Animals; Apoptosis; Apoptosis: drug effects; Blotting; Cell Survival; Cell Survival: drug effects; Cells; Cerebellum; Cerebellum: drug effects; Cerebellum: pathology; Cultured; Cyanobacteria; Cyanobacteria: metabolism; Dose-Response Relationship; Drug; Fluorescence; Inbred BALB C; Mice; Microcystins; Microcystins: chemistry; Microcystins: toxicity; Microscopy; Neurites; Neurites: drug effects; Neurites: pathology; Neurons; Neurons: drug effects; Neurons: pathology; Newborn; Phosphorylation; Western; tau Proteins; tau Proteins: metabolism
Abstract :
[en] Cyanobacterial microcystins (MCs) represent a toxin group with > 100 variants, requiring active uptake into cells via organic anion-transporting polypeptides, in order to irreversibly inhibit serine/threonine-specific protein phosphatases. MCs are a human health hazard with repeated occurrences of severe poisonings. In the well-known human MC intoxication in Caruaru, Brazil (1996), patients developed signs of acute neurotoxicity, e.g., deafness, tinnitus, and intermittent blindness, as well as subsequent hepatotoxicity. The latter data, in conjunction with some animal studies, suggest that MCs are potent neurotoxins. However, there is little data to date demonstrating MC neuron-specific toxicity. MC exposure-induced cytotoxicity, caspase activity, chromatin condensation, and microtubule-associated Tau protein hyperphosphorylation (epitopes serine199/202 and serine396) were determined. Neurite degeneration was analyzed with confocal microscopy and neurite length determined using image analysis. MC-induced apoptosis was significantly increased by MC-LF and MC-LW, however, only at high concentrations (≥ 3µM), whereas significant neurite degeneration was already observed at 0.5µM MC-LF. Moreover, sustained hyperphosphorylation of Tau was observed with all MC congeners. The concentration- and congener-dependent mechanisms observed suggest that low concentrations of MC-LF and MC-LW can induce subtle neurodegenerative effects, reminiscent of Alzheimer's disease type human tauopathies, and thus should be taken more seriously with regard to potential human health effects than the apical cytotoxicity (apoptosis or necrosis) demonstrated at high MC concentrations.
Disciplines :
Neurology
Author, co-author :
Feurstein, Daniel
Stemmer, Kerstin
Kleinteich, Julia ; Université de Liège - ULiège > Département des sciences de la vie > Physiologie et génétique bactériennes
Speicher, Tobias
Dietrich, Daniel R.
Language :
English
Title :
Microcystin congener- and concentration-dependent induction of murine neuron apoptosis and neurite degeneration.
Briand, J. F., Jacquet, S., Bernard, C., and Humbert, J. F. (2003). Health hazards for terrestrial vertebrates from toxic cyanobacteria in surface water ecosystems. Vet. Res. 34, 361-377.
Bronger, H., Konig, J., Kopplow, K., Steiner, H. H., Ahmadi, R., Herold-Mende, C., Keppler, D., and Nies, A. (2005). ABCC drug efflux pumps and organic anion uptake transporters in human gliomas and the blood-tumor barrier. Cancer Res. 65, 11419-11428.
Carmichael, W. W., Azevedo, S. M., An, J. S., Molica, R. J., Jochimsen, E. M., Lau, S., Rinehart, K. L., Shaw, G. R., and Eaglesham, G. K. (2001). Human fatalities from cyanobacteria: Chemical and biological evidence for cyanotoxins. Environ. Health Perspect. 109, 663-668.
Cribbs, D. H., Poon, W. W., Rissman, R. A., and Blurton-Jones, M. (2004). Caspase-mediated degeneration in Alzheimer's disease. Am. J. Pathol. 165, 353-355.
Dahlin, A., Royall, J., Hohmann, J. G., and Wang, J. (2009). Expression profiling of the solute carrier gene family in the mouse brain. J. Pharmacol. Exp. Ther. 329, 558-570.
Dietrich, D. R., Fischer, A., Michel, C., and Hoeger, S. J. (2008). Toxin mixture in cyanobacterial blooms-a critical comparison of reality with current procedures employed in human health risk assessment. Adv. Exp. Med. Biol. 619, 885-912.
Enerson, B. E., and Drewes, L. R. (2006). The rat blood-brain barrier transcriptome. J. Cereb. Blood Flow Metab. 26, 959-973.
Falconer, I. R., and Humpage, A. R. (2005). Health risk assessment of cyanobacterial (blue-green algal) toxins in drinking water. Int. J. Environ. Res. Public Health 2, 43-50.
Falconer, I. R., Smith, J. V., Jackson, A. R., Jones, A., and Runnegar, M. T. (1988). Oral toxicity of a bloom of the Cyanobacterium Microcystis aeruginosa administered to mice over periods up to 1 year. Toxicol. Environ. Health 24, 291-305.
Feurstein, D., Holst, K., Fischer, A., and Dietrich, D. R. (2009). Oatpassociated uptake and toxicity of microcystins in primary murine whole brain cells. Toxicol. Appl. Pharmacol. 234, 247-255.
Feurstein, D., Kleinteich, J., Heussner, A. H., Stemmer, K., and Dietrich, D. R. (2010). Investigation of microcystin congener-dependent uptake into primary murine neurons. Environ. Health Perspect. 118, 1370-1375.
Fischer, A., Hoeger, S. J., Stemmer, K., Feurstein, D., Knobeloch, D., Nussler, A., and Dietrich, D. R. (2010). The role of organic anion transporting polypeptides (OATPs/SLCOs) in the toxicity of different microcystin congeners in vitro: A comparison of primary human hepatocytes and OATP-transfected HEK293 cell. Toxicol. Appl. Pharmacol. 245, 9-20.
Fischer, W. J., Altheimer, S., Cattori, V., Meier, P. J., Dietrich, D. R., and Hagenbuch, B. (2005). Organic anion transporting polypeptides expressed in liver and brain mediate uptake of microcystin. Toxicol. Appl. Pharmacol. 203, 257-263.
Fladmark, K. E., Brustugun, O. T., Hovland, R., Boe, R., Gjertsen, B. T., Zhivotovsky, B., and Doskeland, S. O. (1999). Ultrarapid caspase-3 dependent apoptosis induction by serine/threonine phosphatase inhibitors. Cell Death Differ. 6, 1099-1108.
Fladmark, K. E., Brustugun, O. T., Mellgren, G., Krakstad, C., Boe, R., Vintermyr, O. K., Schulman, H., and Doskeland, S. O. (2002). Ca2+/calmodulin-dependent protein kinase II is required for microcystin-induced apoptosis. J. Biol. Chem. 277, 2804-2811.
Guo, H., Albrecht, S., Bourdeau, M., Petzke, T., Bergeron, C., and LeBlanc, A. C. (2004). Active caspase-6 and caspase-6-cleaved tau in neuropil threads, neuritic plaques, and neurofibrillary tangles of Alzheimer's disease. Am. J. Pathol. 165, 523-531.
Hagenbuch, B., and Meier, P. J. (2003). The superfamily of organic anion transporting polypeptides. Biochim. Biophys. Acta 1609, 1-18.
Hastie, C. J., Borthwick, E. B., Morrison, L. F., Codd, G. A., and Cohen, P. T. (2005). Inhibition of several protein phosphatases by a non-covalently interacting microcystin and a novel cyanobacterial peptide, nostocyclin. Biochim. Biophys. Acta 1726, 187-193.
Iqbal, K., Liu, F., Gong, C. X., Alsonso, A., and Grundke-Iqbal, I. (2009). Mechansims of tau-induced neurodegeneration. Acta Neuropathol. 118, 53-69.
Komatsu, M., Furukawa, T., Ikeda, R., Takumi, S., Nong, Q., Aoyama, K., Akiyama, S., Keppler, D., and Takeuchi, T. (2007). Involvement of mitogenactivated protein kinase signaling pathways in microcystin-LR-induced apoptosis after its selective uptake mediated by OATP1B1 and OATP1B3. Toxicol. Sci. 97, 407-416.
Liu, F., Grundke-Iqbal, I., Iqbal, K., and Gong, C. X. (2005). Contributions of protein phosphatases PP1, PP2A, PP2B and PP5 to the regulation of tau phosphorylation. Eur. J. Neurosci. 22, 1942-1950.
Lu, H., Choudhuri, S., Ogura, K., Csanaky, I. L., Lei, X., Cheng, X., Song, P., and Klaassen, C. D. (2008). Characterization of organic anion transporting polypeptide 1b2-null mice: Essential role in hepatic uptake/toxicity of phalloidin and microcystin-LR. Toxicol. Sci. 103, 35-45.
MacKintosh, C., Beattie, K. A., Klumpp, S., Cohen, P., and Codd, G. A. (1990). Cyanobacterial microcystin-LR is a potent and specific inhibitor of protein phosphatases 1 and 2A from both mammals and higher plants. FEBS Lett. 264, 187-192.
Maidana, M., Carlis, V., Galhardi, F. G., Yunes, J. S., Geracitano, L. A., Monserrat, J. M., and Barros, D. M. (2006). Effects of microcystins over short- and long-term memory and oxidative stress generation in hippocampus of rats. Chem. Biol. Interact. 159, 223-234.
Meriluoto, J. A., Nygard, S. E., Dahlem, A. M., and Eriksson, J. E. (1990). Synthesis, organotropism and hepatocellular uptake of two tritium-labeled epimers of dihydromicrocystin-LR, a cyanobacterial peptide toxin analog. Toxicon 28, 1439-1446.
Meriluoto, J. A., and Spoof, L. E. (2008). Cyanotoxins: Sampling, sample processing and toxin uptake. Adv. Exp. Med. Biol. 619, 483-499.
Miller, D. S. (2010). Regulation of P-glycoprotein and other ABC drug transporters at the blood-brain barrier. Trends Pharmacol. Sci. 31, 246-254.
Monks, N. R., Liu, S., Xu, Y., Yu, H., Bendelow, A. S., and Moscow, J. A. (2007). Potent cytotoxicity of the phosphatase inhibitor microcystin LR and microcystin analogues in OATP1B1- and OATP1B3-expressing HeLa cells. Mol. Cancer Ther. 6, 587-598.
Nishiwaki, R., Ohta, T., Sueoka, E., Suganuma, M., Harada, K., Watanabe, M. F., and Fujiki, H. (1994). Two significant aspects of microcystin-LR: Specific binding and liver specificity. Cancer Lett. 83, 283-289.
Pei, J. J., Gong, C. X., An, W. L., Winblad, B., Cowburn, R. F., Grundke-Iqbal, I., and Iqbal, K. (2003). Okadaic-acid-induced inhibition of protein phosphatase 2A produces activation of mitogen-activated protein kinases ERK1/2, MEK1/2, and p70 S6, similar to that in Alzheimer's disease. Am. J. Pathol. 163, 845-858.
Pouria, S., de Andrade, A., Barbosa, J., Cavalcanti, R. L., Barreto, V. T., Ward, C. J., Preiser, W., Poon, G. K., Neild, G. H., and Codd, G. A. (1998). Fatal microcystin intoxication in haemodialysis unit in Caruaru, Brazil. Lancet 352, 21-26.
Rametti, A., Esclaire, F., Yardin, C., and Terro, F. (2004). Linking alterations in tau phosphorylation and cleavage during neuronal apoptosis. J. Biol. Chem. 279, 54518-54528.
Ray, R. M., Bhattacharya, S., and Johnson, L. R. (2005). Protein phosphatase 2A regulates apoptosis in intestinal epithelial cells. J. Biol. Chem. 280, 31091-31100.
Rudrabhatla, P., Albers, W., and Pant, H. C. (2009). Peptidyl-prolyl isomerase 1 regulates protein phosphatase 2A-mediated topographic phosphorylation of neurofilament proteins. J. Neurosci. 29, 14869-14880.
Sahara, N., Murayama, M., Lee, B., Park, J. M., Lagalwar, S., Binder, L. I., and Takashima, A. (2008). Active c-jun N-terminal kinase induces caspase cleavage of tau and additional phosphorylation by GSK-3b is required for tau aggregation. Eur. J. Neurosci. 27, 2897-2906.
Stewart, I., Seawright, A. A., and Shaw, G. R. (2008). Cyanobacterial poisoning in livestock, wild mammals and birds-an overview. Adv. Exp. Med. Biol. 619, 613-637.
Teixera, M., Costa, M., Carvalho, V., Pereira, M., and Hage, E. (1993). Gastroenteritis epidemic in the area of the Itaparica dam, Bahia, Brazil. Bull. Pan Am. Health Organ. 27, 244-253.
Yoon, S., Choi, J., Yoon, J., Huh, J. W., and Kim, D. (2006). Okadaic acid induces JNK activation, bim overexpression and mitochondrial dysfunction in cultured rat cortical neurons. Neurosci. Lett. 394, 190-195.
