Modeling HepaRG metabolome responses to pyrrolizidine alkaloid exposure for insight into points of departure and modes of action.

Autor: Dubreil E; ANSES, French Agency for Food, Environmental and Occupational Health & Safety, Fougères Laboratory, Toxicology of Contaminants Unit, 10 B rue Claude Bourgelat, 35306 Fougères, France. Electronic address: estelle.dubreil@anses.fr., Darney K; ANSES, French Agency for Food, Environmental and Occupational Health & Safety, Risk Assessment Department, 14 Rue Pierre et Marie Curie, 94701 Maisons-Alfort, France., Delignette-Muller ML; University of Lyon 1, CNRS, VetAgro Sup, UMR 5558, Laboratoire de Biométrie et Biologie Evolutive, 69622 Villeurbanne, France., Barranger A; ANSES, French Agency for Food, Environmental and Occupational Health & Safety, Fougères Laboratory, Toxicology of Contaminants Unit, 10 B rue Claude Bourgelat, 35306 Fougères, France., Huet S; ANSES, French Agency for Food, Environmental and Occupational Health & Safety, Fougères Laboratory, Toxicology of Contaminants Unit, 10 B rue Claude Bourgelat, 35306 Fougères, France., Hogeveen K; ANSES, French Agency for Food, Environmental and Occupational Health & Safety, Fougères Laboratory, Toxicology of Contaminants Unit, 10 B rue Claude Bourgelat, 35306 Fougères, France., Léger T; ANSES, French Agency for Food, Environmental and Occupational Health & Safety, Fougères Laboratory, Toxicology of Contaminants Unit, 10 B rue Claude Bourgelat, 35306 Fougères, France., Fessard V; ANSES, French Agency for Food, Environmental and Occupational Health & Safety, Fougères Laboratory, Toxicology of Contaminants Unit, 10 B rue Claude Bourgelat, 35306 Fougères, France., Hégarat LL; ANSES, French Agency for Food, Environmental and Occupational Health & Safety, Fougères Laboratory, Toxicology of Contaminants Unit, 10 B rue Claude Bourgelat, 35306 Fougères, France.
Jazyk: angličtina
Zdroj: Journal of hazardous materials [J Hazard Mater] 2024 Aug 05; Vol. 474, pp. 134721. Date of Electronic Publication: 2024 May 28.
DOI: 10.1016/j.jhazmat.2024.134721
Abstrakt: The new challenges in toxicology demand novel and innovative in vitro approaches for deriving points of departure (PODs) and determining the mode of action (MOA) of chemicals. Therefore, the aim of this original study was to couple in vitro studies with untargeted metabolomics to model the concentration-response of extra- and intracellular metabolome data on human HepaRG cells treated for 48 h with three pyrrolizidine alkaloids (PAs): heliotrine, retrorsine and lasiocarpine. Modeling revealed that the three PAs induced various monotonic and, importantly, biphasic curves of metabolite content. Based on unannotated metabolites, the endometabolome was more sensitive than the exometabolome in terms of metabolomic effects, and benchmark concentrations (BMCs) confirmed that lasiocarpine was the most hepatotoxic PA. Regarding its MOA, impairment of lipid metabolism was highlighted at a very low BMC (first quartile, 0.003 µM). Moreover, results confirmed that lasiocarpine targets bile acids, as well as amino acid and steroid metabolisms. Analysis of the endometabolome, based on coupling concentration-response and PODs, gave encouraging results for ranking toxins according to their hepatotoxic effects. Therefore, this novel approach is a promising tool for next-generation risk assessment, readily applicable to a broad range of compounds and toxic endpoints.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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