Integrate mechanistic evidence from new approach methodologies (NAMs) into a read-across assessment to characterise trends in shared mode of action

Autor: Alejandro Aguayo-Orozco, Liliana Capinha, Nazanin Golbamaki, Enrico Mombelli, Matthias Wehr, Bart van der Burg, Daria Goldmann, Nanette G Vrijenhoek, Thomas Exner, Richard Maclennan, Katharina Brotzmann, Ulf Norinder, Oliver Hatley, Alice Limonciel, Thomas Braunbeck, Sylvia Escher, Barbara Zdrazil, Frédéric Y. Bois, Paul Jennings, Emilio Benfenati, Domenico Gadaleta, Jose Castel, Ciarán Fisher, Sankalp Jain, Anthony Long, Rabea Graepel, Laia Tolosa, Andrew White, Bob van de Water, Barbara M.A. van Vugt-Lussenburg, Paul Walker, Annette Bitsch, Olivier Taboureau, Iain Gardner
Přispěvatelé: AIMMS, Molecular and Computational Toxicology, Publica
Rok vydání: 2021
Předmět:
Zdroj: Toxicology in Vitro, 79:105269, 1-16. Elsevier Limited
Escher, S E, Aguayo-Orozco, A, Benfenati, E, Bitsch, A, Braunbeck, T, Brotzmann, K, Bois, F, van der Burg, B, Castel, J, Exner, T, Gadaleta, D, Gardner, I, Goldmann, D, Hatley, O, Golbamaki, N, Graepel, R, Jennings, P, Limonciel, A, Long, A, Maclennan, R, Mombelli, E, Norinder, U, Jain, S, Capinha, L S, Taboureau, O T, Tolosa, L, Vrijenhoek, N G, van Vugt-Lussenburg, B M A, Walker, P, van de Water, B, Wehr, M, White, A, Zdrazil, B & Fisher, C 2022, ' Integrate mechanistic evidence from new approach methodologies (NAMs) into a read-across assessment to characterise trends in shared mode of action ', Toxicology in Vitro, vol. 79, 105269, pp. 1-16 . https://doi.org/10.1016/j.tiv.2021.105269
Escher, S E, Aguayo-Orozco, A, Benfenati, E, Bitsch, A, Braunbeck, T, Brotzmann, K, Bois, F, van der Burg, B, Castel, J, Exner, T, Gadaleta, D, Gardner, I, Goldmann, D, Hatley, O, Golbamaki, N, Graepel, R, Jennings, P, Limonciel, A, Long, A, Maclennan, R, Mombelli, E, Norinder, U, Jain, S, Capinha, L S, Taboureau, O T, Tolosa, L, Vrijenhoek, N G, van Vugt-Lussenburg, B M A, Walker, P, van de Water, B, Wehr, M, White, A, Zdrazil, B & Fisher, C 2022, ' Integrate mechanistic evidence from new approach methodologies (NAMs) into a read-across assessment to characterise trends in shared mode of action ', Toxicology in Vitro, vol. 79, 105269 . https://doi.org/10.1016/j.tiv.2021.105269
Toxicology in Vitro
Toxicology In Vitro, 79
ISSN: 1879-3177
0887-2333
DOI: 10.1016/j.tiv.2021.105269
Popis: Read-across approaches often remain inconclusive as they do not provide sufficient evidence on a common mode of action across the category members. This read-across case study on thirteen, structurally similar, branched aliphatic carboxylic acids investigates the concept of using human-based new approach methods, such as in vitro and in silico models, to demonstrate biological similarity. Five out of the thirteen analogues have preclinical in vivo studies. Three out of them induced lipid accumulation or hypertrophy in preclinical studies with repeated exposure, which leads to the read-across hypothesis that the analogues can potentially induce hepatic steatosis. To confirm the selection of analogues, the expression patterns of the induced differentially expressed genes (DEGs) were analysed in a human liver model. With increasing dose, the expression pattern within the tested analogues got more similar, which serves as a first indication of a common mode of action and suggests differences in the potency of the analogues. Hepatic steatosis is a well-known adverse outcome, for which over 55 adverse outcome pathways have been identified. The resulting adverse outcome pathway (AOP) network, comprised a total 43 MIEs/KEs and enabled the design of an in vitro testing battery. From the AOP network, ten MIEs, early and late KEs were tested to systematically investigate a common mode of action among the grouped compounds. The targeted testing of AOP specific MIE/KEs shows that biological activity in the category decreases with side chain length. A similar trend was evident in measuring liver alterations in zebra fish embryos. However, activation of single MIEs or early KEs at in vivo relevant doses did not necessarily progress to the late KE “lipid accumulation”. KEs not related to the read-across hypothesis, testing for example general mitochondrial stress responses in liver cells, showed no trend or biological similarity. Testing scope is a key issue in the design of in vitro test batteries. The Dempster-Shafer decision theory predicted those analogues with in vivo reference data correctly using one human liver model or the CALUX reporter assays. The case study shows that the read-across hypothesis is the key element to designing the testing strategy. In the case of a good mechanistic understanding, an AOP facilitates the selection of reliable human in vitro models to demonstrate a common mode of action. Testing DEGs, MIEs and early KEs served to show biological similarity, whereas the late KEs become important for confirmation, as progression from MIEs to AO is not always guaranteed.
Databáze: OpenAIRE
Externí odkaz: