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M Aschner

Publications and source records attributed to M Aschner.

106 records · Page 6Linked to original sources
PubMed1986

Effects of systemic methyl mercury-adulterated water consumption on fast axonal transport in the rat visual system.

The present study was designed in an effort to determine whether changes in fast axonal transport in the mature rat visual system can be directly correlated with the onset of neurological dysfunction. Methyl mercury was administered in the drinking water at a concentration of 54 micrograms Hg/ml. Fast axonal transport of proteins in the optic nerve and tract was quantified by scintillation spectrometry of protein-bound radioactivity along the visual pathway after an intraocular injection of 3H-proline. At 8 hours after injection the labeled protein had reached the lateral geniculate body both in controls and treated animals. However, two-way analysis of variance revealed a significant decrease in the volume of transported protein-bound radioactivity along the visual pathway. Thus, while the rate of fast axonal transport does not seem to be correlated with the onset of motor dysfunction, the onset of neurological symptoms may be associated with abnormal transport capacity. Treatment lowered body weight to the same extent in males and females. Hind limb cross-over occurred after 25.6 +/- 0.8 days and was followed quickly by hind limb paralysis (32 +/- 0.6 days). The cerebellum revealed pyknotic nuclei throughout the internal granular layer. Purkinje cells appeared normal. No pathological changes were noted in the kidneys.

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PubMed1984

Persistent, differential alterations in developing cerebellar cortex of male and female mice after methylmercury exposure.

Developing animals have long been believed to be more sensitive to methylmercury toxicity than adults, but the reasons for differential effects are not well understood. In the present study, 2-day-old mice received a single per os dose of 4 mg Hg/kg methylmercury and were sacrificed 24 h or 19 days later. This resulted in a mean brain concentration of 1.8 micrograms Hg/g tissue on day 3 and less than 0.1 micrograms Hg/g on day 21. Compared to littermate vehicle controls, the methylmercury-treated mice exhibited a significant reduction in cell numbers in 1 of 4 regions of the developing cerebellar external granular layer 24 h after treatment. Although the mitotic index over the same 4 regions was not significantly altered by methylmercury treatment, the total number of mitotic figures per section of cerebellum was significantly reduced in the treated group. The ratio of late mitotic figures to total mitotic figures was significantly reduced, indicating mitotic arrest. Both of these antimitotic effects were greater in males than females. Cerebellar structure was also examined 19 days after methylmercury treatment. The number of cells in the molecular layer and thickness of the molecular layer and internal granular layer were significantly reduced in males; the number of Purkinje cells in both sexes and all measures in females remained unaltered. This suggests that early cell loss results in persistent reductions in cell number. Although the basis for the differential effect in males and females is not known, the antimitotic effect of methylmercury is most likely the mechanism underlying the reduced cellularity in treated animals.

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PubMedDate not supplied

Methylmercury alters glutamate transport in astrocytes.

Methylmercury (MeHg) is a significant environmental contaminant that will continue to pose great risk to human health. Considerable attention in the scientific and health policy fora is focused on the question of whether MeHg intake from a diet high in fish is associated with aberrant CNS function. A number of recent studies (Kjellstrom et al., 1986: Kjellstrom, T., Kennedy, P., Wallis, S., Mantell, C., 1986. Physical and mental development of children with prenatal exposure to mercury from fish. Stage I: preliminary tests at age 4. Solna, Sweden. National Swedish Environmental Protection Board Report 3080, 1989: Kjellstrom, T., Kennedy, P., Wallis, S., Stewart, A., Friberg, L. et al., 1989. Physical and mental development of children with prenatal exposure to mercury from fish. Stage II: interviews and psychological tests at age 6. Solna, Sweden. National Swedish Environmental Protection Board Report 3642; McKeown-Eyssen et al., 1983: McKeown-Eyssen, G., Ruedy, J., Neims, A. , 1983. Methylmercury exposure in Northern Quebec II: neurologic findings in children. American Journal of Epidemiology 118, 470-479; Grandjean et al., 1997: Grandjean, P., Weihe, P., White, R. F., Debes, F., Araki, S., Yokoyama, K., Murata, K., Sorensen, N., Dahl, R., Jorgensen, P. J., 1997. Cognitive deficit in 7-year-old children with prenatal exposure to methylmercury. Neurotoxicology and Teratology 19, 417-428) suggest that fetal exposure at levels attained by mothers eating fish regularly during pregnancy are associated with neurological deficits in their offspring. Astrocytes play a key role in MeHg-induced excitotoxicity. (1) MeHg preferentially accumulates in astrocytes. (2) MeHg potently and specifically inhibits glutamate uptake in astrocytes. (3) Neuronal dysfunction is secondary to disturbances in astrocytes. (4) Co-application of nontoxic concentrations of MeHg and glutamate leads to the typical appearance of neuronal lesions associated with excitotoxic stimulation. (5) MeHg induces swelling of astrocytes. These observations are fully consistent with MeHg-induced dysregulation of excitatory amino acid homeostasis, and indicate that a glutamate-mediated excitotoxic mechanism is involved. This manuscript details the role of astrocytes in mediating MeHg-induced excitotoxicity, and elaborates on the protective role afforded by metallothioneins (MTs) in attenuating MeHg cytotoxicity.

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PubMedDate not supplied

Manganese uptake and distribution in the central nervous system (CNS).

Information about the nature of manganese (Mn)-binding ligands in plasma and serum, and its transport mechanism across the blood-brain barrier (BBB) is sparse. Most studies to date have focused on distribution, excretion, and accumulation of intravenous and intraperitoneal solutions of soluble divalent salts of Mn. Mn is transported in the blood primarily in the divalent oxidation state (Mn2+) and crosses the BBB via specific carriers at a rate far slower than in other tissues. Mn transport across the BBB occurs both in the 2+ and 3+ oxidation state. Within the CNS, Mn accumulates primarily within astrocytes, presumably because the astrocyte-specific enzyme, glutamine synthetase (GS), represents an important regulatory target of Mn. Compared to Mn2+, Mn3+ has a slower elimination rate and therefore, may have a greater tendency to accumulate in tissues. Furthermore, in view of the dependence of Mn accumulation within the CNS on iron (Fe) homeostasis, the oxidation state of Mn may represent a key determinant in the differential distribution, accumulation and secretion profiles of Mn, a fact that has received little attention in experimental biology toxicology. Accordingly, the distribution and membrane transport of Mn emphasizes the importance of: 1) the oxidation state of Mn, as it governs the affinity of Mn to endogenous ligands, and 2) the reaction of Mn3+ with transferrin, the plasma iron-carrying protein. This review will focus on transport kinetics of Mn across the BBB (both in the 2+ and 3+ oxidation state), the putative role of transferrin in the transport of Mn across the BBB, the transport of Mn by astrocytes, as well as the physiological significance of Mn to the function GS.

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PubMedDate not supplied

Interactions between pesticides and glia: an unexplored experimental field.

It is now well established that the role of astrocytes extends well beyond passive cytoskeletal structural support to neurons. In fact, astrocytes and neurons establish a highly dynamic reciprocal relationship that influences the growth, morphology, behavior, and central nervous system (CNS) repair. It is also well established that acute exposure to the organophosphorous insecticides leads to inhibition of neuronal acetylcholinesterase activity, an enzyme responsible for the inactivation of the neurotransmitter acetylcholine. Although astrocytes are known to express transport systems for choline, as well as acetylcholinesterase activity, little information is available on the potential interactions between the anticholinesterase class organophosphorous insecticides and these cells. This review will focus on astrocytic cholinergic receptors, choline uptake and metabolism, and address the potential importance of astrocytes in organophosphorous insecticide mediated neurotoxicity.

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PubMedDate not supplied

Mitotic arrest in the developing CNS after prenatal exposure to methylmercury.

Methylmercury is toxic to both the mature and the developing nervous system. One mechanism of its effects on the developing neonatal cerebellum is its interference with cell production by mitotic arrest. To investigate whether this mechanism is active in the prenatal CNS, fetuses exposed to methylmercury were compared to control fetuses 24 hours or 48 hours after an 8 mg/kg dose to their dams. By the first sacrifice time, levels of Hg203 in fetuses approached the level in the dam, and by the second sacrifice time methylmercury-exposed fetuses weighed significantly less than controls. Four regions of the developing brain were studied to evaluate methylmercury effects on mitotic activity. General measures such as mitotic index, number of proliferative cells, and thickness of the proliferative zone were not reduced by treatment in any region at either sacrifice time. In contrast, each region showed evidence of methylmercury effects on the pattern of mitosis. Exposed fetuses had increased numbers of early mitotic figures, decreased numbers of late mitotic figures, or a decrease in the proportion of cells reaching late mitosis. Thus, neurons produced during gestation, like those produced postnatally, appear to be sensitive to methylmercury's antimitotic action. Whether the arrest of these cells leads to a permanent reduction in neuron number, as it does in neonates, remains to be investigated.

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PubMedDate not supplied

Astrocytes as modulators of mercury-induced neurotoxicity.

The case for significant toxicity of methylmercury (MeHg) to the CNS is strongly supported by both in vivo and in vitro studies. MeHg perturbs a number of cellular processes which most certainly include astrocytic failure to maintain the composition of the extracellular fluid. Astrocytic predisposition to be damaged by MeHg offers a potential explanation for its neurotoxicity. Consistent with this concept is the ability of astrocytes to preferentially concentrate brain MeHg. The present commentary elaborates on the role of astrocytes in mediating MeHg-induced injuries, detailing their function in maintaining the extracellular concentrations of the excitatory amino acids glutamate and aspartate. It continues with a discussion on the effects of MeHg on astrocytic swelling and the ensuing regulatory volume decrease (RVD). Recent work demonstrating that primary astrocyte cultures constitutively express a cluster of sulfhydryl (-SH)-containing proteins, collectively referred to as metallothioneins (MTs), is also reviewed with particular reference to the role of MTs both as protectors and facilitators of MeHg intoxication.

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PubMedDate not supplied

Metallothionein (MT) isoforms in the central nervous system (CNS): regional and cell-specific distribution and potential functions as an antioxidant.

Similar to the "housekeeping" functions ascribed to MTs in other tissues, central nervous system (CNS) metallothioneins (MTs) are implicated in metal metabolism, cellular repair processes, growth and differentiation, where they are likely to serve as the source of zinc for newly synthesized apoenzymes, as well as regulator molecules in gene expression. Additional likely functions of MTs include control of intracellular redox potential, and metal detoxification. This manuscript will focus on (1) the distribution of MT isoforms within the CNS, with particular emphasis on the cell-specific localization of MTs and its significance, (2) emerging accounts on the function of MT as an antioxidant, and (3) the relationship between MT and ethanol (EtOH)-induced neurotoxicity in a model system of neonatal rat primary astrocyte cultures.

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