Article (Scientific journals)
A structure-activity relationship linking non-planar PCBs to functional deficits of neural crest cells: new roles for connexins
Nyffeler, Johanna; Chovancova, Petra; Dolde, Xenia et al.
2018In Archives of Toxicology, 92 (3), p. 1225–1247
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Keywords :
neural crest cells; connexin; qsar; cytotoxicity; cell migration; cell tracking; high-content imaging; developmental toxicity; human stem cells; polychlorinated biphenyl
Abstract :
[en] Migration of neural crest cells (NCC) is a fundamental developmental process, and test methods to identify interfering toxicants have been developed. By examining cell function endpoints, as in the ‘migration-inhibition of NCC (cMINC)’ assay, a large number of toxicity mechanisms and protein targets can be covered. However, the key events that lead to the adverse effects of a given chemical or group of related compounds are hard to elucidate. To address this issue, we explored here, whether the establishment of two overlapping structure–activity relationships (SAR)—linking chemical structure on the one hand to a phenotypic test outcome, and on the other hand to a mechanistic endpoint—was useful as strategy to identify relevant toxicity mechanisms. For this purpose, we chose polychlorinated biphenyls (PCB) as a large group of related, but still toxicologically and physicochemically diverse structures. We obtained concentration-dependent data for 26 PCBs in the cMINC assay. Moreover, the test chemicals were evaluated by a new high-content imaging method for their effect on cellular re-distribution of connexin43 and for their capacity to inhibit gap junctions. Non-planar PCBs inhibited NCC migration. The potency (1–10 μM) correlated with the number of ortho-chlorine substituents; non-ortho-chloro (planar) PCBs were non-toxic. The toxicity to NCC partially correlated with gap junction inhibition, while it fully correlated (p < 0.0004) with connexin43 cellular re-distribution. Thus, our double-SAR strategy revealed a mechanistic step tightly linked to NCC toxicity of PCBs. Connexin43 patterns in NCC may be explored as a new endpoint relevant to developmental toxicity screening.
Research center :
- Luxembourg Centre for Systems Biomedicine (LCSB): Biomedical Data Science (Glaab Group)
ULHPC - University of Luxembourg: High Performance Computing
Disciplines :
Life sciences: Multidisciplinary, general & others
Author, co-author :
Nyffeler, Johanna
Chovancova, Petra
Dolde, Xenia
Holzer, Anna-Katharina
Purvanov, Vladimir
Kindinger, Ilona
Kerins, Anna
Higton, David
Silvester, Steve
van Vugt-Lussenburg, Barbara M. A.
Glaab, Enrico  ;  University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB)
van der Burg, Bart
Maclennan, Richard
Legler, Daniel F.
Leist, Marcel
More authors (5 more) Less
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Language :
Title :
A structure-activity relationship linking non-planar PCBs to functional deficits of neural crest cells: new roles for connexins
Publication date :
March 2018
Journal title :
Archives of Toxicology
Publisher :
Springer Science & Business Media B.V.
Volume :
Issue :
Pages :
Peer reviewed :
Peer Reviewed verified by ORBi
Focus Area :
Systems Biomedicine
Name of the research project :
National Centre of Excellence in Research (NCER) on Parkinson’s disease (I1R-BIC-PFN-15NCER)
Funders :
FNR - Fonds National de la Recherche [LU]
Available on ORBilu :
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