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Developmental Exposure to an Environmental PCB Mixture Delays the Propagation of Kindling in the Amygdala
Bandara, S., R. Sadowski, S. Schantz, AND M. Gilbert. Developmental Exposure to an Environmental PCB Mixture Delays the Propagation of Kindling in the Amygdala. NEUROTOXICOLOGY. Elsevier B.V., Amsterdam, Netherlands, , n/a, (2016).
The EPA must evaluate the risk of exposure of the developing brain to chemicals with the potential to disrupt thyroid hormone (TH) homeostasis. Polychlorinated biphenyls are a group of persistent organic pollutants that reduce TH and result in developmental neurotoxicity. PCBs are lipophilic and can be mobilized from the adipose tissue of the mother and enter the fetus and newborn through the placenta and through breast milk. PCB exposure during development impairs both neuroplasticity in forebrain structures and cognitive processes such as working memory that rely on these structures and to cause peripheral sensory deficits in hearing. It has been hypothesized that at least some of the adverse effects associated with PCB exposure may stem from this action on TH status in the developing animal. Recently, the Schantz lab reported the induction of seizure activity in the adult offspring of pregnant rats exposed to an environmental mixture of PCB congeners, the Fox River PCB mix. In a study designed to investigate the interaction of PCB-induced hearing loss with noise-induced hearing loss, they observed the precipitation of audiogenic seizures in animals exposed to noise. The objective of the current study was to determine the generality of this phenomenon using a different seizure model that offers more experimental control over seizure and engages higher brain centers critical of other aspects of PCB-induced developmental impairments. In addition to its use as an epilepsy model, kindling embodies many of the same neural machinery of neuroplasticity in brain regions critical for learning. The present study was designed to investigate the susceptibility of animals with perinatal exposure to PCBs to seizure development using the electrical kindling model of epilepsy. In contrast to previous findings of an enhanced susceptibility to noise-induced seizures, a delay in electrical kindling of the amygdala was observed in developmentally PCB exposed animals. Focal electrographic seizures, afterdischarges (AD) recorded from the amygdala were not affected by PCB exposure, but the total cumulative AD required to induce fully generalized seizures was increased and the behavioral manifestations of the kindling process were delayed. These results indicate an alteration in the cellular and physiological processes that underlie activity-dependent plasticity that drives this epileptogenic process. Developmental PCB-induced reductions in the capacity for activity-dependent plasticity synaptic plasticity pathways for learning and memory previously reported by Gilbert and colleagues are consistent with these impairments of kindling. These findings indicate that not all seizure mechanisms are the same and that PCB induced neurotoxicity will vary in its expression dependent upon the brain region investigated. Although additional work is required to elucidate the mechanism of delayed kindling development, disruption in the functionality of the neurological substrates that support synaptic plasticity may contribute to these deficits and impairments in cognitive function associated with developmental PCB exposure in humans and animals.
Developmental PCB exposure impairs hearing and induces brainstem audiogenic seizures in adult offspring. The degree to which this enhanced susceptibility to seizure is manifest in other brain regions has not been examined. Thus, electrical kindling of the amygdala was used to evaluate the effect of developmental exposure to an environmentally relevant PCB mixture on seizure susceptibility in the rat. Female Long-Evans rats were dosed orally with 0 or 6 mg/kg/day of the PCB mixture dissolved in corn oil vehicle during the perinatal period. On postnatal day (PND) 21, pups were weaned, and two males from each litter were randomly selected for the kindling study. As adults, the male rats were implanted bilaterally with electrodes in the basolateral amygdala. For each animal, afterdischarge (AD) thresholds in the amygdala were determined on the first day of testing followed by once daily stimulation at a standard 200 µA stimulus intensity until three stage 5 generalized seizures (GS) ensued. Developmental PCB exposure did not affect the AD threshold or total cumulative AD duration, but PCB exposure did increase the latency to behavioral manifestations of seizure propagation. PCB exposed animals required significantly more stimulations to reach stage 2 seizures compared to control animals, indicating an attenuated focal (amygdala) excitability. A delay in kindling progression from a focally stimulated limbic site stands in contrast to our previous finding of increased susceptibility to brainstem-mediated audiogenic seizures in PCB-exposed rats. These seemingly divergent results are not unexpected given the distinct source, type, and mechanistic underpinnings of these different seizure models. A delay in epileptogenesis following focal amygdala stimulation may reflect a decrease in neuroplasticity following developmental PCB exposure consistent with reductions in use-dependent synaptic plasticity that have been reported in the hippocampus of developmentally PCB exposed animals.
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