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dc.contributor.authorXue, Peng
dc.contributor.authorWang, Huihui
dc.contributor.authorYang, Lili
dc.contributor.authorJiang, Zhiqiang
dc.contributor.authorLi, Hongliang
dc.contributor.authorLiu, Qinxin
dc.contributor.authorZhang, Qiang
dc.contributor.authorAndersen, Melvin E.
dc.contributor.authorCrabbe, M. James C.
dc.contributor.authorHao, Lipeng
dc.contributor.authorQu, Weidong
dc.date.accessioned2022-07-25T08:23:39Z
dc.date.available2023-07-14T00:00:00Z
dc.date.available2022-07-25T08:23:39Z
dc.date.issued2022-07-14
dc.identifier.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)en_US
dc.identifier.issn0041-008X
dc.identifier.pmid35842135
dc.identifier.doi10.1016/j.taap.2022.116163
dc.identifier.urihttp://hdl.handle.net/10547/625460
dc.description.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.en_US
dc.description.sponsorshipThis 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.).en_US
dc.language.isoenen_US
dc.publisherElsevieren_US
dc.relation.urlhttps://www.sciencedirect.com/science/article/abs/pii/S0041008X22003088en_US
dc.rightsGreen - can archive pre-print and post-print or publisher's version/PDF
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 International*
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/*
dc.subjectpharmacokineticsen_US
dc.subjectdrinking-wateren_US
dc.subjectWater Quality Indexen_US
dc.subjectwater contaminationen_US
dc.subjectSubject Categories::H122 Water Quality Controlen_US
dc.titleNRF2-ARE signaling is responsive to haloacetonitrile-induced oxidative stress in human keratinocytesen_US
dc.typeArticleen_US
dc.contributor.departmentFudan Universityen_US
dc.contributor.departmentChina Medical Universityen_US
dc.contributor.departmentPudong New Area Center for Diseases Control & Preventionen_US
dc.contributor.departmentEmory Universityen_US
dc.contributor.departmentScitoVation LLCen_US
dc.contributor.departmentOxford Universityen_US
dc.contributor.departmentUniversity of Bedfordshireen_US
dc.identifier.journalToxicology and Applied Pharmacologyen_US
dc.date.updated2022-07-25T08:16:14Z
dc.description.note12m embargo https://v2.sherpa.ac.uk/id/publication/11415


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