Repeated exposure of adult rats to Aroclor 1254 causes brain region-specific changes in intracellular Ca2+ buffering and protein kinase C activity inthe absence of changes in tyrosine hydroxylase

Polychlorinated biphenyls (PCBs) are ubiquitous environmental contaminants, some of which may be neurotoxic. In vitro studies from this laboratory ind icated that noncoplanar PCBs perturbed intracellular signal transduction me chanisms including Ca2+ homeostasis, receptor-mediated inositol phosphate p roduction, and translocation of protein kinase C (PKC). In the present stud y, we examined the effects of PCBs in vivo by dosing adult male Long-Evans rats orally with Aroclor 1254 (0, 10, or 30 mg/kg/day; 5 days/week for 4 we eks) in corn oil. At 24 h after the last dose, rats were tested for motor a ctivity in a photocell device for 30 min. Immediately, the rats were euthan ized, blood was collected for thyroid hormone analysis, and brains were rem oved, dissected into regions (cerebellum, frontal cortex, and striatum), an d subcellular fractions were obtained for neurochemical analysis. Following Aroclor 1254 treatment, body weight gain in the high-dose group was signif icantly lower than the control and low-dose groups. Horizontal motor activi ty was significantly lower in rats dosed with 30 mg/kg Aroclor 1254. Ca2+ b uffering by microsomes was significantly lower in all three brain regions f rom the 30 mg/kg group. In the same dose group, mitochondrial Ca2+ bufferin g was affected in cerebellum but not in cortex or striatum. Similarly, tota l cerebellar PKC activity was decreased significantly while membrane-bound PKC activity was significantly elevated at 10 and 30 mg/kg. PKC activity wa s not altered either in cortex or the striatum. Neurotransmitter levels in striatum or cortex were slightly altered in PCB-exposed rats compared to co ntrols. Furthermore, repeated oral administration of Aroclor 1254 to rats d id not significantly alter forebrain tyrosine hydroxylase immunoreactivity or enzymatic activity. Circulating T-4 (total and free) concentrations were severely depressed at both doses in Aroclor 1254-exposed rats compared to control rats, suggesting a severe hypothyroid state. These results indicate that (1) in vivo exposure to a PCB mixture can produce changes in second m essenger systems that are similar to those observed after in vitro exposure of neuronal cell cultures; (2) second messenger systems seem to be more se nsitive than alterations in neurotransmitter levels or tyrosine hydroxylase involved in dopamine synthesis during repeated exposure to PCBs; and (3) t he observed motor activity changes were independent of changes in striatal dopamine levels.