Methylmercury-induced reactive oxygen species formation in neonatal cerebral astrocytic cultures is attenuated by antioxidants

Shanker, Gouri; Aschner, Michael

doi:10.1016/s0169-328x(02)00642-3

Cited by 127 publications

(65 citation statements)

References 34 publications

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“…Prevailing evidences suggest that ROS acts as a potent mediator of MeHg cytotoxicity (23). In this study, we confirmed that MeHg alone decreased cell viability at higher concentration for longer exposure time, which was accompanied by the increase of ROS and the decrease of GSH (Figs.…”

Section: Discussionsupporting

confidence: 85%

L-Glutamate Enhances Methylmercury Toxicity by Synergistically Increasing Oxidative Stress

et al. 2008

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Abstract. Methylmercury (MeHg) is a well-known environmental toxicant. With its lipophilic nature and high reactivity to sulfhydryl groups, it is widely distributed and accumulated in the body to damage cells. Oxidative stress is proposed as a major mechanism underlying the cytotoxic action of MeHg. In the present study, we found that L-glutamate (L-Glu) concentrationdependently increased MeHg cytotoxicity in HeLa S3 cells. The enhancement of the toxicity was accompanied by enhanced apoptosis, increased production of reactive oxygen species, and decreased glutathione level. An anti-oxidant N-acetylcysteine largely alleviated the cytotoxicity, suggesting enhanced oxidative stress behind L-Glu-elicited increase of MeHg toxicity. The effect was specific to L-Glu and L-α-aminoadipate, whereas D-Glu, L-aspartate, and D-aspartate were not effective. In addition, the cystine uptake by the cells was mostly mediated by a L-Glu / L-α-aminoadipate-sensitive amino acid transport system x − C . All these results suggest that the inhibition of system x − C by L-Glu underlies the enhancement of MeHg cytotoxicity. The enhancement was highly synergistic because MeHg and L-Glu alone had little toxic effect in the conditions used. This synergism was confirmed in neural cells (neuroblastoma cell lines). It is proposed that similar mechanisms may underlie the neural toxicity of MeHg, particularly in the locality of lesions characteristic of MeHg toxicity.

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Section: Discussionsupporting

confidence: 85%

L-Glutamate Enhances Methylmercury Toxicity by Synergistically Increasing Oxidative Stress

et al. 2008

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“…MeHg exposure increases ROS generation in the nervous system, both in vivo (Ali et al, 1992;Yee and Choi, 1994) and in vitro (Bondy and McKee, 1990;Shanker and Aschner, 2003;Yee and Choi, 1996;Gassó et al, 2001;Limke and Atchison, 2002;Sarafian et al, 1994;Shnaker et al, 2005;Mundy and Freudenrich, 2000), suggesting the key role of oxidative stress in MeHg-neurotoxicity.…”

Section: Resultsmentioning

confidence: 99%

Methylmercury inhibits electron transport chain activity and induces cytochrome c release in cerebellum mitochondria

et al. 2011

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-The involvement of oxidative stress has been suggested as a mechanism for toxicity caused by methylmercury (MeHg). One of the major critical sites for oxidative stress is the mitochondria. In this research, to clarify the target site in mitochondria affected by MeHg, the individual activities of the mitochondrial electron transport chain (ETC) (I IV) were examined in the liver, cerebrum and cerebellum of MeHg-intoxicated rats. In addition, to elucidate the mechanism underlying MeHg toxicity, cytochrome c release, caspase 3 activity and histological study were examined in the cerebrum and cerebellum. The cerebellum was found to be an exclusive tissue in which significant MeHg-induced alterations were observed. The complex II activity in the cerebellum mitochondria significantly decreased after MeHg exposure. Cytochrome c release from mitochondria increased only in the cerebellum by MeHg exposure. However, no significant alterations in caspase 3 activity or histological structure were found in brain tissues. These results suggest that MeHg acts on the constituents of complex II in the cerebellum, and induces mitochondrial dysfunction, leading to a release of cytochrome c from mitochondria. These events were considered to occur at the early stage of MeHg intoxication.

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“…In vivo and in vitro biochemical studies employing neuronal cultures and mixed neuronal/glial cultures as well as recent studies with primary astrocyte cultures have shown increased ROS formation with MeHg exposure [1,35,53,63,69,74]. Mitochondria are believed to be major targets of MeHg-induced toxicity [43].…”

Section: Discussionmentioning

confidence: 99%

“…While MeHg can directly cause damage to neurons, numerous studies have established a prominent role for astrocytes in mediating MeHg neurotoxicity [23,36]. The evidence includes observations that MeHg preferentially accumulate in astrocytes [5,18,34] and inhibits uptake systems for glutamate and cysteine transport, both of which will compromise glutathione (GSH) synthesis and redox status in astrocytes [2,16,30,61,62,63]. Furthermore, MeHg causes the activation of cytosolic phospholipase A 2 (cPLA 2 ), leading to arachidonic acid release and further inhibition of glutamate transporters and neuronal dysfunction [6,8].…”

Section: Introductionmentioning

confidence: 99%

Methylmercury induces oxidative injury, alterations in permeability and glutamine transport in cultured astrocytes

Yin¹,

Milatović²,

Aschner³

et al. 2007

Brain Research

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100

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The neurotoxicity of high levels of methylmercury (MeHg) is well established both in humans and experimental animals. Astrocytes accumulate MeHg and play a prominent role in mediating MeHg toxicity in the central nervous system (CNS). Although the precise mechanisms of MeHg neurotoxicity are ill-defined, oxidative stress and altered mitochondrial and cell membrane permeability appear to be critical factors in its pathogenesis. The present study examined the effects of MeHg treatment on oxidative injury, mitochondrial inner membrane potential, glutamine uptake and expression of glutamine transporters in primary astrocyte cultures. MeHg caused a significant increase in F 2 -isoprostanes (F 2 -IsoPs), lipid peroxidation biomarkers of oxidative damage, in astrocyte cultures treated with 5 or 10 μ M MeHg for 1 or 6 hours. Consistent with this observation, MeHg induced a concentration-dependant reduction in the inner mitochondrial membrane potential (ΔΨm), as assessed by the potentiometric dye, tetramethylrhodamine ethyl ester (TMRE). Our results demonstrate that ΔΨ m is a very sensitive endpoint for MeHg toxicity, since significant reductions were observed after only 1 h exposure to concentrations of MeHg as low as 1 μ M. MeHg pretreatment (1, 5 and 10 μ M) for 30 min also inhibited the net uptake of glutamine ( 3 H-glutamine) measured at 1 min and 5 min. Expression of the mRNA coding the glutamine transporters, SNAT3/SN1 and ASCT2, was inhibited only at the highest (10 μ M) MeHg concentration, suggesting that the reduction in glutamine uptake observed after 30 min treatment with lower concentrations of MeHg (1 and 5 μ M) was not due to inhibition of transcription. Taken together, these studies demonstrate that MeHg exposure is associated with increased mitochondrial membrane permeability, alterations in glutamine/glutamate cycling, increased ROS formation and consequent oxidative injury. Ultimately, MeHg initiates multiple additive or synergistic disruptive mechanisms that lead to cellular dysfunction and cell death.Please send request for reprints to Michael Aschner, Ph.D.,

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Methylmercury-induced reactive oxygen species formation in neonatal cerebral astrocytic cultures is attenuated by antioxidants

Cited by 127 publications

References 34 publications

L-Glutamate Enhances Methylmercury Toxicity by Synergistically Increasing Oxidative Stress

L-Glutamate Enhances Methylmercury Toxicity by Synergistically Increasing Oxidative Stress

Methylmercury inhibits electron transport chain activity and induces cytochrome c release in cerebellum mitochondria

Methylmercury induces oxidative injury, alterations in permeability and glutamine transport in cultured astrocytes

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