Toxicological Research

Korean Society of Toxicology & Korea Environmental Mutagen Society (한국독성학회)
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Chlorination of ortho-position on Polychlorinated Biphenyls Increases Protein Kinase C Activity in Neuronal Cells

  • Lee, Youn-Ju (Department of Pharmacology and Toxicology, School of Medicine, Catholic University of Daegu) ;
  • Yang, Jae-Ho (Department of Pharmacology and Toxicology, School of Medicine, Catholic University of Daegu)
  • Received : 2012.04.03
  • Accepted : 2012.04.18
  • Published : 2012.06.30
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Abstract

Polychlorinated biphenyls (PCBs) are persistent and bioaccumulative environmental pollutants. Recently, it is suggested that neurotoxic effects such as motor dysfunction and impairment in memory and learning have been associated with PCB exposure. However, structure relationship of PCB congeners with neurotoxic effects remains unknown. Since PKC signaling pathway is implicated in the modulation of motor behavior as well as learning and memory and the role of PKC are subspecies-specific, we attempted to study the effects of structurally distinct PCBs on the total PKC activity as well as subspecies of PKC in cerebellar granule cell culture model. Cells were exposed to 0, 25 and 50 ${\mu}M$ of PCB-126, PCB-169, PCB-114, PCB-157, PCB-52 and PCB-4 for 15 min. Cells were subsequently analyzed by [$^3H$] phorbol ester binding assay or immunoblotted against PKC-${\alpha}$ and -${\varepsilon}$ monoclonal antibodies. While non-dioxin-like-PCB (PCB-52 and PCB-4) induced a translocation of PKC-${\alpha}$ and -${\varepsilon}$ from cytosol to membrane fraction, dioxin-like PCBs (PCB-126, -169, -114, -157) had no effects. [$^3H$] Phorbol ester binding assay also revealed structure-dependent increase similar to translocation of PKC isozymes. While PCB-4 induced translocation of PKC-${\alpha}$ and -${\varepsilon}$ was inhibited by ROS inhibitor, the pattern of translocation was not affected in presence of AhR inhibitor. It is suggested that PCB-4-induced PKC activity may not be mediated via AhR-dependent pathway. Taken together, our findings suggest that chlorination of ortho-position in PCB may be a critical structural moiety associated with neurotoxic effects, which may be preferentially mediated via non-AhR-dependent pathway. Therefore, the present study may contribute to understanding the neurotoxic mechanism of PCBs as well as providing a basis for establishing a better neurotoxic assessment.

Keywords

References

  1. Carpenter, D.O. (1998). Polychlorinated biphenyls and human health. Int. J. Occup. Med. Environ. Health, 11, 291-303.
  2. Chen, C., Kano, M., Abeliovich, A., Chen, L., Bao, S., Kim, J.J., Hashimoto, K., Thompson, R.F. and Tonegawa, S. (1995). Impaired motor coordination correlates with persistent multiple climbing fiber innervation in PKC gamma mutant mice. Cell, 83, 1233-1242. https://doi.org/10.1016/0092-8674(95)90148-5
  3. Hama, T., Huang, K.P. and Guroff, G. (1986). Protein kinase C as a component of a nerve growth factor-sensitive phosphorylation system in PC12 cells. Proc. Natl. Acad. Sci. USA., 83, 2353- 2357. https://doi.org/10.1073/pnas.83.8.2353
  4. Jacobson, J.L. and Jacobson, S.W. (1996). Intellectual impairment in children exposed to polychlorinated biphenyls in utero. N. Engl. J. Med., 335, 783-789. https://doi.org/10.1056/NEJM199609123351104
  5. Kodavanti, P.R., Shafer, T.J., Ward, T.R., Mundy, W.R., Freundrich, T., Harry, G.J. and Tilson, H.A. (1994). Differential effects of polychlorinated biphenyl congeners on phosphoinositide hydrolysis and protein kinase C translocation in rat cerebellar granule cells. Brain Res., 662, 75-82. https://doi.org/10.1016/0006-8993(94)90797-8
  6. Kodavanti, P.R., Ward, T.R., McKinney, J.D., Waller, C.L. and Tilson, H.A. (1996). Increased [3H]phorbol ester binding in rat cerebellar granule cells and inhibition of 45Ca2+ sequestration in rat cerebellum by polychlorinated diphenyl ether congeners and analogs: structure-activity relationships. Toxicol. Appl. Pharmacol., 138, 251-261. https://doi.org/10.1006/taap.1996.0123
  7. Kodavanti, P.R., Shin, D.S., Tilson, H.A. and Harry, G.J. (1993). Comparative effects of two polychlorinated biphenyl congeners on calcium homeostasis in rat cerebellar granule cells. Toxicol. Appl. Pharmacol., 123, 97-106. https://doi.org/10.1006/taap.1993.1226
  8. Manji, H.K., Etcheberrigaray, R., Chen, G. and Olds, J.L. (1993). Lithium decreases membrane-associated protein kinase C in hippocampus: Selectivity for the ${\alpha}$ isozyme. J. Neurochem., 61, 2303-2310. https://doi.org/10.1111/j.1471-4159.1993.tb07474.x
  9. Mariussen, E., Myhre, O., Reistad, T. and Fonnum, F. (2002). The polychlorinated biphenyl mixture aroclor 1254 induces death of rat cerebellar granule cells: The involvement of the N-methyl- D-aspartate receptor and reactive oxygen species. Toxicol. Appl. Pharmacol., 179, 137-144. https://doi.org/10.1006/taap.2002.9353
  10. Matsushima, H., Shimohama, S., Chachin, M., Taniguchi, T. and Kimura, J. (1996). $Ca^{2+}$-dependent and $Ca^{2+}$-independent protein kinase C changes in the brain of patients with Alzheimer's disease. J. Neurochem., 67, 317-323.
  11. Meiri, K.F., Willard, M. and Johnson, M.I. (1988). Distribution and phosphorylation of the growth-associated protein GAP-43 in regenerating sympathetic neurons in culture. J. Neurosci., 8, 2571-2581
  12. Molchan, S.E., Sunderland, T., McIntosh, A.R. and Schreurs, B.G. (1994). A functional anatomical study of associative learning in humans. Proc. Natl. Acad. Sci. USA., 91, 8122-8126. https://doi.org/10.1073/pnas.91.17.8122
  13. Nishizuka, Y. (1988). The molecular heterogeneity of protein kinase C and its implications for cellular regulation. Nature, 334, 661-665. https://doi.org/10.1038/334661a0
  14. Schantz, S.L., Moshtaghian, J. and Ness, D.K. (1995). Spatial learning deficits in adult rats exposed to ortho-substituted PCB congeners during gestation and lactation Fundam. Appl. Toxicol., 26, 117-126. https://doi.org/10.1006/faat.1995.1081
  15. Son, H., Madelian, V. and Carpenter, D.O. (1996). The translocation and involvement of protein kinase C in mossy fiber-CA3 long-term potentiation in hippocampus of the rat brain. Brain Res., 739, 282-292. https://doi.org/10.1016/S0006-8993(96)00836-0
  16. Swanson, G.M., Ratcliffe, H.E. and Fischer, L.J. (1995). Human exposure to polychlorinated biphenyls (PCBs): a critical assessment of the evidence for adverse health effects. Regul. Toxicol. Pharmacol., 21, 136-150. https://doi.org/10.1006/rtph.1995.1018
  17. Vaccarino, F.M., Liljequist, S. and Tallman, J.F. (1991). Modulation of protein kinase C translocation by excitatory and inhibitory amino acids in primary cultures of neurons. J. Neurochem., 57, 391-396. https://doi.org/10.1111/j.1471-4159.1991.tb03765.x
  18. Yang, J.H. and Kodavanti, P.R. (2001). Possible molecular targets of halogenated aromatic hydrocarbons in neuronal cells. Biochem. Biophys. Res. Commun., 280, 1372-1377. https://doi.org/10.1006/bbrc.2001.4283
  19. Yang, J.H., Vogel, C. and Abel, J. (1999). A malignant transformation of human cells by 2,3,7,8-tetrachlorodibenzo-p-dioxin exhibits altered expressions of growth regulatory factors. Carcinogenesis, 20, 13-18. https://doi.org/10.1093/carcin/20.1.13