3,3′‐Dichlorobiphenyl (PCB 11) Promotes Dendritic Arborization in Primary Neurons via CREB‐Dependent Mechanisms

Abstract

PCB 11 is a byproduct of contemporary paint pigment production that has been detected in environmental media around the world, including milk produced for human consumption. We previously reported that PCB 11 enhances dendritic arborization in primary rat neuronal cell cultures. Since increased dendritic arborization, or hyperconnectivity, is a shared characteristic of many neurodevelopmental disorders (NDDs), our findings suggest this chemical poses a risk to the developing brain. The goal of this study was to understand how PCB 11 promotes dendritic growth. We tested canonical mechanisms of PCB developmental neurotoxicity, including signaling mediated by the ryanodine receptor (RyR), aryl hydrocarbon receptor (AhR), thyroid hormone receptor (THR), and cAMP response element binding protein (CREB). [3H]Ryanodine binding assays were used to assess effects of PCB 11 on RyR activity; luciferase‐reporter cell lines, to assess effects on AhR or THR activation. To assess a functional role for these signaling molecules in PCB 11‐mediated dendritic growth, primary neuron‐glia co‐cultures dissociated from neocortices of neonatal Sprague Dawley rats were transfected at 6 days in vitro (DIV) with a MAP2B‐FusRed construct to label the dendritic arbors of individual neurons. At 7 DIV, cultures were pretreated with pharmacological antagonists and then co‐treated for 48 h with PCB 11 or vehicle (0.1% DMSO). Dendritic morphology was quantified in FusRed‐labeled neurons by quantifying the number of dendritic tips and primary dendrites. PCB 11 had no activity at RyR, AhR or THR, and pharmacological antagonism of these receptors had no significant effect on PCB 11‐induced dendritic growth. However, the dendritic promoting effect of PCB 11 was blocked by the selective inhibitor of CREB, 666‐15 (3‐(3‐Aminopropoxy)‐N‐[2‐[[3‐[[(4‐chloro‐2‐hydroxyphenyl)amino]carbonyl]‐2‐naphthalenyl]oxy]ethyl]‐2‐naphthalenecarboxamide), or by co‐transfection with a short hairpin RNA construct specific for CREB. These results indicate that PCB 11 promotes dendritic growth via interaction with CREB or CREB‐dependent mechanism(s), but not directly interfering with known molecular targets of the higher chlorinated PCBs. In light of emerging evidence implicating perturbations of CREB signaling in the etiology of many NDDs, these findings add to the weight of evidence suggesting that PCB 11 poses a threat to the developing human brain.Support or Funding InformationSupported by NIEHS (R01 ES014901 to PJL & INP; T32 ES007059 to SS; P01 ES013661 to HJL) & NICHD (F32 HD088016 to KPK and U54 HD079125).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.