dc.contributor.author
Göpfert, Alina
dc.contributor.author
Schuster, David M.
dc.contributor.author
Rülker, Claudia
dc.contributor.author
Eichenlaub, Michael
dc.contributor.author
Tokovenko, Bogdan
dc.contributor.author
Dammann, Martina
dc.contributor.author
Funk-Weyer, Dorothee
dc.contributor.author
Honarvar, Naveed
dc.contributor.author
Landsiedel, Robert
dc.date.accessioned
2025-01-13T12:58:16Z
dc.date.available
2025-01-13T12:58:16Z
dc.identifier.uri
https://refubium.fu-berlin.de/handle/fub188/46227
dc.identifier.uri
http://dx.doi.org/10.17169/refubium-45939
dc.description.abstract
Mutagenicity testing is a component of the hazard assessment of industrial chemicals, biocides, and pesticides. Mutations induced by test substances can be detected by in vitro and in vivo methods that have been adopted as OECD Test Guidelines. One of these in vivo methods is the Transgenic Rodent Assay (TGRA), OECD test guideline no. 488. An analogous in vitro TGRA has been described, but experience with this test method is limited. In this study, six in vivo TGRA positive mutagens were tested in the in vitro TGRA based on primary MutaMouse hepatocytes. In addition to the functional read-out of the lacZ reporter gene, induced mutations were analysed by next-generation sequencing (NGS). Five of the six in vivo TGRA positive mutagens (N-ethyl-N-nitrosourea (ENU), ethyl methanesulfonate (EMS), mitomycin C (MMC), benzo[a]pyrene (B[a]P), and azathioprine (AZA), but not cyproterone acetate) mutated the lacZ gene in vitro. NGS identified mutations which matched the mutagenic mechanisms described in the literature. The alkylating agent ENU induced a greater proportion of A:T to T:A transversions than did the other alkylating agent, EMS, whereas EMS increased smaller deletions (1–4 bp). G:C to T:A transversions accounted for the majority of mutations identified after treatments with MMC and B[a]P, both of which form monoadducts at the guanine N2 position. AZA induced mainly G:C to A:T transitions, explained by the structural similarity of one of its metabolites to guanine. An increased proportion of mid-size changes (0.3–2.5 kb) was detected only for the crosslinking mutagen MMC. The in vitro TGRA based on primary MutaMouse hepatocytes is a promising in vitro assay for the assessment of mutation induction, reflecting many aspects of the corresponding in vivo TGRA and allowing for mutation spectra analysis to evaluate the induced mutations.
en
dc.format.extent
13 Seiten
dc.rights.uri
https://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subject
Primary hepatocytes
en
dc.subject
Next-generation sequencing
en
dc.subject
Mutation spectra
en
dc.subject.ddc
500 Naturwissenschaften und Mathematik::570 Biowissenschaften; Biologie::570 Biowissenschaften; Biologie
dc.title
The transgenic MutaMouse hepatocyte mutation assay in vitro: Mutagenicity and mutation spectra of six substances with different mutagenic mechanisms
dc.type
Wissenschaftlicher Artikel
dcterms.bibliographicCitation.articlenumber
503836
dcterms.bibliographicCitation.doi
10.1016/j.mrgentox.2024.503836
dcterms.bibliographicCitation.journaltitle
Mutation Research - Genetic Toxicology and Environmental Mutagenesis
dcterms.bibliographicCitation.volume
901
dcterms.bibliographicCitation.url
https://doi.org/10.1016/j.mrgentox.2024.503836
refubium.affiliation
Biologie, Chemie, Pharmazie
refubium.affiliation.other
Institut für Pharmazie
refubium.resourceType.isindependentpub
no
dcterms.accessRights.openaire
open access
dcterms.isPartOf.eissn
1879-3592
refubium.resourceType.provider
WoS-Alert