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

Abstract

PCB 11 (3,3'-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.

Evidence Implicating Non-Dioxin-Like Congeners as the Key Mediators of Polychlorinated Biphenyl (PCB) Developmental Neurotoxicity

“…An early study reported that the hydroxylated metabolites of eight different LC-PCBs increase ROS formation and induce cell death in cultured cerebellar granule cells [245]. Later studies demonstrated that PCB 11 and its known human hydroxyl and sulfated metabolites increase dendritic arborization in primary rat hippocampal and cortical neurons [259]. These dendritic effects are observed in cultures exposed to PCB 11 at fM concentrations, which are within the range of PCB 11 concentrations detected in the serum of pregnant women [259].…”

“…Later studies demonstrated that PCB 11 and its known human hydroxyl and sulfated metabolites increase dendritic arborization in primary rat hippocampal and cortical neurons [259]. These dendritic effects are observed in cultures exposed to PCB 11 at fM concentrations, which are within the range of PCB 11 concentrations detected in the serum of pregnant women [259]. In contrast to the HC-PCBs 95 and 136, PCB 11 and its metabolites not only increase dendritic arborization, but also enhance axonal growth [13].…”

“…In contrast to the HC-PCBs 95 and 136, PCB 11 and its metabolites not only increase dendritic arborization, but also enhance axonal growth [13]. Subsequent mechanistic studies indicated that the dendrite-promoting activity of PCB 11 is not blocked by pharmacological antagonism of the RyR, the AhR, or the THR [259]. The antioxidant α-tocopherol and inhibitors of the L-type Ca 2+ channel or IP 3 R also have no effect on PCB 11-induced dendritic growth [259].…”

“…Subsequent mechanistic studies indicated that the dendrite-promoting activity of PCB 11 is not blocked by pharmacological antagonism of the RyR, the AhR, or the THR [259]. The antioxidant α-tocopherol and inhibitors of the L-type Ca 2+ channel or IP 3 R also have no effect on PCB 11-induced dendritic growth [259]. However, pharmacological inhibition or siRNA knockdown of CREB effectively blocks the dendritic effects of PCB 11 [259].…”

“…The antioxidant α-tocopherol and inhibitors of the L-type Ca 2+ channel or IP 3 R also have no effect on PCB 11-induced dendritic growth [259]. However, pharmacological inhibition or siRNA knockdown of CREB effectively blocks the dendritic effects of PCB 11 [259]. PCB 95, an NDL legacy congener, also enhances dendritic arborization through CREB activation in vitro [146], suggesting that CREB may be a point of mechanistic convergence for PCB-induced dendritic growth.…”