Citation:

Han, J., W. Gu, H. Barrett, D. Yang, S. Tang, J. Sun, J. Liu, H. Krause, K. Houck, AND H. Peng. A Roadmap to the Structure-Related Metabolism Pathways of Per- and Polyfluoroalkyl Substances in the Early Life Stages of Zebrafish (Danio rerio). ENVIRONMENTAL HEALTH PERSPECTIVES. National Institute of Environmental Health Sciences (NIEHS), Research Triangle Park, NC, 129(7):077004, (2021). https://doi.org/10.1289/EHP7169

Impact/Purpose:

Thousands of per- and polyfluoroalkyl substances (PFASs) with diverse structures have been detected in the ambient environment. Apart from a few classic PFASs, the structure-related toxicokinetics of a broader set of PFASs remain unclear. To understand the toxicokinetics of PFASs, we used early life stages of zebrafish (Danio rerio) as a model and determined bioconcentration factors and phenotypic toxicities (i.e., mortality, heart rate) of 74 PFAS samples. Our findings identified five structural categories of PFASs prone to metabolism. The metabolism pathways of PFASs are highly related to their structures and significantly impact their bioaccumulations and toxicities. We also verified CES1 as an enzyme capable of hydrolyzing diverse PFASs, with strong substrate preferences towards perfluoroalkyl amides. We suggest that the roadmap of the structure-related toxicokinetics of PFASs established in this study would provide a starting point to inform the potential health risks of other PFASs.

Description:

Background: Thousands of per- and polyfluoroalkyl substances (PFAS) with diverse structures have been detected in the ambient environment. Apart from a few well-studied PFAS, the structure-related toxicokinetics of a broader set of PFAS remain unclear. Objectives: To understand the toxicokinetics of PFAS, we attempted to characterize the metabolism pathways of 74 structurally diverse PFAS samples from the U.S. Environmental Protection Agency's PFAS screening library. Methods: Using the early life stages of zebrafish (Danio rerio) as a model, we determined the bioconcentration factors and phenotypic toxicities of 74 PFAS. Then, we applied high-resolution mass spectrometry-based nontargeted analysis to identify metabolites of PFAS in zebrafish larvae after 5 d of exposure by incorporating retention time and mass spectra. In vitro enzymatic activity experiments with human recombinant liver carboxylesterase (hCES1) were employed to validate the structure-related hydrolysis of 11 selected PFAS. Results: Our findings identified five structural categories of PFAS prone to metabolism. The metabolism pathways of PFAS were highly related to their structures as exemplified by fluorotelomer alcohols that the predominance of β-oxidationβ-oxidation or taurine conjugation pathways were primarily determined by the number of hydrocarbons. Hydrolysis was identified as a major metabolism pathway for diverse PFAS, and perfluoroalkyl carboxamides showed the highest in vivo hydrolysis rates, followed by carboxyesters and sulfonamides. The hydrolysis of PFAS was verified with recombinant hCES1, with strong substrate preferences toward perfluoroalkyl carboxamides. Conclusions: We suggest that the roadmap of the structure-related metabolism pathways of PFAS established in this study would provide a starting point to inform the potential health risks of other PFAS.

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