title: Iodoacetic acid activates Nrf2-mediated antioxidant response in vitro and in vivo.
abstract: Iodoacetic acid (IAA) is an unregulated drinking-water disinfection byproduct with potent cytotoxicity, genotoxicity, and tumorigenicity in animals. Oxidative stress is thought to be essential for IAA toxicity, but the exact mechanism remains unknown. Here we evaluated the toxicity of IAA by examining nuclear factor E2-related factor 2 (Nrf2)-mediated antioxidant response, luciferase antioxidant response element (ARE) activity, and intracellular glutathione (GSH) in HepG2 cells. IAA showed significant activation of ARE-luciferase reporter, mRNA, and protein expression of Nrf2 and its downstream genes (GCLC, NQO1, and HO-1). IAA also increased the intracellular GSH level in HepG2 cells in a time- and concentration-dependent manner. Moreover, we verified IAA induced Nrf2-mediated antioxidant response in rats. Subsequently, we confirmed the specific role of Nrf2 in IAA induced toxicity using NRF2-knockdown cells. Deficiency of NRF2 significantly enhanced sensitivity to IAA toxicity and led to an increase of IAA induced micronulei. We also examined the effects of antioxidant on Nrf2-mediated response in IAA treated cells. Pretreatment with curcumin markedly reduced cytotoxicity and genotoxicity (micronuclei formation) IAA in HepG2 cells. Our work here provides direct evidence that IAA activates Nrf2-mediated antioxidant response in vitro and in vivo and that oxidative stress plays a role in IAA toxicity.
authors.affiliation: Key Laboratory of the Public Health Safety, Ministry of Education, Department of Environmental Health, School of Public Health, Fudan University , Yi Xue Yuan Road 138, Shanghai 200032, China.
authors.forename: Shu
authors.initials: S
authors.lastname: Wang
authors.forename: Weiwei
authors.initials: W
authors.lastname: Zheng
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Liu
authors.forename: Peng
authors.initials: P
authors.lastname: Xue
authors.forename: Songhui
authors.initials: S
authors.lastname: Jiang
authors.forename: Daru
authors.initials: D
authors.lastname: Lu
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhang
authors.forename: Gensheng
authors.initials: G
authors.lastname: He
authors.forename: Jingbo
authors.initials: J
authors.lastname: Pi
authors.forename: Melvin E
authors.initials: ME
authors.lastname: Andersen
authors.forename: Hui
authors.initials: H
authors.lastname: Tan
authors.forename: Weidong
authors.initials: W
authors.lastname: Qu
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D003474:Curcumin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005978:Glutathione / Q000378:metabolism; D056945:Hep G2 Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D019807:Iodoacetic Acid / Q000494:pharmacology*; D008297:Male; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D013997:Time Factors
chemical_list: D000975:Antioxidants; D004791:Enzyme Inhibitors; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D005978:Glutathione; D003474:Curcumin; D019807:Iodoacetic Acid