Journal article
NRF2-ARE signaling is responsive to haloacetonitrile-induced oxidative stress in human keratinocytes
Toxicology and applied pharmacology, Vol.450, pp.116163-116163
09/01/2022
DOI: 10.1016/j.taap.2022.116163
Abstract
Humans 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.
Details
- Title: Subtitle
- NRF2-ARE signaling is responsive to haloacetonitrile-induced oxidative stress in human keratinocytes
- Creators
- Peng Xue - Key Laboratory of the Public Health Safety, Ministry of Education, Department of Environmental Health, School of Public Health, Fudan University, Shanghai 200032, China.Huihui Wang - China Medical UniversityLili Yang - Fudan UniversityZhiqiang Jiang - Key Laboratory of the Public Health Safety, Ministry of Education, Department of Environmental Health, School of Public Health, Fudan University, Shanghai 200032, China.Hongliang Li - Pudong New Area People's HospitalQinxin Liu - Key Laboratory of the Public Health Safety, Ministry of Education, Department of Environmental Health, School of Public Health, Fudan University, Shanghai 200032, China.Qiang Zhang - Emory UniversityMelvin E Andersen - Research Triangle Park FoundationM James C Crabbe - University of BedfordshireLipeng Hao - Pudong New Area People's HospitalWeidong Qu - Fudan University
- Resource Type
- Journal article
- Publication Details
- Toxicology and applied pharmacology, Vol.450, pp.116163-116163
- DOI
- 10.1016/j.taap.2022.116163
- ISSN
- 0041-008X
- eISSN
- 1096-0333
- Grant note
- DOI: 10.13039/501100001809, name: National Natural Science Foundation of China, award: 81273035, 81325017, 81402643, 81630088; DOI: 10.13039/501100002855, name: Ministry of Science and Technology of the People's Republic of China, award: 2017YFC1600200; DOI: 10.13039/501100003347, name: Fudan University; DOI: 10.13039/501100005240, name: Changjiang Scholar Program of Chinese Ministry of Education, award: T2014089; DOI: 10.13039/501100012166, name: National Key Research and Development Program of China
- Language
- English
- Date published
- 09/01/2022
- Academic Unit
- Neurology
- Record Identifier
- 9984302200802771
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