NRF2-ARE signaling is responsive to haloacetonitrile-induced oxidative stress in human keratinocytes
Andersen, Melvin E.
Crabbe, M. James C.
China Medical University
Pudong New Area Center for Diseases Control & Prevention
University of Bedfordshire
Water Quality Index
Subject Categories::H122 Water Quality Control
MetadataShow full item record
AbstractHumans are exposed to disinfection by-products through oral, inhalation, and dermal routes, during bathing and swimming, potentially causing skin lesions, asthma, and bladder cancer. Nuclear factor E2-related factor 2 (NRF2) is a master regulator of the adaptive antioxidant response via the antioxidant reaction elements (ARE) orchestrating the transcription of a large group of antioxidant and detoxification genes. Here we used an immortalized human keratinocyte model HaCaT cells to investigate NRF2-ARE as a responder and protector in the acute cytotoxicity of seven haloacetonitriles (HANs), including chloroacetonitrile (CAN), bromoacetonitrile (BAN), iodoacetonitrile (IAN), bromochloroacetonitrile (BCAN), dichloroacetonitrile (DCAN), dibromoacetonitrile (DBAN), and trichloroacetonitrile (TCAN) found in drinking water and swimming pools. The rank order of cytotoxicity among the HANs tested was IAN ≈ BAN ˃ DBAN ˃ BCAN ˃ CAN ˃ TCAN ˃ DCAN based on their LC50. The HANs induced intracellular reactive oxygen species accumulation and activated cellular antioxidant responses in concentration- and time-dependent fashions, showing elevated NRF2 protein levels and ARE activity, induction of antioxidant genes, and increased glutathione levels. Additionally, knockdown of NRF2 by lentiviral shRNAs sensitized the HaCaT cells to HANs-induced cytotoxicity, emphasizing a protective role of NRF2 against the cytotoxicity of HANs. These results indicate that HANs cause oxidative stress and activate NRF2-ARE-mediated antioxidant response, which in turn protects the cells from HANs-induced cytotoxicity, highlighting that NRF2-ARE activity could be a sensitive indicator to identify and characterize the oxidative stress induced by HANs and other environmental pollutants.
CitationXue P, Wang H, Yang L, Jiang Z, Li H, Liu Q, Zhang Q, Andersen M, Crabbe MJC, Hao L, Qu W (2022) 'NRF2-ARE signaling is responsive to haloacetonitrile-induced oxidative stress in human keratinocytes', Toxicology and Applied Pharmacology, 450 (116163)
SponsorsThis project was supported by the National Natural Science Foundation of China 81630088, 81325017 & 81273035 (W.Q.), and 81402643 (P.X.), National Key Research and Development Program of China of the Ministry of Science and Technology of the People’s Republic of China 2017YFC1600200 (W.Q.), and Chang Jiang Scholars Program No. T2014089 (W.Q.).
The following license files are associated with this item:
- Creative Commons
Except where otherwise noted, this item's license is described as Green - can archive pre-print and post-print or publisher's version/PDF
- Comparative Quantitative Toxicology and QSAR Modeling of the Haloacetonitriles: Forcing Agents of Water Disinfection Byproduct Toxicity.
- Authors: Wei X, Yang M, Zhu Q, Wagner ED, Plewa MJ
- Issue date: 2020 Jul 21
- Haloacetonitriles vs. regulated haloacetic acids: are nitrogen-containing DBPs more toxic?
- Authors: Muellner MG, Wagner ED, McCalla K, Richardson SD, Woo YT, Plewa MJ
- Issue date: 2007 Jan 15
- Oxidative injury induced by drinking water disinfection by-products dibromoacetonitrile and dichloroacetonitrile in mouse hippocampal neuronal cells: The protective effect of N-acetyl-L-cysteine.
- Authors: Li F, Zhou J, Zhu X, Lu R, Ye Y, Wang S, Xing G, Shen H
- Issue date: 2022 Jul 15
- [Simultaneous determination of six haloacetonitriles in finished water for drinking by purge and trap-gas chromatography-triple quadrupole mass spectrometry].
- Authors: Zhan W, Han Z, Li Y, Liu F, Zhang Y
- Issue date: 2021 Jul 8
- Single and combined effects of selected haloacetonitriles in a human-derived hepatoma line.
- Authors: Lu G, Qin D, Wang Y, Liu J, Chen W
- Issue date: 2018 Nov 15