Long-term effects of developmental exposure to 2,2',3,5',6-pentachlorobiphenyl (PCB 95) on locomotor activity, spatial learning and memory and brain ryanodine binding.
There is mounting evidence that perinatal exposure to ortho-substituted PCB congeners causes neurobehavioral and neurochemical alterations. The molecular mechanism for these effects is not understood, but certain ortho-substituted PCBs have been found to interact specifically with ryanodine-sensitive Ca2+ channels in vitro. These channels are widely expressed in brain and are thought to be responsible for Ca(2+)-induced Ca2+ release. Thus, the ryanodine receptor may represent a selective molecular target through which ortho-substituted PCBs disrupt calcium signaling in neurons, and produce neurochemical and neurobehavioral alterations. Of the PCBs evaluated, 2,2',3,5',6-pentachlorobiphenyl (PCB 95) exhibits the highest potency and efficacy towards the ryanodine receptor in vitro. Therefore, we conducted an in vivo study to investigate the effects of developmental exposure to PCB 95 on neurobehavioral functional and regional brain ryanodine binding. Time-mated Sprague-Dawley rats were dosed with PCB 95 (8 or 32 mg/kg/day) or corn oil vehicle via gavage on gestation days 10-16. One male and one female from each litter were evaluated for neurobehavioral effects. Locomotor activity was evaluated in an automated open field at 35 and 100 days of age. Spatial learning and memory was assessed using an eight arm radial maze working memory task at 60 days of age and a T-maze delayed spatial alternation task at 140 days of age. The animals were then euthanized and [3H] ryanodine binding was assayed in homogenates of cerebral cortex, hippocampus and cerebellum. Rats exposed to PCB 95 showed normal levels of activity as juveniles, but were hypoactive in adulthood. They also showed a faster acquisition of the working memory task on the radial arm maze, but did not differ from controls on the T-maze delayed spatial alteration task. Region-specific changes in ryanodine binding to Ca2+ channels were also observed, with decreased binding in the hippocampus, increased binding in the cerebral cortex and a biphasic effect in the cerebellum. How these changes in ryanodine receptor function are related to the alterations in behavior will be a challenging problem to elucidate.
Schantz
S L
SL
Department of Veterinary Biosciences, University of Illinois at Urbana-Champaign 61802, USA.
Seo
B W
BW
Wong
P W
PW
Pessah
I N
IN
D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects*; D015220:Calcium Channels / Q000187:drug effects*; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D018782:Maze Learning / Q000187:drug effects*; D008568:Memory / Q000187:drug effects*; D009043:Motor Activity / Q000187:drug effects*; D009124:Muscle Proteins / Q000187:drug effects*; D011078:Polychlorinated Biphenyls / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012098:Reproduction / Q000187:drug effects; D019837:Ryanodine Receptor Calcium Release Channel
D015220:Calcium Channels; D009124:Muscle Proteins; D019837:Ryanodine Receptor Calcium Release Channel; C032904:2,2',3,5',6-pentachlorobiphenyl; D011078:Polychlorinated Biphenyls