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NRF2-ARE signaling is responsive to haloacetonitrile-induced oxidative stress in human keratinocytes

  • Peng Xue
    ,
  • Huihui Wang
    ,
  • Lili Yang
    ,
  • Zhiqiang Jiang
    ,
  • Hongliang Li
    ,
  • Qinxin Liu
  • Fudan University
    ,
  • China Medical University
    ,
  • Pudong New Area Center for Diseases Control & Prevention
    ,
  • Emory University
    ,
  • ScitoVation LLC
    ,
  • University of Oxford
Research Output:
Contribution to journal
Article
 Peer-review

Open access

Sustainable Development Goals

  • SDG 3 - Good Health and Well-being
    SDG 3 Good Health and Well

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.

Publication Information

Output type

Research Output:
Contribution to journal
Article
 Peer-review

Original language

English

Article number

116163

Journal (Volume, Issue Number)

Toxicology and Applied Pharmacology (Volume 450)

Publication milestones

  • Accepted/In press - 09/07/2022
  • Published - 14/07/2022

Publication status

Published - 14/07/2022

ISSN

0041-008X

Publication IDs

  • handle.net: 10547/625460
  • Scopus: 85134538307

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