https://doi.org/10.1101/2024.06.12.598661

Ankley Phillip J., Junior Francisco C.da Silva, Roberts Catherine, Eriksson Andreas N.M., Kohlman Evan, Dubiel Justin, Hunnie Blake, Anderson-Bain Katherine, Urrutia Rayen M., Hogan Natacha, Giesy John P., Krol Ed, Wiseman Steve, Hecker Markus, Brinkmann Markus (2024) Xenometabolome of Early-Life Stage Salmonids Exposed to 6PPD-Quinone, bioRxiv 2024.06.12.598661

N-(1,3-Dimethylbutyl)-N?-phenyl-p-phenylenediamine-quinone (6PPD-Q) is a ubiquitous and acutely toxic transformation product (TP) derived from the rubber tire antioxidant N-(1,3-Dimethylbutyl)-N?-phenyl-p-phenylenediamine (6PPD). While not all salmonids are sensitive to acute lethality caused by 6PPD-Q, its potency can vary by several orders of magnitude among fish species. The main driver(s) of species sensitivity differences is a pressing question, with one area of interest examining whether differences in their ability to biotransform and detoxify 6PPD-Q could be a driving factor. This study utilized liquid-chromatography high-resolution mass spectrometry (LC-HRMS) to assess biotransformation and metabolome-wide effects of 6PPD-Q on early-life stage salmonids, including two sensitive species, rainbow trout (Oncorhynchus mykiss) and lake trout (Salvelinus namaycush), and one tolerant species, brown trout (Salmo trutta). Three phase I TPs and seven phase II TPs were detected, with differences in peak areas revealing that brown trout had the greatest ability to detoxify 6PPD-Q. TP-OH1, an alkyl sidechain monohydroxylated TP, was detected in both rainbow and lake trout but not in brown trout, with more research needed to understand potential TP-OH1 mediated toxicity. Several endogenous metabolites were found to be dysregulated in rainbow and lake trout, indicative of mitochondrial dysfunction and altered metabolism. Results of this study indicate a difference in the biotransformation capability of 6PPD-Q among salmonid fish species and subsequent unique metabolome responses.