Activation of redox signaling pathways by environmental chemicals through adduct formation with sensor proteins

Abstract

People are exposed to numerous compounds throughout daily life. We have been focusing on reactive chemicals such as electrophiles and electron acceptors. Electrophiles directly modify protein and DNA leading to the formation of electrophile adducts. Electron acceptors oxidize those macromolecules through the generation of reactive oxygen species. We have found that whereas lower concentrations of electrophiles and electron acceptors activate redox signaling pathways through protein adduct formation by chemical modification of protein thiols, higher concentrations of these compounds disrupt the signaling pathways and cause cell death through extensive modification of proteins. Our studies with representative redox signaling pathways such as PTP1B/EGFR signaling and the Keap1/Nrf2 pathway, which are respectively activated by modification of PTP1B and Keap1, revealed that combined exposure to electrophiles, even at low concentrations, can induce stronger activation of redox signaling than individual exposure. These findings indicate that combining different electrophiles may produce unexpected effects by increasing protein adduct formation. Herein, we would like to introduce our research about the activation of redox signaling pathways by environmental chemicals–protein adduct formation.