Reference : A structure-activity relationship linking non-planar PCBs to functional deficits of n...
Scientific journals : Article
Life sciences : Biotechnology
Life sciences : Multidisciplinary, general & others
Human health sciences : Neurology
Systems Biomedicine
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 []
Holzer, Anna-Katharina []
Purvanov, Vladimir []
Kindinger, Ilona []
Kerins, Anna []
Higton, David []
Silvester, Steve []
van Vugt-Lussenburg, Barbara M. A. []
Glaab, Enrico mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > >]
van der Burg, Bart []
Maclennan, Richard []
Legler, Daniel F. []
Leist, Marcel []
Archives of Toxicology
Springer Science & Business Media B.V.
Yes (verified by ORBilu)
[en] neural crest cells ; connexin ; qsar ; cytotoxicity ; cell migration ; cell tracking ; high-content imaging ; developmental toxicity ; human stem cells ; polychlorinated biphenyl
[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.
Luxembourg Centre for Systems Biomedicine (LCSB): Biomedical Data Science (Glaab Group) ; University of Luxembourg: High Performance Computing - ULHPC
Fonds National de la Recherche - FnR
National Centre of Excellence in Research (NCER) on Parkinson’s disease (I1R-BIC-PFN-15NCER)
Researchers ; Professionals ; Students

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