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Exposure to the Tire Rubber-Derived Contaminant 6PPD-Quinone Causes Mitochondrial Dysfunction In Vitro

  • Hannah Mahoney
    Hannah Mahoney
    Toxicology Centre, University of Saskatchewan, Saskatoon S7N 5B3, Canada
  • Francisco C. da Silva Junior
    Francisco C. da Silva Junior
    Toxicology Centre, University of Saskatchewan, Saskatoon S7N 5B3, Canada
    Department of Cell Biology and Genetics, Biosciences Center, Federal University of Rio, Grande do Norte, Natal, RN 59078-970, Brazil
  • Catherine Roberts
    Catherine Roberts
    Toxicology Centre, University of Saskatchewan, Saskatoon S7N 5B3, Canada
  • Matthew Schultz
    Matthew Schultz
    Toxicology Centre, University of Saskatchewan, Saskatoon S7N 5B3, Canada
  • Xiaowen Ji
    Xiaowen Ji
    School of Environment and Sustainability (SENS), University of Saskatchewan, Saskatoon S7N 5CN, Canada
    More by Xiaowen Ji
  • Alper James Alcaraz
    Alper James Alcaraz
    Toxicology Centre, University of Saskatchewan, Saskatoon S7N 5B3, Canada
  • David Montgomery
    David Montgomery
    Toxicology Centre, University of Saskatchewan, Saskatoon S7N 5B3, Canada
  • Summer Selinger
    Summer Selinger
    Toxicology Centre, University of Saskatchewan, Saskatoon S7N 5B3, Canada
  • Jonathan K. Challis
    Jonathan K. Challis
    Toxicology Centre, University of Saskatchewan, Saskatoon S7N 5B3, Canada
  • John P. Giesy
    John P. Giesy
    Toxicology Centre, University of Saskatchewan, Saskatoon S7N 5B3, Canada
    Department of Veterinary Biomedical Sciences, Western College of Veterinary Medicine University of Saskatchewan, Saskatoon S7N 5B4, Canada
    Department of Environmental Science, Baylor University, One Bear Place 97266, Waco, Texas 76706, United States
  • Lynn Weber
    Lynn Weber
    Toxicology Centre, University of Saskatchewan, Saskatoon S7N 5B3, Canada
    Department of Veterinary Biomedical Sciences, Western College of Veterinary Medicine University of Saskatchewan, Saskatoon S7N 5B4, Canada
    More by Lynn Weber
  • David Janz
    David Janz
    Toxicology Centre, University of Saskatchewan, Saskatoon S7N 5B3, Canada
    Department of Veterinary Biomedical Sciences, Western College of Veterinary Medicine University of Saskatchewan, Saskatoon S7N 5B4, Canada
    More by David Janz
  • Steve Wiseman
    Steve Wiseman
    Department of Biological Sciences, University of Lethbridge, Lethbridge T1K 3M4, Canada
  • Markus Hecker
    Markus Hecker
    Toxicology Centre, University of Saskatchewan, Saskatoon S7N 5B3, Canada
    School of Environment and Sustainability (SENS), University of Saskatchewan, Saskatoon S7N 5CN, Canada
  • , and 
  • Markus Brinkmann*
    Markus Brinkmann
    Toxicology Centre, University of Saskatchewan, Saskatoon S7N 5B3, Canada
    School of Environment and Sustainability (SENS), University of Saskatchewan, Saskatoon S7N 5CN, Canada
    Global Institute for Water Security (GIWS), University of Saskatchewan, Saskatoon S7N 3H5, Canada
    *Email: [email protected]
Cite this: Environ. Sci. Technol. Lett. 2022, 9, 9, 765–771
Publication Date (Web):August 4, 2022
https://doi.org/10.1021/acs.estlett.2c00431
Copyright © 2022 American Chemical Society

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    Abstract

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    N-(1,3-Dimethylbutyl)-N′-phenyl-p-phenylenediamine-quinone (6PPD-quinone), a rubber tire oxidation product found in road runoff, is highly and acutely toxic to selected salmonids including coho salmon, brook trout, and rainbow trout but not other fish species and invertebrates studied to date. Sensitive species displayed increased ventilation and gasping, suggesting a possible impact on respiration. Here, adherent cell lines RTL-W1 and RTgill-W1 were exposed to 5–80 μg/L 6PPD-quinone, and cytotoxicity, oxygen consumption rate (OCR), and biotransformation of 6PPD-quinone were measured to assess the ability of 6PPD-quinone to uncouple mitochondrial respiration in vitro. RTL-W1 cells were not sensitive to 6PPD-quinone, and exposure did not result in significant impacts on cytotoxicity or OCR. In contrast, RTgill-W1 cells demonstrated decreased cell viability at 80 μg/L and a 2-fold increase in OCR at 20 μg/L. Effects appear to be partly driven by toxicokinetic differences where incubation of RTL-W1 cells with 6PPD-quinone led to almost quantitative conversion of 6PPD-quinone into a suspected hydroxy-metabolite, which was not observed in RTgill-W1 cells. Exposure studies with primary cultures of rainbow trout gill cells indicated that 6PPD-quinone increased OCR by uncoupling the mitochondrial electron transport chain. Together, these findings suggest that 6PPD-quinone toxicity might be driven by a tissue-specific disruption of mitochondrial respiration.

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.estlett.2c00431.

    • Chromatograms and mass spectra of 6PPD-quinone and the suspected 6PPD-quinone monohydroxy metabolite from various treatments, including negative controls, as well as rainbow trout liver and gill cells (PDF)

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    Cited By

    This article is cited by 18 publications.

    1. Fabian Balk, Bastian Hüsser, Juliane Hollender, Kristin Schirmer. Bioconcentration Assessment of Three Cationic Surfactants in Permanent Fish Cell Lines. Environmental Science & Technology 2024, 58 (3) , 1452-1461. https://doi.org/10.1021/acs.est.3c05360
    2. David Montgomery, Xiaowen Ji, Jenna Cantin, Danielle Philibert, Garrett Foster, Summer Selinger, Niteesh Jain, Justin Miller, Jenifer McIntyre, Benjamin de Jourdan, Steve Wiseman, Markus Hecker, Markus Brinkmann. Interspecies Differences in 6PPD-Quinone Toxicity Across Seven Fish Species: Metabolite Identification and Semiquantification. Environmental Science & Technology 2023, 57 (50) , 21071-21079. https://doi.org/10.1021/acs.est.3c06891
    3. Xin Hua, Dayong Wang. Exposure to 6-PPD Quinone at Environmentally Relevant Concentrations Inhibits Both Lifespan and Healthspan in C. elegans. Environmental Science & Technology 2023, 57 (48) , 19295-19303. https://doi.org/10.1021/acs.est.3c05325
    4. Nico Grasse, Bettina Seiwert, Riccardo Massei, Stefan Scholz, Qiuguo Fu, Thorsten Reemtsma. Uptake and Biotransformation of the Tire Rubber-derived Contaminants 6-PPD and 6-PPD Quinone in the Zebrafish Embryo (Danio rerio). Environmental Science & Technology 2023, 57 (41) , 15598-15607. https://doi.org/10.1021/acs.est.3c02819
    5. Joseph Monaghan, Angelina Jaeger, Joshua K. Jai, Haley Tomlin, Jamieson Atkinson, Tanya M. Brown, Chris G. Gill, Erik T. Krogh. Automated, High-Throughput Analysis of Tire-Derived p-Phenylenediamine Quinones (PPDQs) in Water by Online Membrane Sampling Coupled to MS/MS. ACS ES&T Water 2023, 3 (10) , 3293-3304. https://doi.org/10.1021/acsestwater.3c00275
    6. Khaled Zoroufchi Benis, Ali Behnami, Shahab Minaei, Markus Brinkmann, Kerry N. McPhedran, Jafar Soltan. Environmental Occurrence and Toxicity of 6PPD Quinone, an Emerging Tire Rubber-Derived Chemical: A Review. Environmental Science & Technology Letters 2023, 10 (10) , 815-823. https://doi.org/10.1021/acs.estlett.3c00521
    7. Justin B. Greer, Ellie M. Dalsky, Rachael F. Lane, John D. Hansen. Tire-Derived Transformation Product 6PPD-Quinone Induces Mortality and Transcriptionally Disrupts Vascular Permeability Pathways in Developing Coho Salmon. Environmental Science & Technology 2023, 57 (30) , 10940-10950. https://doi.org/10.1021/acs.est.3c01040
    8. Justin B. Greer, Ellie M. Dalsky, Rachael F. Lane, John D. Hansen. Establishing an In Vitro Model to Assess the Toxicity of 6PPD-Quinone and Other Tire Wear Transformation Products. Environmental Science & Technology Letters 2023, 10 (6) , 533-537. https://doi.org/10.1021/acs.estlett.3c00196
    9. Xin Hua, Xiao Feng, Geyu Liang, Jie Chao, Dayong Wang. Exposure to 6-PPD Quinone at Environmentally Relevant Concentrations Causes Abnormal Locomotion Behaviors and Neurodegeneration in Caenorhabditis elegans. Environmental Science & Technology 2023, 57 (12) , 4940-4950. https://doi.org/10.1021/acs.est.2c08644
    10. Lixi Zeng, Yi Li, Yuxin Sun, Liang-Ying Liu, Mingjie Shen, Bibai Du. Widespread Occurrence and Transport of p-Phenylenediamines and Their Quinones in Sediments across Urban Rivers, Estuaries, Coasts, and Deep-Sea Regions. Environmental Science & Technology 2023, 57 (6) , 2393-2403. https://doi.org/10.1021/acs.est.2c07652
    11. Kyoshiro Hiki, Hiroshi Yamamoto. The Tire-Derived Chemical 6PPD-quinone Is Lethally Toxic to the White-Spotted Char Salvelinus leucomaenis pluvius but Not to Two Other Salmonid Species. Environmental Science & Technology Letters 2022, 9 (12) , 1050-1055. https://doi.org/10.1021/acs.estlett.2c00683
    12. Bibai Du, Bowen Liang, Yi Li, Mingjie Shen, Liang-Ying Liu, Lixi Zeng. First Report on the Occurrence of N-(1,3-Dimethylbutyl)-N′-phenyl-p-phenylenediamine (6PPD) and 6PPD-Quinone as Pervasive Pollutants in Human Urine from South China. Environmental Science & Technology Letters 2022, 9 (12) , 1056-1062. https://doi.org/10.1021/acs.estlett.2c00821
    13. Xiaoli Chen, Tao He, Xinlu Yang, Yijing Gan, Xian Qing, Jun Wang, Yumei Huang. Analysis, environmental occurrence, fate and potential toxicity of tire wear compounds 6PPD and 6PPD-quinone. Journal of Hazardous Materials 2023, 452 , 131245. https://doi.org/10.1016/j.jhazmat.2023.131245
    14. Fabian Balk, Juliane Hollender, Kristin Schirmer. Investigating the bioaccumulation potential of anionic organic compounds using a permanent rainbow trout liver cell line. Environment International 2023, 174 , 107798. https://doi.org/10.1016/j.envint.2023.107798
    15. Liya Fang, Chanlin Fang, Shanshan Di, Yundong Yu, Caihong Wang, Xinquan Wang, Yuanxiang Jin. Oral exposure to tire rubber-derived contaminant 6PPD and 6PPD-quinone induce hepatotoxicity in mice. Science of The Total Environment 2023, 869 , 161836. https://doi.org/10.1016/j.scitotenv.2023.161836
    16. Jiabin Wu, Guodong Cao, Feng Zhang, Zongwei Cai. A new toxicity mechanism of N-(1,3-Dimethylbutyl)-N′-phenyl-p-phenylenediamine quinone: Formation of DNA adducts in mammalian cells and aqueous organisms. Science of The Total Environment 2023, 866 , 161373. https://doi.org/10.1016/j.scitotenv.2022.161373
    17. Anders Foldvik, Fedor Kryuchkov, Roar Sandodden, Silvio Uhlig. Acute Toxicity Testing of the Tire Rubber–Derived Chemical 6PPD‐quinone on Atlantic Salmon ( Salmo salar ) and Brown Trout ( Salmo trutta ). Environmental Toxicology and Chemistry 2022, 41 (12) , 3041-3045. https://doi.org/10.1002/etc.5487
    18. Jing Xu, Yanfen Hao, Zhiruo Yang, Wenjuan Li, Wenjing Xie, Yani Huang, Deliang Wang, Yuqing He, Yong Liang, Julius Matsiko, Pu Wang. Rubber Antioxidants and Their Transformation Products: Environmental Occurrence and Potential Impact. International Journal of Environmental Research and Public Health 2022, 19 (21) , 14595. https://doi.org/10.3390/ijerph192114595

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