Differential effects of metal ions on TCDD-induced cytotoxicity and cytochrome P4501A1 gene expression in a zebrafish liver (ZFL) cell-line

Abstract

Trace metal ions and trace organic compounds are common co-contaminants in the environment that pose risks to human health. We evaluated the effects of four metal ions (As³⁺, Cu²⁺, Hg²⁺, and Zn²⁺) on 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induced cytotoxicity and the expression of the cytochrome P4501A1 gene (cyp1a1) in the zebrafish liver (ZFL) cell line. A metal accumulation study showed that Cu and Zn did not accumulate in ZFL cells. However, As and Hg did accumulate, which resulted in the inhibition of TCDD-mediated induction of cyp1a1 mRNA and protein expression, and 7-ethoxyresorufin O-deethylase activity. A luciferase assay showed that both As³⁺ and Hg²⁺ inhibited the TCDD-induced activity of gene constructs containing either synthetic 3XRE or a distal cyp1a1 promoter region, implying that the decreased levels of TCDD-induced cyp1a1 were due to transcriptional effects. A proteomic study showed that the toxic effects of As³⁺ might be due to changes in cellular metabolic processes, the cellular stimulation response and the cellular redox state in ZFL cells.