Differential effects of arsenic species on Nrf2 and Bach1 nuclear localization in cultured hepatocytes

Toxicol Appl Pharmacol. 2021 Feb 15:413:115404. doi: 10.1016/j.taap.2021.115404. Epub 2021 Jan 9.

Abstract

Arsenic is a ubiquitous metalloid element present in both inorganic and organic forms in the environment. The liver is considered to be a primary organ of arsenic biotransformation and methylation, as well as the main target of arsenic toxicity. Studies have confirmed that Chang human hepatocytes have an efficient arsenic methylating capacity. Our previous studies have proven that arsenite activates nuclear factor erythroid 2-related factor 2 (Nrf2) pathway in hepatocytes. This study aimed to explore the activation of the Nrf2 pathway upon treatment of arsenic in various forms, including inorganic and organic arsenic. Our results showed that inorganic arsenic-both As2O3 and Na2HAsO4 significantly induced the expression of Nrf2 protein and mRNA, enhanced the transcription activity of Nrf2, and induced the expression of downstream target genes. These results confirmed the inorganic arsenic-induced Nrf2 pathway activation in hepatocytes. Although all arsenic chemicals used in the study induced Nrf2 protein accumulation, the organic arsenic C2H7AsO2 did not affect the expression of Nrf2 downstream genes which were elevated by inorganic arsenic exposures. Through qRT-PCR and Nrf2 luciferase reporter assays, we further confirmed that C2H7AsO2 neither increased Nrf2 mRNA level nor activated the Nrf2 transcription activity. Mechanistically, our results confirmed inorganic arsenic-induced both the nuclear import of Nrf2 and export of Bach1 (BTB and CNC homology 1), which is an Nrf2 transcriptional repressor, while organic arsenic only induced Nrf2 translocation. The unique pattern of Nrf2 regulation by organic arsenic underlines the critical role of Nrf2 and Bach1 in the arsenic toxicology.

Keywords: Inorganic arsenic; Nuclear factor erythroid 2-related factor; Organic arsenic; Reactive oxygen species; Transcriptional repressor BTB and CNC homology 1.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus
  • Arsenates / toxicity*
  • Arsenic Trioxide / toxicity*
  • Arsenites / toxicity*
  • Basic-Leucine Zipper Transcription Factors / metabolism*
  • Cacodylic Acid / toxicity*
  • Cell Line
  • Cell Nucleus / drug effects*
  • Cell Nucleus / metabolism
  • Gene Expression Regulation
  • Hepatocytes / drug effects*
  • Hepatocytes / metabolism
  • Humans
  • NF-E2-Related Factor 2 / genetics
  • NF-E2-Related Factor 2 / metabolism*
  • Sodium Compounds / toxicity*
  • Transcription, Genetic

Substances

  • Arsenates
  • Arsenites
  • BACH1 protein, human
  • Basic-Leucine Zipper Transcription Factors
  • NF-E2-Related Factor 2
  • NFE2L2 protein, human
  • Sodium Compounds
  • sodium arsenite
  • sodium arsenate
  • Cacodylic Acid
  • Arsenic Trioxide