Astrocytes as potential modulators of mercuric chloride neurotoxicity

Aschner, Michael; Mullaney, K.J.; Fehm, M.N.; Wagoner, David; Vitarella, Domenico

doi:10.1007/bf02088673

Cited by 26 publications

(24 citation statements)

References 42 publications

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“…However, astrocyte nuclei labelled with the TUNEL technique were still visualized on these sections. This suggests that 1) either the mercuryinduced glial dysfunction lead indirectly to neuronal death, as it has been proposed by several authors (Largo et al, 1996;Aschner et al, 1995;Dave et al, 1994), or 2) at this high concentration, mercury induced directly a general cytotoxicity of neurons.…”

Section: Induction Of Apoptosis By Mercurymentioning

confidence: 82%

Induction of apoptosis by mercury compounds depends on maturation and is not associated with microglial activation

Monnet‐Tschudi

1998

J. Neurosci. Res.

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The earliest sign of neurotoxicity observed after exposure of three-dimensional brain cell cultures to low concentrations of mercury compounds is a microglial reaction. We hypothesized that an induction of apoptosis by mercury compounds could be an activating signal of the microglial reaction. Aggregating brain cell cultures of fetal rat telencephalon were treated for 10 days with either mercury chloride or monomethylmercury chloride at noncytotoxic concentrations during two developmental periods: from day 5 to 15, corresponding to an immature stage, and from day 25 to 35 corresponding to a mature stage. Apoptosis was evaluated by the TUNEL technique. It was found that both mercury compounds caused a significant increase in the number of apoptotic cells, but exclusively in immature cultures exhibiting also spontaneous apoptosis. Double staining by the TUNEL technique combined with either neuronal or astroglial markers revealed that the proportion of cells undergoing apoptosis was highest for astrocytes. Furthermore neither an association nor a colocalization was found between apoptotic cells and microglial cells. In conclusion, it appears that the induction of apoptosis by mercury compounds in immature cells is only an acceleration of a spontaneously occurring process, and that it is not a directly related to the early microglial reaction.

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Section: Induction Of Apoptosis By Mercurymentioning

confidence: 82%

Induction of apoptosis by mercury compounds depends on maturation and is not associated with microglial activation

Monnet‐Tschudi

1998

J. Neurosci. Res.

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“…While culture models indicate that MeHg alters neuronal precursor proliferation, in vivo changes in cell proliferation may reflect not only neuronal but also glial susceptibility (Garg and Chang 2006) to the toxicant. In addition, glial cells alter markedly the sensitivity of neurons in culture to metal toxicants, including both MeHg (Aschner, 1996;Shanker et al, 2003;Morken et al, 2005) and lead (Tiffany-Castiglioni and Qian, 2001;Zurich et al, 2002). Also, while glutathione may play a protective role following oxidative stress, both regions exhibit comparable levels of antioxidant defenses that protect cells from neurotoxicant insults (Li et al, 1996).…”

Section: Mehg Has Rapid Differential Effects On Proliferation In Devmentioning

confidence: 99%

Methylmercury elicits rapid inhibition of cell proliferation in the developing brain and decreases cell cycle regulator, cyclin E

Burke

Cheng

et al. 2006

NeuroToxicology

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The developing brain is highly sensitive to methylmercury (MeHg). Still, the initial changes in cell proliferation that may contribute to long-term MeHg effects are largely undefined. Our previous studies with growth factors indicate that acute alterations of G1/S phase transition can permanently affect cell numbers and organ size. Therefore, we determined whether an environmental toxicant could also impact brain development with rapid (6-7h) effects on DNA synthesis and cell cycle machinery in neuronal precursors. In vivo studies in newborn rat hippocampus and cerebellum, two regions of postnatal neurogenesis, were followed by in vitro analysis of two precursor models, cortical and cerebellar cells, focusing on the proteins that regulate G1/S transition. In postnatal day 7 (P7) pups, a single subcutaneous injection of MeHg (3μg/g) acutely (7h) decreased DNA synthesis in the hippocampus by 40% and produced long-term (2 weeks) reductions in total cell number, estimated by DNA quantification. Surprisingly, cerebellar granule cells were resistant to MeHg effects in vivo at comparable tissue concentrations, suggesting region-specific differences in precursor populations. In vitro, MeHg altered proliferation and cell viability, with DNA synthesis selectively inhibited at an early timepoint (6h) corresponding to our in vivo observations. Considering that G1/ S regulators are targets of exogenous signals, we used a well-defined cortical cell model to examine MeHg effects on relevant cyclin dependent kinases (CDK) and CDK inhibitors. At 6h, MeHg decreased by 75% levels of cyclin E, a cell cycle regulator with roles in proliferation and apoptosis, without altering p57, p27, or CDK2 nor levels of activated caspase 3. In aggregate, our observations identify the G1/S transition as an early target of MeHg toxicity and raise the possibility that cyclin E degradation contributes to both decreased proliferation and eventual cell death.

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“…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

162

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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Astrocytes as potential modulators of mercuric chloride neurotoxicity

Cited by 26 publications

References 42 publications

Induction of apoptosis by mercury compounds depends on maturation and is not associated with microglial activation

Induction of apoptosis by mercury compounds depends on maturation and is not associated with microglial activation

Methylmercury elicits rapid inhibition of cell proliferation in the developing brain and decreases cell cycle regulator, cyclin E

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

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