Abstract
PCB 11 (3,3ʹ-dichlorobiphenyl), a contemporary congener produced as a byproduct of current pigment production processes, has recently emerged as a prevalent worldwide pollutant. We recently demonstrated that exposure to PCB 11 increases dendritic arborization in vitro, but the mechanism(s) mediating this effect remain unknown. To address this data gap, primary cortical neuron–glia co-cultures derived from neonatal Sprague–Dawley rats were exposed for 48 h to either vehicle (0.1% DMSO) or PCB 11 at concentrations ranging from 1 fM to 1 nM in the absence or presence of pharmacologic antagonists of established molecular targets of higher chlorinated PCBs. Reporter cell lines were used to test activity of PCB 11 at the aryl hydrocarbon receptor (AhR) and thyroid hormone receptor (THR). PCB 11 lacked activity at the AhR and THR, and antagonism of these receptors had no effect on the dendrite-promoting activity of PCB 11. Pharmacologic antagonism of various calcium channels or treatment with antioxidants also did not alter PCB 11-induced dendritic arborization. In contrast, pharmacologic blockade or shRNA knockdown of cAMP response element-binding protein (CREB) significantly decreased dendritic growth in PCB 11-exposed cultures, suggesting PCB 11 promotes dendritic growth via CREB-mediated mechanisms. Since CREB signaling is crucial for normal neurodevelopment, and perturbations of CREB signaling have been associated with neurodevelopmental disorders, our findings suggest that this contemporary pollutant poses a threat to the developing brain, particularly in individuals with heritable mutations that promote CREB signaling.
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Acknowledgements
This research was supported by the National Institutes of Health (R01 ES014901, P30 ES023513, P01 ES011269, T32 ES007059 [predoctoral fellowship to SS] and F32 HD088016 [postdoctoral fellowship to KPK]) and by the United States Environmental Protection Agency (RD 83543201). This project used core facilities supported by the MIND Institute Intellectual and Developmental Disabilities Research Center (Grant U54 HD079125). The synthesis of PCB 11 provided by Dr. Xueshu Li (The University of Iowa, Iowa City, IA) was supported by the Superfund Research Center at The University of Iowa (P42 ES013661). We gratefully acknowledge Dr. Michael Denison (University of California-Davis, Davis, CA), who performed the AhR luciferase assays, and Dr. J. David Furlow (University of California-Davis, Davis, CA) who provided the TRE-Luc cell line. The contents of this work do not necessarily represent the official views of the funding agencies, and the funding agencies do not endorse the purchase of any commercial products or services mentioned in the publication.
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Sethi, S., Keil, K.P. & Lein, P.J. 3,3ʹ-Dichlorobiphenyl (PCB 11) promotes dendritic arborization in primary rat cortical neurons via a CREB-dependent mechanism. Arch Toxicol 92, 3337–3345 (2018). https://doi.org/10.1007/s00204-018-2307-8
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DOI: https://doi.org/10.1007/s00204-018-2307-8