Alterations in brain protein kinase C isoforms following developmental exposure to a polychlorinated biphenyl mixture.
PCBs have been shown to alter several neurochemical end-points and are implicated in the etiology of some neurological diseases. Recent in vivo studies from our laboratory indicated that developmental exposure to a commercial PCB mixture, Aroclor 1254, caused perturbations in calcium homeostasis and changes in protein kinase C (PKC) activities in rat brain. However, it is not known which molecular substances are targets for PCB-induced developmental neurotoxicity. Since the PKC signaling pathway has been implicated in the modulation of motor behavior as well as learning and memory, and the roles of PKC are subspecies specific, the present study attempted to analyze the effects on selected PKC isozymes in the cerebellum and the hippocampus following developmental exposure (gestational day 6 through postnatal day 21) to a PCB mixture, Aroclor 1254. The results indicated that the developmental exposure to PCBs caused significant hypothyroxinemia and age-dependent alterations in the translocation of PKC isozymes; the effects were greatly significant at postnatal day (PND) 14. Immunoblot analysis of PKC-alpha (alpha) from both cerebellum and hippocampus revealed that developmental exposure to Aroclor 1254 caused a significant decrease in cytosolic fraction and an increase in particulate fraction. There was no significant difference between these two brain regions on the level of fractional changes. However, the ratio between the fractions (particulate/cytosol) from cerebellum only was increased in a dose-dependent manner. Analysis of PKC-gamma (gamma) in cerebellum on PND14 showed a decrease in cytosolic fraction in both dose groups and an increase in particulate fraction at high dose (6 mg/kg) only. The ratio between the two fractions was increased in a dose-dependent manner. In the hippocampus, there was a significant decrease in PKC-gamma in cytosolic fraction of the high-dose group and a significant increase in particulate fraction of the low-dose group. But, the ratio between the fractions showed a significant increase (2.6-fold increase in high dose on PND14). Analysis of PKC-epsilon (epsilon) in cerebellum showed a significant decrease in cytosolic fraction at PND14, while particulate PKand an increase in ratio between fractions at 6 mg/kg on PND14. The results from this study indicate that the patterns of subcellular distributions of PKC isoforms following a developmental PCB exposure were PKC isozyme- and developmental stage-specific. Considering the significant role of PKC signaling in motor behavior, learning and memory, it is suggested that altered subcellular distribution of PKC isoforms at critical periods of brain development may be a possible mechanism of PCB-induced neurotoxic effects and that PKC-alpha, gamma, and epsilon may be among the target molecules implicated with PCB-induced neurological impairments during developmental exposure. It is believed that this is the first report successfully identifying PKC isoforms responding to PCBs during developmental exposure.
Yang
Jae-Ho
JH
National Academy of Sciences, National Research Council, Washington, DC, USA.
Derr-Yellin
Ethel C
EC
Kodavanti
Prasada Rao S
PR
D000375:Aging / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development; D002531:Cerebellum / Q000187:drug effects / Q000201:enzymology / Q000254:growth & development; D003600:Cytosol / Q000187:drug effects / Q000201:enzymology; D004305:Dose-Response Relationship, Drug; D004781:Environmental Exposure / Q000009:adverse effects*; D006624:Hippocampus / Q000187:drug effects / Q000201:enzymology / Q000254:growth & development; D007527:Isoenzymes / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology; D009498:Neurotoxins / Q000633:toxicity*; D011078:Polychlorinated Biphenyls / Q000633:toxicity*; D011493:Protein Kinase C / Q000187:drug effects* / Q000378:metabolism; D051571:Protein Kinase C-alpha; D051744:Protein Kinase C-epsilon; D051381:Rats; D020318:Rats, Long-Evans; D013347:Subcellular Fractions / Q000187:drug effects / Q000201:enzymology
D007527:Isoenzymes; D009498:Neurotoxins; D011078:Polychlorinated Biphenyls; C497257:Prkce protein, rat; C087857:protein kinase C gamma; D011493:Protein Kinase C; D051571:Protein Kinase C-alpha; D051744:Protein Kinase C-epsilon