated following chronic exposure included the transcriptional regulator early growth response protein 1. Ingenuity Pathway Analysis revealed that the top networks altered by acute exposure were lipid metabolism, small molecule biosynthesis, cell morphology, organization, and development; while top networks altered by chronic exposure were organ morphology, cell cycle, cell signaling, and renal and urological diseases/cancer. Many of the dysregulated genes play important roles in cellular growth, proliferation, and apoptosis, and may be involved in carcinogenesis. In addition to gene expression changes, HepG2 cells treated with cadmium for 24h indicated a reduction in global levels of histone methylation and acetylation that persisted 72 h post-treatment.
镉（Cd）是一种有毒的致癌金属，自然存在于地壳中。人类接触镉的常见途径是通过饮食，镉会在肝脏中蓄积。本研究检测了镉暴露对人肝癌（HepG2）细胞基因表达的影响。将HepG2细胞分别用0.1、0.5或1.0μM镉急性处理24小时；或用0.01、0.05或0.1μM镉慢性处理三周，然后使用Affymetrix GeneChip®人类基因1.0 ST阵列进行基因表达分析。急性和慢性暴露分别显著改变了333个和181个基因的表达。急性暴露上调最明显的基因包括几种金属硫蛋白。下调的基因包括参与药物和脂质代谢的单加氧酶CYP3A7。相比之下，CYP3A7在慢性镉暴露下上调，抗凋亡J蛋白DNAJB9也上调。慢性暴露后下调的基因包括转录调节因子早期生长反应蛋白1。 Ingenuity通路分析显示，急性暴露改变的主要网络是脂质代谢、小分子生物合成、细胞形态、组织和发育；而慢性暴露改变的主要网络是器官形态、细胞周期、细胞信号传导以及肾脏和泌尿系统疾病/癌症。许多失调的基因在细胞生长、增殖和凋亡中起重要作用，可能参与致癌过程。除了基因表达变化外，用镉处理24小时的HepG2细胞显示组蛋白甲基化和乙酰化的整体水平降低，这种降低在处理后72小时仍持续存在。
