Title |
A structure–activity relationship linking non-planar PCBs to functional deficits of neural crest cells: new roles for connexins
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Published in |
Archives of Toxicology, November 2017
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DOI | 10.1007/s00204-017-2125-4 |
Pubmed ID | |
Authors |
Johanna Nyffeler, Petra Chovancova, Xenia Dolde, Anna-Katharina Holzer, Vladimir Purvanov, Ilona Kindinger, Anna Kerins, David Higton, Steve Silvester, Barbara M. A. van Vugt-Lussenburg, Enrico Glaab, Bart van der Burg, Richard Maclennan, Daniel F. Legler, Marcel Leist |
Abstract |
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. |
X Demographics
Geographical breakdown
Country | Count | As % |
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Germany | 1 | 50% |
Luxembourg | 1 | 50% |
Demographic breakdown
Type | Count | As % |
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Members of the public | 2 | 100% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
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Unknown | 26 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
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Researcher | 7 | 27% |
Student > Ph. D. Student | 5 | 19% |
Other | 2 | 8% |
Professor | 1 | 4% |
Lecturer | 1 | 4% |
Other | 2 | 8% |
Unknown | 8 | 31% |
Readers by discipline | Count | As % |
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Agricultural and Biological Sciences | 5 | 19% |
Pharmacology, Toxicology and Pharmaceutical Science | 4 | 15% |
Environmental Science | 3 | 12% |
Computer Science | 3 | 12% |
Biochemistry, Genetics and Molecular Biology | 2 | 8% |
Other | 1 | 4% |
Unknown | 8 | 31% |