Polychlorinated diphenyl sulfides can induce ROS and genotoxicity via the AhR-CYP1A1 pathway

Chemosphere. 2019 May;223:165-170. doi: 10.1016/j.chemosphere.2019.01.169. Epub 2019 Feb 1.

Abstract

Polychlorinated diphenyl sulfides (PCDPSs) are a group of chemicals that can interact and activate the aryl hydrocarbon receptor (AhR). Previous studies have shown that PCDPSs can cause oxidative stress in livers. However, information on genotoxicity of PCDPSs is limited. In this study, it is hypothesized that PCDPSs can produce reactive oxygen species (ROS) by activating the AhR and inducing expression of CYP1A1, which subsequently causes genotoxicity. HepG2 cells (transfected with AhR and CYP1A1 siRNA or not) were exposed to six PCDPSs. ROS and expression of five genes were measured to confirm relationships between genotoxicity and signaling along AhR pathway. After 24 h, a significant concentration-dependent ROS was observed. Production of ROS varied with the number of Cl atoms. And the formation of ROS decreases with the increase of the number of Cl atoms, which was consistent with results observed for polychlorinated biphenyls (PCBs). Most of the tested PCDPSs up-regulated expression of CYP1A1 enzyme via signaling AhR pathways. The exposure to 2,3',4,5-tetra-CDPS at 10 μM up-regulated the CYP1A1 mRNA in HepG2 cells to 29-fold. Expression of CYP1A1 mRNA was related to the number of substituted Cl, probably due to the stronger ability of more chlorinated PCDPSs to bind to and activate the AhR. However, there was no significant quantitative relationship between expression of CYP1A1 and concentrations of ROS, probably due to other oxidases' influence. Furthermore, PCDPSs also caused induction of OGG1 and XRS2 more than 2 times, indicates oxidation of bases and breaks of strands. The transfection of cells with siRNA to silence expression of the CYP1A1 gene results in ROS at background levels, further supporting the proposed mechanism PCDPSs inducing ROS and DNA damage via the AhR-mediated pathway.

Keywords: Aryl hydrocarbon receptor (AhR); Cytochrome P4501A1(CYP1A1); Dioxin; PCBs; Signal transduction; Transactivation bioassay.

MeSH terms

  • Cytochrome P-450 CYP1A1 / metabolism*
  • DNA Damage*
  • Gene Expression Regulation
  • Hep G2 Cells
  • Humans
  • Polychlorinated Biphenyls / pharmacology*
  • Reactive Oxygen Species / metabolism*
  • Receptors, Aryl Hydrocarbon / metabolism*
  • Signal Transduction
  • Sulfides / pharmacology*
  • Transcriptional Activation

Substances

  • Reactive Oxygen Species
  • Receptors, Aryl Hydrocarbon
  • Sulfides
  • diphenyl sulfide
  • Polychlorinated Biphenyls
  • CYP1A1 protein, human
  • Cytochrome P-450 CYP1A1