Interaction of methylmercury with microtubules in cultured cells and in vitro

Sager, Polly R.; Doherty, Richard A.; Olmsted, J.B.

doi:10.1016/0014-4827(83)90331-2

Cited by 104 publications

(27 citation statements)

References 24 publications

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“…Early effects on the neuritic processes found during neuronal apoptosis (Mills et al, 1998) are also consistent with the findings of Choi et al (1981) who described separation of degenerated neurites from neuronal cell bodies and disappearance of microtubules in human organotypic cultures of fetal cerebrum exposed to concentrations of MeHg 20-to 200-fold higher than those used in the present study. Other studies have demonstrated that MeHg promotes the depolymerization of cerebral microtubules in vitro (Abe et al, 1975) and microtubule disruption in several cell models (Prasad et al, 1979;Sager et al, 1983;Miura et al, 1984;Cadrin et al, 1988;Wasteneys et al, 1988;Roy et al, 1991;Graff et al, 1993). Our results further support the susceptibility of microtubules to MeHg-induced disassembly; however, the finding that, in our experimental model, taxol was ineffective toward the apoptotic action of MeHg, makes it unlikely that microtubule breakdown is directly involved in the initiation of MeHg-induced apoptotic cascade.…”

Section: Effects Of Drugs On Mehg-induced Apoptosissupporting

confidence: 59%

“…To date, MeHg has been shown to possess high affinity for tubulin sulfhydryl groups (Vogel et al, 1985), to depolymerize cerebral microtubules in vitro (Abe et al, 1975) and to directly inhibit in vitro microtubule assembly (Sager et al, 1983). Moreover, MeHg has been reported to promote microtubule disruption in several cell models, including human fibroblasts (Sager et al, 1983), mouse splenic lymphocytes (Roy et al, 1991), neuroblastoma (Prasad et al, 1979), glioma cells (Prasad et al, 1979;Miura et al, 1984) and embryonal carcinoma cells Wasteneys et al, 1988;Graff et al, 1993). Evidence supporting a role for cytoskeletal alterations and microtubule disruption in the onset of CGC apoptosis has been recently provided by Bonfoco et al (1995a), whose results indicated that an initial cytoskeletal damage, such as that caused by a microtubule disrupting agent, is sufficient to trigger the apoptotic degeneration of these neurons (Bonfoco et al, 1995a).…”

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confidence: 99%

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Early acute necrosis, delayed apoptosis and cytoskeletal breakdown in cultured cerebellar granule neurons exposed to methylmercury

et al. 2000

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Cerebellar granule cells (CGCs) are a sensitive target for methylmercury (MeHg) neurotoxicity. In vitro exposure of primary cultures of rat CGCs to MeHg resulted in a time- and concentration-dependent cell death. Within 1 hr exposure, MeHg at 5-10 microM caused impairment of mitochondrial activity, de-energization of mitochondria and plasma membrane lysis, resulting in necrotic cell death. Lower MeHg concentrations (0.5-1 microM) did not compromise cell viability, mitochondrial membrane potential and function at early time points. Later, however, the cells progressively underwent apoptosis and 100% cell death was reached by 18 hr treatment. Neuronal network fragmentation and microtubule depolymerization were detected as early as within 1.5 hr of MeHg (1 microM) exposure, long before the occurrence of nuclear condensation (6-9 hr). Neurite damage worsened with longer exposure time and proceeded to the complete dissolution of microtubules and neuronal processes (18 hr). Microtubule stabilization by taxol did not prevent MeHg-induced delayed apoptosis. Similarly ineffective were the caspase inhibitors z-VAD-fluoromethylketone and z-DEVD-chloromethylketone, the L-type calcium channel inhibitor nifedipine, the calcium chelator EGTA and BAPTA, and the NMDA receptor antagonist MK-801. On the other hand, insulin-like growth factor-I partially rescued CGCs from MeHg-triggered apoptosis. Altogether these results provide evidence that the intensity of MeHg insult is decisive in the time of onset and the mode of neuronal death that follows, i.e., necrosis vs. apoptosis, and suggest that cytoskeletal breakdown and deprivation of neurotrophic support play a role in MeHg delayed toxicity.

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Section: Effects Of Drugs On Mehg-induced Apoptosissupporting

confidence: 59%

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confidence: 99%

Early acute necrosis, delayed apoptosis and cytoskeletal breakdown in cultured cerebellar granule neurons exposed to methylmercury

et al. 2000

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“…The arresting of the G2/Mphase because of microtubules being disrupted may be an important factor in MeHg leading to apoptosis . MeHg has long been known to be a potent inhibitor of microtubule polymerization, and this effect is presumably caused by the S-mercuration of the microtubules by MeHg (Abe et al, 1975;Sager et al, 1983;Vogel et al, 1985Vogel et al, , 1989. Vogel et al (1989) found that there is a class of binding sites that have high affinities for MeHg on tubulin and that MeHg binds to tubulin stoichiometrically within microtubules.…”

Section: The Disruption Of Microtubules and S-mercurationmentioning

confidence: 99%

<i>S</i>-Mercuration of cellular proteins by methylmercury and its toxicological implications

2014

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-The accumulation of methylmercury (MeHg) through the daily consumption of large predatory fish poses potential health risks. MeHg has been found to cause Minamata disease, but the full nature of MeHg toxicity remains unclear. Because of its chemical properties, MeHg covalently binds to cellular proteins through their reactive thiols, referred to as S-mercuration, resulting in the formation of protein adducts. In this review, we summarize how the S-mercuration of cellular proteins could be involved in the major mechanisms that have been suggested to underlie MeHg toxicity. Additionally, we introduce our attempts to identify cases of S-mercuration for the research to reveal the true nature of MeHg toxicity.

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“…The genotoxicity of mercury is generally attributed to its binding with tubulin-SH, causing the impairment of spindle function and chromosome segregational error during cell division (Onfelt 1983, Sager et al 1983). This has been regarded as the cause of the increased frequency of polyploidy and aneuploidy in Allium and Drosophila (Ramel & Magnusson 1969, 1979, Fiskesjo 1988.…”

Section: Discussionmentioning

confidence: 99%

Cytogenetic damage related to low levels of methyl mercury contamination in the Brazilian Amazon

Amorim

Mergler

Bahia

et al. 2000

An. Acad. Bras. Ciênc.

105

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The mercury rejected in the water system, from mining operations and lixiviation of soils after deforestation, is considered to be the main contributors to the contamination of the ecosystem in the Amazon Basin. The objectives of the present study were to examine cytogenetic functions in peripheral lymphocytes within a population living on the banks of the Tapajós River with respect to methylmercury (MeHg) contamination, using hair mercury as a biological indicator of exposure. Our investigation shows a clear relation between methylmercury contamination and cytogenetic damage in lymphocytes at levels well below 50 micrograms/gram, the level at which initial clinical signs and symptoms of mercury poisoning occur. The first apparent biological effect with increasing MeHg hair level was the impairment of lymphocyte proliferation measured as mitotic index (MI). The relation between mercury concentration in hair and MI suggests that this parameter, an indicator of changes in lymphocytes and their ability to respond to culture conditions, may be an early marker of cytotoxicity and genotoxicity in humans and should be taken into account in the preliminary evaluation of the risks to populations exposed in vivo. This is the first report showing clear cytotoxic effects of long-term exposure to MeHg. Although the results strongly suggest that, under the conditions examined here, MeHg is both a spindle poison and a clastogen, the biological significance of these observations are as yet unknown. A long-term follow-up of these subjects should be undertaken.

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Interaction of methylmercury with microtubules in cultured cells and in vitro

Cited by 104 publications

References 24 publications

Early acute necrosis, delayed apoptosis and cytoskeletal breakdown in cultured cerebellar granule neurons exposed to methylmercury

Early acute necrosis, delayed apoptosis and cytoskeletal breakdown in cultured cerebellar granule neurons exposed to methylmercury

<i>S</i>-Mercuration of cellular proteins by methylmercury and its toxicological implications

Cytogenetic damage related to low levels of methyl mercury contamination in the Brazilian Amazon

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