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Structure-activity relationship study: Mechanism of cyto-genotoxicity of Nitropyrazole-derived high energy density materials family.

Authors
  • Guyot, Laetitia1
  • Simon, Florian2
  • Garcia, Jessica2
  • Vanhalle, Floriane2
  • Vilchez, Gaelle2
  • Bardel, Claire2
  • Manship, Brigitte3
  • Puisieux, Alain4
  • Machon, Christelle2
  • Jacob, Guy5
  • Guitton, Jérôme6
  • Payen, Léa7
  • 1 Hospices Civils de Lyon, Centre Hospitalier Lyon-Sud, Laboratoire de biochimie-toxicologie, France; UMR INSERM U1052/CNRS 5286, Centre de Recherche en Cancérologie de Lyon, Centre Léon Bérard, France. , (France)
  • 2 Hospices Civils de Lyon, Centre Hospitalier Lyon-Sud, Laboratoire de biochimie-toxicologie, France. , (France)
  • 3 UMR INSERM U1052/CNRS 5286, Centre de Recherche en Cancérologie de Lyon, Centre Léon Bérard, France. , (France)
  • 4 UMR INSERM U1052/CNRS 5286, Centre de Recherche en Cancérologie de Lyon, Centre Léon Bérard, France; Université Lyon 1, ISPBL, Faculté de pharmacie, Laboratoire de Toxicologie, France. , (France)
  • 5 Université Lyon 1, Faculté des sciences et technologies, UMR CNRS 5278 Hydrazines et Composés Energetiques Polyazotés, France; ArianeGroup Centre de Recherche du Bouchet, France. , (France)
  • 6 Hospices Civils de Lyon, Centre Hospitalier Lyon-Sud, Laboratoire de biochimie-toxicologie, France; Université Lyon 1, ISPBL, Faculté de pharmacie, Laboratoire de Toxicologie, France. Electronic address: [email protected] , (France)
  • 7 Hospices Civils de Lyon, Centre Hospitalier Lyon-Sud, Laboratoire de biochimie-toxicologie, France; UMR INSERM U1052/CNRS 5286, Centre de Recherche en Cancérologie de Lyon, Centre Léon Bérard, France; Université Lyon 1, ISPBL, Faculté de pharmacie, Laboratoire de Toxicologie, France. , (France)
Type
Published Article
Journal
Toxicology and Applied Pharmacology
Publisher
Elsevier
Publication Date
Oct 15, 2019
Volume
381
Pages
114712–114712
Identifiers
DOI: 10.1016/j.taap.2019.114712
PMID: 31437493
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Stringent toxicological tests have to be performed prior to the industrial development of alternative chemicals particularly high energy dense materials (HEDMs) such as explosives. The properties (e.g., power, stability) of these compounds are constantly being improved, the current axis of research being the nitration of nitrogen heterocycles leading to HEDMs such as nitropyrazole-derived molecules. However, except for 3,4,5-trinitropyrazole (3,4,5-TNP), which was shown to be highly toxic in mice, the toxicological impact of these HEDMs has so far not been investigated. Furthermore, as industrials are strongly advised to develop alternative safety testing assays to in vivo experiments, we herein focused on determining the cytotoxic and genotoxic effects of seven Nitropyrazole-derived HEDMs on three rodent cell lines (mouse embryonic BALB/3T3 clone A31 cells, Chinese hamster ovary cells CHO-K1 and mouse lymphoma L5178Y TK +/- clone (3.7.2C) cells), two human fibroblast lines (CRC05, PFS04062) and on the human hepatic HepaRG model (both in proliferative and differentiated cells). A stronger cytotoxic effect was observed for 1,3-dinitropyrazole (1, 3-DNP) and 3,4,5-TNP in all cell lines, though differentiated HepaRG cells clearly displayed fewer likely due to the metabolism and elimination of these molecules by their functional biotransformation pathways. At the mechanistic level, the sub-chronic cytotoxic and genotoxic effects were linked to ROS/RNS production (experimental assays), HA2.X and to transcriptomic data highlighting the increase in DNA repair mechanisms. Copyright © 2019 Elsevier Inc. All rights reserved.

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