A structure-activity relationship linking non-planar PCBs to functional deficits of neural crest cells: new roles for connexins

Arch Toxicol. 2018 Mar;92(3):1225-1247. doi: 10.1007/s00204-017-2125-4. Epub 2017 Nov 21.


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.

Keywords: Cell migration; Cell tracking; Cytotoxicity; Developmental toxicity; High-content imaging; Human stem cells.

MeSH terms

  • Animals
  • Biological Availability
  • Cell Movement / drug effects
  • Connexin 43 / metabolism
  • Gap Junctions / drug effects
  • Humans
  • Mice
  • NIH 3T3 Cells
  • Neural Crest / cytology
  • Neural Crest / drug effects*
  • Polychlorinated Biphenyls / chemistry*
  • Polychlorinated Biphenyls / pharmacokinetics
  • Polychlorinated Biphenyls / toxicity*
  • Structure-Activity Relationship*
  • Time-Lapse Imaging


  • Connexin 43
  • Polychlorinated Biphenyls