title: Gene expression and pathway analysis of human hepatocellular carcinoma cells treated with cadmium.
abstract: 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.
authors: Department of Environmental Medicine, New York University School of Medicine, New York, NY, United States.
authors: Laura
authors: L
authors: Cartularo
authors: Department of Environmental Medicine, New York University School of Medicine, New York, NY, United States.
authors: Freda
authors: F
authors: Laulicht
authors: Department of Environmental Medicine, New York University School of Medicine, New York, NY, United States.
authors: Hong
authors: H
authors: Sun
authors: Department of Environmental Medicine, New York University School of Medicine, New York, NY, United States.
authors: Thomas
authors: T
authors: Kluz
authors: Department of Pharmacology and Toxicology, University of Louisville Health Sciences Center, Louisville, KY, United States.
authors: Jonathan H
authors: JH
authors: Freedman
authors: Department of Environmental Medicine, New York University School of Medicine, New York, NY, United States. Electronic address: max.costa@nyumc.org.
authors: Max
authors: M
authors: Costa
mesh_terms: D000107:Acetylation; D017209:Apoptosis / Q000187:drug effects; D002104:Cadmium / Q000633:toxicity*; D006528:Carcinoma, Hepatocellular / Q000235:genetics*; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D019175:DNA Methylation; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D056945:Hep G2 Cells; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000473:pathology; D008113:Liver Neoplasms / Q000235:genetics; D046228:Microarray Analysis; D020411:Oligonucleotide Array Sequence Analysis; D017422:Sequence Analysis, DNA; D023382:Toxicity Tests, Acute; D036401:Toxicity Tests, Chronic; D015854:Up-Regulation
chemical_list: D006657:Histones; D002104:Cadmium
keywords: Affymetrix; Cadmium; Epigenetics; Gene expression; HepG2 cells; Histone modifications