title: Hazard assessment through hybrid in vitro / in silico approach: The case of zearalenone.
abstract: Within the framework of reduction, refinement and replacement of animal experiments, new approaches for identification and characterization of chemical hazards have been developed. Grouping and read across has been promoted as a most promising alternative approach. It uses existing toxicological information on a group of chemicals to make predictions on the toxicity of uncharacterized ones. In the present work, the feasibility of applying in vitro and in silico techniques to group chemicals for read across was studied using the food mycotoxin zearalenone (ZEN) and metabolites as a case study. ZEN and its reduced metabolites are known to act through activation of the estrogen receptor α (ERα). The ranking of their estrogenic potencies appeared highly conserved across test systems including binding, in vitro and in vivo assays. This data suggests that activation of ERα may play a role in the molecular initiating event (MIE) and be predictive of adverse effects and provides the rationale to model receptor-binding for hazard identification. The investigation of receptor-ligand interactions through docking simulation proved to accurately rank estrogenic potencies of ZEN and reduced metabolites, showing the suitability of the model to address estrogenic potency for this group of compounds. Therefore, the model was further applied to biologically uncharacterized, commercially unavailable, oxidized ZEN metabolites (6α-, 6β-, 8α-, 8β-, 13- and 15-OH-ZEN). Except for 15-OH-ZEN, the data indicate that in general, the oxidized metabolites would be considered a lower estrogenic concern than ZEN and reduced metabolites.
authors.affiliation: Chemical Food Safety Group, Food Quality & Safety Department, Nestlé Research Center, Lausanne, Switzerland.
authors.forename: Veronika A
authors.initials: VA
authors.lastname: Ehrlich
authors.affiliation: Molecular Modelling Laboratory, Department of Food Science, University of Parma, Parma, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Dellafiora
authors.affiliation: Chemical Food Safety Group, Food Quality & Safety Department, Nestlé Research Center, Lausanne, Switzerland.
authors.forename: Julie
authors.initials: J
authors.lastname: Mollergues
authors.affiliation: Molecular Modelling Laboratory, Department of Food Science, University of Parma, Parma, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Dall'Asta
authors.affiliation: Chemical Food Safety Group, Food Quality & Safety Department, Nestlé Research Center, Lausanne, Switzerland.
authors.forename: Patrick
authors.initials: P
authors.lastname: Serrant
authors.affiliation: Chemical Food Safety Group, Food Quality & Safety Department, Nestlé Research Center, Lausanne, Switzerland.
authors.forename: Maricel
authors.initials: M
authors.lastname: Marin-Kuan
authors.affiliation: Chemical Food Safety Group, Food Quality & Safety Department, Nestlé Research Center, Lausanne, Switzerland.
authors.forename: Elena
authors.initials: E
authors.lastname: Lo Piparo
authors.affiliation: Chemical Food Safety Group, Food Quality & Safety Department, Nestlé Research Center, Lausanne, Switzerland.
authors.forename: Benoit
authors.initials: B
authors.lastname: Schilter
authors.affiliation: Molecular Modelling Laboratory, Department of Food Science, University of Parma, Parma, Italy.
authors.forename: Pietro
authors.initials: P
authors.lastname: Cozzini
mesh_terms: D000826:Animal Testing Alternatives; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D052244:Endocrine Disruptors / Q000633:toxicity*; D047628:Estrogen Receptor alpha / Q000187:drug effects; D004968:Estrogens, Non-Steroidal / Q000633:toxicity*; D005240:Feasibility Studies; D015386:Hazardous Substances / Q000633:toxicity*; D006801:Humans; D015025:Zearalenone / Q000633:toxicity*
chemical_list: D052244:Endocrine Disruptors; D047628:Estrogen Receptor alpha; D004968:Estrogens, Non-Steroidal; D015386:Hazardous Substances; D015025:Zearalenone
keywords: biological activity; docking; endocrine disrupting compounds; read-across; zearalenone