Molecular & Cellular Toxicology

The Korean Society of Toxicogenomics and Toxicoproteomics (대한독성유전 단백체학회)
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Identification of Genes Associated with Early and Late Response of Methylmercury in Human Neuroblastoma Cell Line

  • Kim, Youn-Jung (Cellular and Molecular Toxicology Laboratory, Korea Institute of Science & Technology) ;
  • Kim, Mi-Soon (Cellular and Molecular Toxicology Laboratory, Korea Institute of Science & Technology) ;
  • Jeon, Hee-Kyung (Cellular and Molecular Toxicology Laboratory, Korea Institute of Science & Technology) ;
  • Ryu, Jae-Chun (Cellular and Molecular Toxicology Laboratory, Korea Institute of Science & Technology)
  • Published : 2008.06.30
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Abstract

Methylmercury (MeHg) is known to have devastating effects on the mammalian nervous system. In order to characterize the mechanism of MeHg-induced neurotoxicity, we investigated the analysis of transcriptional profiles on human 8k cDNA microarray by treatment of $1.4{\mu}M$ MeHg at 3, 12, 24 and 48h in human neuroblastoma SH-SY5Y cell line. Some of the identified genes by MeHg treatment were significant at early time points (3h), while that of others was at late time points (48h). The early response genes that may represent those involved directly in the MeHg response included pantothenate kinase 3, a kinase (PRKA) anchor protein (yotiao) 9, neurotrophic tyrosine kinase, receptor, type 2 gene, associated with NMDA receptor activity regulation or perturbations of central nervous system homeostasis. Also, when SH-SY5Y cells were subjected to a longer exposure (48h), a relative increase was noted in a gene, glutamine-fructose-6-phosphate transaminase 1, reported that overexpression of this gene may lead to the increased resistance to MeHg. To confirm the alteration of these genes in cultured neurons, we then applied real time-RT PCR with SYBR green. Thus, this result suggests that a neurotoxic effect of the MeHg might be ascribed that MeHg alters neuronal receptor regulation or homeostasis of neuronal cells in the early phase. However, in the late phase, it protects cells from neurotoxic effects of MeHg.

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References

  1. Zheng, W., Perry, D. F., Nelson, D. L. & Aposhian, H. V. Choroid plexus protects cerebrospinal fluid against toxic metals. FASEB J 5:2188-2193 (1991) https://doi.org/10.1096/fasebj.5.8.1850706
  2. Davidson, P. W., Myers, G. J. & Weiss, B. Mercury exposure and child development outcomes. Pediatrics 113(4 suppl):1023-1029 (2004)
  3. Choi, B. H. The effects of methylmercury on the developing brain. Prog Neurobiol 32:447-470 (1989)
  4. Vogel, D. G., Margolis, R. L. & Mottet, N. K. The effects of methylmercury binding to microtubules. Toxicol Appl Pharmacol 80:473-486 (1985) https://doi.org/10.1016/0041-008X(85)90392-8
  5. Naganuma, A. et al. GFAT as a target molecule of methylmercury toxicity in Saccharomyces cerevisiae. FASEB J 14:968-972 (2000) https://doi.org/10.1096/fasebj.14.7.968
  6. Kim, Y. J., Chai, Y. G. & Ryu, J. C. Selenoprotein W as molecular target of methylmercury in human neuronal cells is down-regulated by GSH depletion. Biochem Biophys Res commun 300:1095-1102 (2005)
  7. Wilke, R. A., Kolbert, C. P., Rahimi, R. A. & Windebank, A. J. Thylmercury induces apoptosis in cultured rat dorsal root ganglion neurons. Neurotoxicology 24: 369-378 (2003) https://doi.org/10.1016/S0161-813X(03)00032-9
  8. Tu, H., Tang, T. S., Wang, Z. & Bezprozvanny, I. Association of type 1 inositol 1,4,5-trisphosphate receptor with AKAP9 (Yotiao) and protein kinase A. J Biol Chem 279:19375-19382 (2004) https://doi.org/10.1074/jbc.M313476200
  9. Lin, J. W. et al. Yotiao, a novel protein of neuromuscular junction and brain that interacts with specific splice variants of NMDA receptor subunit NR1. J Neurosci 18:2017-2027 (1998) https://doi.org/10.1523/JNEUROSCI.18-06-02017.1998
  10. Miura, N. et al. 1999. Overexpression of L-glutamine: D-fructose-6-phosphate amidotransferase provides resistance to methylmercury in Saccharomyces cerevisiae. FEBS Lett 458:215-218 (1998) https://doi.org/10.1016/S0014-5793(99)01158-8
  11. Caricasole, A. et al. Induction of Dickkopf-1, a negative modulator of the Wnt pathway, is associated with neuronal degeneration in Alzheimer's brain. J Neurosci 24:6021-6027 (2004) https://doi.org/10.1523/JNEUROSCI.1381-04.2004
  12. Hwang, G. W., Furuchi, T. & Naganuma, A. A. Ubiquitin- proteasome system is responsible for the protection of yeast and human cells against methylmercury. FASEB J 16:709-711 (2002) https://doi.org/10.1096/fj.01-0899fje
  13. Busselberg, D. Calcium channels as target sites of heavy metals. Toxicol ett 82-83:255-261 (1995) https://doi.org/10.1016/0378-4274(95)03559-1
  14. Beilstein, M. A., Vendeland, S. C., Barofsky, E., Jensen, O. N. & Whanger, P. D. Selenoprotein W of rat muscle binds glutathione and an unknown small molecular weight moiety. J Inorg Biochem 61:117-124 (1996) https://doi.org/10.1016/0162-0134(95)00045-3
  15. Gu, Q. P., Beilstein, M. Barofsky, A., Ream, E. W. & Whanger, P. D. Purification, characterization, and glutathione binding to selenoprotein W from monkey muscle. Arch Biochem Biophys 361:25-33 (1999) https://doi.org/10.1006/abbi.1998.0949
  16. Yeh, J. Y., Gu, Q. P., Beilstein, M. A., Forsberg, N. E. & Whanger, P. D. Selenium influences tissue levels of selenoprotein W in sheep. J Nutr 127:394-402 (1997)
  17. Yang, Y. H. et al. Normalization for cDNA microarray data: a robust composite method addressing single and multiple slide systematic variation. Nucleic Acids Res 30:e15 (2002) https://doi.org/10.1093/nar/30.4.e15