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-substitute d PCB congeners causes neurobehavioral and neurochemical alterations. The molecular mechanism for these effects is not understood, but certa in ortho-substituted PCBs ha ve been found to interact specifically wi th ryanodine-sensitive Ca2+ channels in vitro. These channels are wide ly expressed in brain and are thought to be responsible for Ca2+-induc ed Ca2+ release. Thus, the ryanodine receptor may represent a selectiv e molecular target through which ortho-substituted PCBs disrupt calciu m signaling in neurons, and produce neurochemical and neurobehavioral alterations. Of the PCBs evaluated, 2,2',3,5',6-pentachlorobiphenyl (P CB 95) exhibits the highest potency and efficacy towards the ryanodine receptor in vitro. Therefore, we conducted an in vivo study to invest igate the effects of developmental exposure to PCB 95 on neurobehavior al function and regional brain ryanodine binding. Time-mated Sprague-D awley rats were dosed with PCB 95 (8 or 32 mg/kg/day) or corn oil vehi cle via gavage on gestation days 10-16. One male and one female from e ach litter were evaluated for neurobehavioral effects. Locomotor activ ity 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 m aze 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 [H-3] ryanodine binding was assayed in homogenates of cerebral co rtex, hippocampus and cerebellum. Rats exposed to PCB 95 showed normal levels of activity as juveniles, but were hypoactive in adulthood. Th ey 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 delaye d spatial alternation task. Region-specific changes in ryanodine bindi ng to Ca2+ channels were also observed, with decreased binding in the hippocampus, increased binding in the cerebral cortex and a biphasic e ffect in the cerebellum. How these changes in ryanodine receptor funct ion are related to the alterations in behavior will be a challenging p roblem to elucidate. (C) 1997 Intox Press, Inc.