Developmental Exposure to Polychlorinated Biphenyls Interferes with Experience-Dependent Dendritic Plasticity and Ryanodine Receptor Expression in Weanling Rats

Abstract

BackgroundNeurodevelopmental disorders are associated with altered patterns of neuronal connectivity. A critical determinant of neuronal connectivity is the dendritic morphology of individual neurons, which is shaped by experience. The identification of environmental exposures that interfere with dendritic growth and plasticity may, therefore, provide insight into environmental risk factors for neurodevelopmental disorders.ObjectiveWe tested the hypothesis that polychlorinated biphenyls (PCBs) alter dendritic growth and/or plasticity by promoting the activity of ryanodine receptors (RyRs).Methods and ResultsThe Morris water maze was used to induce experience-dependent neural plasticity in weanling rats exposed to either vehicle or Aroclor 1254 (A1254) in the maternal diet throughout gestation and lactation. Developmental A1254 exposure promoted dendritic growth in cerebellar Purkinje cells and neocortical pyramidal neurons among untrained animals but attenuated or reversed experience-dependent dendritic growth among maze-trained littermates. These structural changes coincided with subtle deficits in spatial learning and memory, increased [3H]-ryanodine binding sites and RyR expression in the cerebellum of untrained animals, and inhibition of training-induced RyR upregulation. A congener with potent RyR activity, PCB95, but not a congener with negligible RyR activity, PCB66, promoted dendritic growth in primary cortical neuron cultures and this effect was blocked by pharmacologic antagonism of RyR activity.ConclusionsDevelopmental exposure to PCBs interferes with normal patterns of dendritic growth and plasticity, and these effects may be linked to changes in RyR expression and function. These findings identify PCBs as candidate environmental risk factors for neurodevelopmental disorders, especially in children with heritable deficits in calcium signaling.

An Extended Structure–Activity Relationship of Nondioxin-Like PCBs Evaluates and Supports Modeling Predictions and Identifies Picomolar Potency of PCB 202 Towards Ryanodine Receptors

“…The difference in potency, as compared with the pM-nM range reported here, may be due to drastic differences in assay conditions. Specifically, (Wayman et al, 2012b;Yang et al, 2009) supporting the pM to nM toxicity range demonstrated in the current study.…”

“…Organisms exposed during development to PCB 95 and Aroclor 1254, a mixture with increased ortho-substituted PCBs, have altered dendritic arborization in the hippocampus (Yang et al, 2009) and altered RyR1 and RyR, isoform 2 (RyR2) expression in their cerebellum. In these studies, the exposed animals had altered learning and had PCB congeners in their brains that consisted of numerous RyR active congeners including PCB 99, 153, 170, 180, 183, and 187 but did not contain PCB 77, 126, and 169 (Yang et al, 2009). Another study with weanling mice exposed to a mixture of PCB 28, 52, 101, 138, 153, and 180 through lactation displayed age specific disruption in motor function and persistent anxiety like behavior (Elnar et al, 2012).…”

“…Of the 209 PCB congeners, varying by the position and number of chlorine substitutions, the nondioxin-like PCBs (NDL PCB) have been identified as potential neurological toxicants due to observed cognitive deficits in PCB exposed organisms (Boix et al, 2011;Lilienthal et al, 2015;Schantz et al, 1997Schantz et al, , 2001Yang et al, 2009). Numerous modes of action have been described that may contribute to neurotoxicity.…”

Permanently compromised NADPH-diaphorase activity within the osmotically activated supraoptic nucleus after in utero but not adult exposure to Aroclor 1254

“…Since NO participates in synaptic plasticity, neurite outgrowth and extension, synaptogenesis, neuronal proliferation and maturation (Holscher, 1997;Sanchez-Islas and Leon-Olea, 2004;Wu et al, 1994), the early PCB-induced changes in NOS activity may be associated with altered nervous system development and function (Kodavanti, 2005). Others have suggested that PCB-induced disruption of thyroid hormone signaling in PCB-exposed animals may explain the long-term effects of developmental PCB exposure on nervous system structure and function (Yang et al, 2009). Indeed, perinatal exposure to PCB significantly lowers circulating thyroid hormone levels in rodents Zoeller and Crofton, 2000) and maternal exposure to PCBs is associated with an elevation in thyroid and thyroglobulin antibodies that can pass through the placenta and interfere with thyroid status in the fetus (Langer et al, 1998).…”

Upstream adverse effects in risk assessment: A model of polychlorinated biphenyls, thyroid hormone disruption and neurological outcomes in humans

“…For example, some PCB (and OH-PCB) congeners are estrogenic (Matthews et al, 2007;Wang et al, 2006). Some PCB congeners bind to the ryanodine receptor with high affinity and can alter calcium signaling in cells of the central nervous system (Pessah et al, 2009;Yang et al, 2009). Our Relationship 3, modeling the effect of PCBs on IQ, cannot separate out these mechanisms.…”