A quantitative evaluation of the neurotoxic effect of silver on the volumes of the components of the developing rat hippocampus

doi:10.1016/0300-483X(87)90085-0

Toxicology

Volume 43, Issue 3, March 1987, Pages 261-268

https://doi.org/10.1016/0300-483X(87)90085-0 Get rights and content

Abstract

The volumes of the components of the hippocampus of rats subjected to subcutaneous injections of silver during the first 4 postnatal weeks were compared to those of littermate controls. Of the 14 components measured, only the pyramidal cell layer was found to be significantly smaller in the treated animals. These findings indicate that the perikaria of the pyramidal cells are either the first elements in the developing hippocampus to show signs of silver toxicity or that they are the selective sites of silver neurotoxicity. The volumetric approach is shown to be a sensitive means by which small localized neurotoxic effects can be detected.

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Citation Excerpt :
The rapid rise in commercial AgNP use raises concern for exposures to Ag+, particularly because the developing brain is a specific target for the adverse effects of heavy metals (Bondy and Campbell, 2005; Costa et al., 2004). Silver crosses the placental barrier, accumulates in the human fetus (Lyon et al., 2002), and alters neuroanatomy in developing rodents (Rungby et al., 1987). In an in vitro model of neuronal development, we recently found that Ag+ has adverse effects on cell replication and viability, and interferes with the emergence of specific neurotransmitter phenotypes (Powers et al., 2010b).
Silver nanoparticles (AgNPs) act as antibacterials by releasing monovalent silver (Ag⁺) and are increasingly used in consumer products, thus elevating exposures in human and wildlife populations. In vitro models indicate that AgNPs are likely to be developmental neurotoxicants with actions distinct from those of Ag⁺. We exposed developing zebrafish (Danio rerio) to Ag⁺ or AgNPs on days 0–5 post-fertilization and evaluated hatching, morphology, survival and swim bladder inflation. Larval swimming behavior and responses to different lighting conditions were assessed 24 h after the termination of exposure. Comparisons were made with AgNPs of different sizes and coatings: 10 nm citrate-coated AgNP (AgNP-C), and 10 or 50 nm polyvinylpyrrolidone-coated AgNPs (AgNP-PVP). Ag⁺ and AgNP-C delayed hatching to a similar extent but Ag⁺ was more effective in slowing swim bladder inflation, and elicited greater dysmorphology and mortality. In behavioral assessments, Ag⁺ exposed fish were hyperresponsive to light changes, whereas AgNP-C exposed fish showed normal responses. Neither of the AgNP-PVPs affected survival or morphology but both evoked significant changes in swimming responses to light in ways that were distinct from Ag⁺ and each other. The smaller AgNP-PVP caused overall hypoactivity whereas the larger caused hyperactivity. AgNPs are less potent than Ag⁺ with respect to dysmorphology and loss of viability, but nevertheless produce neurobehavioral effects that highly depend on particle coating and size, rather than just reflecting the release of Ag⁺. Different AgNP formulations are thus likely to produce distinct patterns of developmental neurotoxicity.
Expression of genes related to oxidative stress in the mouse brain after exposure to silver-25 nanoparticles
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Nanoparticles are small scale substances (<100 nm) used in biomedical applications, electronics, and energy production. Increased exposure to nanoparticles being produced in large-scale industry facilities elicits concerns for the toxicity of certain classes of nanoparticles. This study evaluated the effects of silver-25 nm (Ag-25) nanoparticles on gene expression in different regions of the mouse brain. Adult-male C57BL/6N mice were administered (i.p.) 100 mg/kg, 500 mg/kg or 1000 mg/kg Ag-25 and sacrificed after 24 h. Regions from the brain were rapidly removed and dissected into caudate nucleus, frontal cortex and hippocampus. Total RNA was isolated from each of the three brain regions collected and real-time RT-PCR analysis was performed using Mouse Oxidative Stress and Antioxidant Defense Arrays. Array data revealed the expression of genes varied in the caudate nucleus, frontal cortex and hippocampus of mice when treated with Ag-25. The data suggest that Ag-25 nanoparticles may produce neurotoxicity by generating free radical-induced oxidative stress and by altering gene expression, producing apoptosis and neurotoxicity.
The effect of low-level toluene exposure on the developing hippocampal region of the rat: Histological evidence and volumetric findings
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With the intention of investigating possible morphological alterations effected by toluene in the developing CNS, rat pups were exposed to 100 ppm and 500 ppm of atmosphoric toluene from postnatal day 1 until sacrifice at postnatal day 28, when the hippocampal region (area dentata, Ammon's horn, subiculum) was examined light microscopically and alterations in the volumes of the layers of the subdivisions were determined.
The layers of Ammon's horn and the subiculum were not affected qualitatively or quantitatively by the 500 ppm exposure. Within the area dentata, the volume of the granule cell layer was 6% smaller in animals exposed to 100 ppm and 13% smaller in animals exposed to 500 ppm than they were in controls. The volumes of the hilus, which is a terminal field of granule cell axons, and the commissural-associational zone of the dentate molecular layer, which is the terminal field of the hilar projection to the granule cells, were smaller (12% and 19%) in animals exposed to 500 ppm than they were in controls. Argyrophilic cells were found in the granule cell layer of all animals exposed to 500 ppm. Pronounced granule cell degeneration was found in one animal exposed to 500 ppm. The granule cell layer of animals exposed to 100 ppm appeared qualitatively normal.
The alterations reported her support the few earlier reports of morphological alterations in the CNS of adult laboratory animals. Effects of toluene similar to those described, that is alterations in specific neuron populations and their afferent and efferent terminal fields may complement changes in neurophysiology and behavior that have been observed in prenatally and perinatally exposed rodent pups. Causal relationships, however, remain to be elucidated.
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The volumes of the fascia dentata, hilus, regio inferior, regio superior and subiculum of 9 species that differ significantly in size and degree of forebrain evolution have been compared with the intent of identifying phylogenetic trends in the internal organization of the mammalian hippocampus. The study includes data from the hippocampi of a basal insectivore, 2 species of wild mice, 3 commonly used laboratory rodents and 3 species (including man) that resemble an ascending primate series. In addition to comparisons of the absolute and relative volumes, an allometric approach is used to identify “progressive” size differences not related to body size. Both regio superior and hilus become larger during evolution, while fascia dentata and regio inferior maintain a relationship to body size that is similar to that for the hippocampus in basal insectivores. The inter-species differences are discussed in terms of neuron number and size, for which data are presented from two species, and with reference to a neural model of the cognitive map theory for hippocampal function. Special emphasis is placed on the unique aspects of the human hippocampus. The data represents a quantitative morphological framework within which the observations from physiological, biochemical and behavioral studies in laboratory animals can be related to studies of the human hippocampus.
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1988, Toxicology Letters
Addition of silver nitrate or silver laetate to freshly isolated hepatocytes caused dose-dependent loss of cell viability, measured by trypan blue exclusion, at concentrations within 30–70 μM. Silver cytotoxicity was accompanied by a decrease in hepatic thiol concentration and an increase in lipid peroxidation. Treatment of hepatocytes with the reduced glutathione (GSH)-depleting agent diethylmaleate markedly increased their vulnerability to silver toxicity whereas protective effects were produced by the thiolreducing agent, dithiothreitol. Both α-tocopherol, which protected from the onset of silver-associated lipid peroxidation, and the iron chelator agent, deferoxamine failed to prevent loss of cell viability. These data suggest that perturbation of intracellular thiol homeostasis may play a critical role in the mechanism underlying silver-induced lethal damage to isolated rat hepatocytes.
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A quantitative evaluation of the neurotoxic effect of silver on the volumes of the components of the developing rat hippocampus

Abstract

Silver

The Timm-stained hippocampus of the European hedgehog: A basal mammalian form

J. Comp. Neurol.

Commissural connections of the hippocampal region in the rat with special reference to their mode of termination

J. Comp. Neurol.

Heavy metals in the brain. A light microscope study of the rat with Timm's sulphide silver method. Methodological considerations and cytological and regional staining patterns

Adv. Anat., Embryol. Cell. Biol.

Hippocampal development in the rat: Cytogenesis and morphogenesis examined with autoradiography and low level X-irradiation

J. Comp. Neurol.

An autoradiographic study of the time of origin and the pattern of granule cell migration in the dentate gyrus of the rat

J. Comp. Neurol.

The development of the dentate area and the hippocampal mossy fiber projection of the rat

J. Comp. Neurol.

An improved Timm sulphide silver method for light and electron microscopic localization of heavy metals in biological tissues

Histochemistry