3,3ʹ-Dichlorobiphenyl (PCB 11) promotes dendritic arborization in primary rat cortical neurons via a CREB-dependent mechanism

Sunjay Sethi, Kimberly P. Keil, Pamela J Lein

Research output: Contribution to journalArticle

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.

LanguageEnglish (US)
Pages3337-3345
Number of pages9
JournalArchives of Toxicology
Volume92
Issue number11
DOIs
StatePublished - Nov 1 2018

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Cyclic AMP Response Element-Binding Protein
Neuronal Plasticity
Polychlorinated Biphenyls
Neurons
Rats
Aryl Hydrocarbon Receptors
Thyroid Hormone Receptors
Calcium Channels
Growth
Dendrites
Coculture Techniques
Dimethyl Sulfoxide
Pigments
Neuroglia
Small Interfering RNA
Sprague Dawley Rats
Byproducts
Brain
Antioxidants
Cells

Keywords

  • Developmental neurotoxicity
  • In vitro model
  • Neuronal connectivity
  • Persistent organic pollutants

ASJC Scopus subject areas

  • Toxicology
  • Health, Toxicology and Mutagenesis

Cite this

3,3ʹ-Dichlorobiphenyl (PCB 11) promotes dendritic arborization in primary rat cortical neurons via a CREB-dependent mechanism. / Sethi, Sunjay; Keil, Kimberly P.; Lein, Pamela J.

In: Archives of Toxicology, Vol. 92, No. 11, 01.11.2018, p. 3337-3345.

Research output: Contribution to journalArticle

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