| Developmental exposure to non-coplanar PCBs has been associated with neurotoxicity in animals and humans. This dissertation focused on the neurotoxicity of two non-coplanar PCBs (2,2'3,3',4,4',5-heptacholorobiphenyl (PCB170), 2,2'3,5'6-pentachlorobiphenyl (PCB95)) produced by in vivo or in vitro exposures on (1) synaptic transmission of rat hippocampal slices, and (2) seizure susceptibility.; Exposure of rat hippocampal slices to 100 nM PCB 170 or 10 nM PCB 95 changed the slope of field excitatory postsynaptic potentials (fEPSPs) in distinct ways. PCB 95 enhanced fEPSP slope in a manner inhibited by dantrolene, a RyR blocker. [3H]ryanodine-binding analysis showed that PCB 170 and PCB 95 differentially altered regulation of hippocampal RyRs by Ca 2+ in a manner that could explain their differential influence on fEPSP. Co-treatment of hippocampal slices with PTX, a GABAA receptor blocker, and PCB 170 synergized the pure excitatory actions of this PCB and produced prominent after-charges (epileptic waveforms). Flurothyl (bis-2,2,2-triflurothyl ether)-induced seizures and pentylenetetrazole (PTZ)-induced kindling were tested to determine whether lactational exposure (during GD 19 to PND21) to PCB 95 lowers seizure threshold. Offspring exposed during lactation to I1 mg/kg/day PCB 95 had significantly lower seizure threshold and kindled faster than vehicle groups and had significantly higher [3H]ryanodine-binding levels in their hippocampi.; Perinatal exposure (during GD5∼PND 21) to 6 mg/kg/day PCB 95 also altered hippocampal excitability ex vivo with enhanced fEPSP slopes once PTX was applied to hippocampal slices from PCB exposed rats compared to the slices from the vehicle exposed group. Animals exposed to PCB 95 (1mg//kg/day) during the perinatal period had higher seizure susceptibility compared to the vehicle and higher dose (6 mg/kg/day) groups.; These results show that specific non-coplanar PCB congeners perturb the balance of excitatory and inhibitory neurotransmission and significantly sensitize seizure susceptibility in vivo. RyR dysfunctions appear to mediate, at least in part, aspects of hippocampal excitotoxicity by non-coplanar PCBs with a complex dose-response relationship. |
