Toxicokinetic Characterization of the Inter-Species Differences in 6PPD-Quinone Toxicity Across Seven Fish Species: Metabolite Identification and Semi-Quantification

Montgomery, D. J.; Ji, X.; Cantin, J.; Philibert, D.; Foster, G.; Selinger, S.; Jain, N.; Miller, J.; McIntyre, J.; de Jourdan, B.; Wiseman, S.; Hecker, M.; Brinkmann, M.

doi:10.1101/2023.08.18.553920

bioRxiv · 10.1101/2023.08.18.553920

Toxicokinetic Characterization of the Inter-Species Differences in 6PPD-Quinone Toxicity Across Seven Fish Species: Metabolite Identification and Semi-Quantification

Montgomery, D. J.·Ji, X.·Cantin, J.·Philibert, D.·Foster, G.·Selinger, S.·Jain, N.·Miller, J.·McIntyre, J.·de Jourdan, B.·Wiseman, S.·Hecker, M.·Brinkmann, M.

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Abstract

N-(1,3-Dimethylbutyl)-N-Phenyl-P-Phenylenediamine-Quinone (6PPD-Q) is a recently identified contaminant that originates from the oxidation of the tire anti-degradant 6PPD. 6PPD-Q is acutely toxic to select salmonids at environmentally relevant concentrations, while other fish species display tolerance to concentrations surpassing those measured in the environment. The reasons for these marked differences in sensitivity are presently unknown. The objective of this research was to explore potential toxicokinetic drivers of species sensitivity by characterizing biliary metabolites of 6PPD-Q in sensitive and tolerant fishes. For the first time, we identified an O-glucuronide metabolite of 6PPD-Q using high-resolution mass spectrometry. The semi-quantified levels of this metabolite in tolerant species or life stages, including white sturgeon (Acipenser transmontanus), chinook salmon (Oncorhynchus tshawytscha), westslope cutthroat trout (Oncorhynchus clarkia lewisi) and non-fry life stages of Atlantic salmon (Salmo salar), were greater than those in sensitive species, including coho salmon (Oncorhynchus kisutch), brook trout (Salvelinus fontinalis), and rainbow trout (Oncorhynchus mykiss), suggesting that tolerant species might more effectively detoxify 6PPD-Q. Thus, we hypothesize that differences in species sensitivity are a result of differences in basal expression of biotransformation enzyme across various fish species. Moreover, the semi-quantification of 6PPD-Q metabolites in bile extracted from wild-caught fish might be a useful biomarker of exposure to 6PPD-Q, thereby being invaluable to environmental monitoring and risk assessment.

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Montgomery, D. J., Ji, X., Cantin, J., Philibert, D., Foster, G., Selinger, S., Jain, N., Miller, J., McIntyre, J., de Jourdan, B., Wiseman, S., Hecker, M., Brinkmann, M.. 2023-08-20. Toxicokinetic Characterization of the Inter-Species Differences in 6PPD-Quinone Toxicity Across Seven Fish Species: Metabolite Identification and Semi-Quantification. https://doi.org/10.1101/2023.08.18.553920

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