This is a blog about the effect of mitochondrial neurotoxins on glucocorticoid II receptors. It will mostly be about toxins other than the one that I was exposed to, hexachlorophene. I have addressed that research in related blogs.This is an attempt to raise a broader question. Besides hexachlorophene, don't other mitochondrial neurotoxins (eg trimethyltin) also cause life-long glucocorticoid receptor deficiencies that ,in turn, cause disorders of hypercortisolemia, neuroendocrine type
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To begin with,there is a question of whether hexachlorophene and other
mitochondrial neurotoxins are related to glucocorticoid receptor toxicity. So, first, there are a number of articles that relate hexachlorophene and similar mitochondrial neurotoxins with the one that is the focus of this glucocorticoid receptor toxicity research, trimethyltin.
Xenobiotica. 1985 Aug-Sep;15(8-9):727-33.
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Effects of toxic chemicals on the respiratory activity of cultured mouse neuroblastoma cells.Varnbo I, Peterson A, Walum E.Twenty common toxic chemicals were tested for their ability to inhibit respiratory activity in cultured mouse neuroblastoma C1300 cells, clone 41A3. Pentachlorophenol and hexachlorophene exhibited the properties of uncouplers of oxidative phosphorylation, whereas for KCN, pyridine, 2,5-hexandione, NaAsO2, K2Cr2O7, HgCl2, methylmercury and triethyltin more simple time-courses of inhibition ............ Among the effective compounds, those with well-known neurotoxic properties were the most potent in inhibiting respiration in 41A3 cells.
2: Chem Biol Interact. 1979 Sep;27(1):125-32.
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Effect of organotin compounds and hexachlorophene on brain adenosine cyclic 3',5'-monophosphate metabolism.Leow AC, Towns KM, Leaver DD.The effect of triethyltin (TET), triphenyltin (TPT), hexachlorophene (HCP) and cuprizone on adenosine cyclic 3',5'-monophosphate (cyclic AMP) production in rat brain was examined both in vitro and in vivo. TET and TPT inhibited basal adenylate cyclase activity of brain........ On the basis of these results the inhibition of adenylate cyclase produced by TET in brain homogenates in vitro would not appear to be involved in the development of nervous changes associated with acute TET toxicity, or in the production of progressive brain oedema caused by TET, HCP and cuprizone.PMID: 225045 [PubMed - indexed for MEDLINE]
3: Hum Exp Toxicol. 1991 Nov;10(6):439-44.
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A comparison of spongiosis induced in the brain by hexachlorophene, cuprizone and triethyl tin in the Sprague-Dawley rat.Purves DC, Garrod IJ, Dayan AD.DH Department of Toxicology, St Bartholomew's Hospital Medical College, London, UK.The effect of hexachlorophene (HCP; 2,2'-methylenebis(3,4,6-trichlorophenol), cuprizone (CPZ; bicyclohexone oxaldihydrazone) and triethyl tin (TET; triethyl tin sulphate) in producing vacuoles in the brain of the Sprague-Dawley rat has been quantified by image analysis of the extent of the spongy change in the white matter.
4: Biochem J. 1971 Aug;124(1):221-34.
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Oxidative phosphorylation. The relation between the specific binding of trimethylytin and triethyltin to mitochondria and their effects on various mitochondrial functions.Aldridge WN, Street BW.1. A binding site (site 1) is present in mitochondria with affinity for trimethyltin and triethyltin adequate for a site to which they could be attached when the processes of energy conservation are inhibited. 2. The quantitative relationships between the binding of trimethyltin and triethyltin to site 1 and their effects on various mitochondrial functions have been examined. ............. Possible interpretations of these findings are discussed with reference to published arrangements for coupling of electron transport to ATP synthesis and also to our present knowledge of the chemical and biological specificity of trialkyltin compounds.
Cell Mol Neurobiol. 1994 Dec;14(6):591-7.
The public health significance of metal neurotoxicity.
Carpenter DO.
Wadsworth Center for Laboratories and Research, New York State Department of Health, Albany 12201-0509, USA.
Here is an excerpt from the article about the effect of the mitochondridrial neurotoxin,triethyltin, whose effects have been compared to hexachlorophene.
............. The organotins are the major concerns with regard to human health,
especially triethyltin, since the inorganic tins are not known to be toxic (Manzo et
al., 1985). Organotin compounds have a number of industrial uses as biocides,
catalysts, preservatives and polymer stabilizers. In the early 1950s, 110 people
died in France from taking a medicine which contained some triethyltin, and
patients showed nausea and vomiting, headache, photophobia, altered consciousness,
visual impairment, and convulsions (Foucin and Gruner, 1979). Those that
survived showed psychological and intellectual impairments. Triethyltin is an
uncoupler of oxidative phosphorylation which leads to cytotoxic brain edema and
pathological changes in myelin sheaths, axons, and astrocytes. Animal studies
have shown that triethyltin can produce behavioral and neurophysiological
changes at doses lower than those that produce brain edema (Fox and Doctor,
1983).......................
Thursday, June 26, 2008
THE GLUCOCORTICOID RECEPTORS ARE IN MITOCHONDRIA
The next step is to focus on the research that shows why glucocorticoid receptors are vulnerable to mitochondrial neurotoxins. The articles cited below indicate this vulnerability is due to their location in the mitochondria of the cell.
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: IUBMB Life. 2008 Apr;60(4):210-23.
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Steroid and thyroid hormone receptors in mitochondria.Psarra AM, Sekeris CE.Biomedical Research Foundation, Academy of Athens, Center for Basic Research, Athens, Greece.Receptors for glucocorticoids, estrogens, androgens, and thyroid hormones have been detected in mitochondria of various cell types by Western blotting, immunofluorescence labeling, confocal microscopy, and immunogold electron microscopy. A role of these receptors in mitochondrial transcription, OXPHOS biosynthesis, and apoptosis is now being revealed. Steroid and thyroid hormones regulate energy production, inducing nuclear and mitochondrial OXPHOS genes by way of cognate receptors. In addition to the action of the nuclearly localized receptors on nuclear OXPHOS gene transcription, a parallel direct action of the mitochondrially localized receptors on mitochondrial transcription has been demonstrated. The coordination of transcription activation in nuclei and mitochondria by the respective receptors is in part realized by their binding to common trans acting elements in the two genomes. Recent evidence points to a role of the mitochondrial receptors in cell survival .....
2: Semin Reprod Med. 2007 May;25(3):154-64.
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Actions of steroids in mitochondria.Gavrilova-Jordan LP, Price TM.Division of Reproductive Endocrinology and Fertility, Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, North Carolina, USA.Investigations of indirect and direct actions of steroids on the mitochondria are relatively new areas of research. In this review we provide brief background information regarding mitochondrial structure and function and then focus upon interactions of glucocorticoid, estrogen, androgen, and progesterone receptors with mitochondria. We evaluate the current evidence for steroid receptor localization in the mitochondria based on techniques of Western blot analysis, immunocytochemistry, electron microscopy, and mass spectrometry..... These interactions may play a role in mitochondrial-dependent processes of oxidative phosphorylation and apoptosis. Physiological examples of these interactions are discussed.
3: Mol Cell Endocrinol. 2003 Nov 14;209(1-2):51-60.
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Links
The dynamic localization of the glucocorticoid receptor in rat C6 glioma cell mitochondria.Koufali MM, Moutsatsou P, Sekeris CE, Breen KC.Department of Psychiatry, Ninewells Hospital, University of Dundee Medical School, Dundee, DD1 9SY, UK.Glucocorticoids modify gene expression via the translocation of receptors from the cytosol to the nucleus following agonist-associated receptor activation. In this study, we have characterized mitochondrial glucocorticoid (GR) localization and associated translocation kinetics in the C6 mouse glioma cell line. Treatment of the cells, which were cultured in steroid-depleted culture medium, with the GR agonist dexamethasone (dex) resulted in a dramatic decrease in mitochondrial GR levels in parallel with those of the cytosolic receptor. The effect was not observed in isolated intact mitochondria suggesting that the effect is unlikely to be direct but is rather a component of the combined cellular response to GR activation. A marked stimulation of the expression of the mitochondrially-encoded cytochrome oxidase-1 (COX-1) gene was found following GR activation and its export from mitochondria. The effects were inhibited by RU486. Therefore, GR is likely to have a functional role at the level of the mitochondria within intact cells.
-------------------------------------------------------------------------------------
: IUBMB Life. 2008 Apr;60(4):210-23.
Related Articles,
Links
Steroid and thyroid hormone receptors in mitochondria.Psarra AM, Sekeris CE.Biomedical Research Foundation, Academy of Athens, Center for Basic Research, Athens, Greece.Receptors for glucocorticoids, estrogens, androgens, and thyroid hormones have been detected in mitochondria of various cell types by Western blotting, immunofluorescence labeling, confocal microscopy, and immunogold electron microscopy. A role of these receptors in mitochondrial transcription, OXPHOS biosynthesis, and apoptosis is now being revealed. Steroid and thyroid hormones regulate energy production, inducing nuclear and mitochondrial OXPHOS genes by way of cognate receptors. In addition to the action of the nuclearly localized receptors on nuclear OXPHOS gene transcription, a parallel direct action of the mitochondrially localized receptors on mitochondrial transcription has been demonstrated. The coordination of transcription activation in nuclei and mitochondria by the respective receptors is in part realized by their binding to common trans acting elements in the two genomes. Recent evidence points to a role of the mitochondrial receptors in cell survival .....
2: Semin Reprod Med. 2007 May;25(3):154-64.
Related Articles,
Links
Actions of steroids in mitochondria.Gavrilova-Jordan LP, Price TM.Division of Reproductive Endocrinology and Fertility, Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, North Carolina, USA.Investigations of indirect and direct actions of steroids on the mitochondria are relatively new areas of research. In this review we provide brief background information regarding mitochondrial structure and function and then focus upon interactions of glucocorticoid, estrogen, androgen, and progesterone receptors with mitochondria. We evaluate the current evidence for steroid receptor localization in the mitochondria based on techniques of Western blot analysis, immunocytochemistry, electron microscopy, and mass spectrometry..... These interactions may play a role in mitochondrial-dependent processes of oxidative phosphorylation and apoptosis. Physiological examples of these interactions are discussed.
3: Mol Cell Endocrinol. 2003 Nov 14;209(1-2):51-60.
Related Articles,
Links
The dynamic localization of the glucocorticoid receptor in rat C6 glioma cell mitochondria.Koufali MM, Moutsatsou P, Sekeris CE, Breen KC.Department of Psychiatry, Ninewells Hospital, University of Dundee Medical School, Dundee, DD1 9SY, UK.Glucocorticoids modify gene expression via the translocation of receptors from the cytosol to the nucleus following agonist-associated receptor activation. In this study, we have characterized mitochondrial glucocorticoid (GR) localization and associated translocation kinetics in the C6 mouse glioma cell line. Treatment of the cells, which were cultured in steroid-depleted culture medium, with the GR agonist dexamethasone (dex) resulted in a dramatic decrease in mitochondrial GR levels in parallel with those of the cytosolic receptor. The effect was not observed in isolated intact mitochondria suggesting that the effect is unlikely to be direct but is rather a component of the combined cellular response to GR activation. A marked stimulation of the expression of the mitochondrially-encoded cytochrome oxidase-1 (COX-1) gene was found following GR activation and its export from mitochondria. The effects were inhibited by RU486. Therefore, GR is likely to have a functional role at the level of the mitochondria within intact cells.
TRIMETHYLTIN
1: Exp Neurol. 2001 Sep;171(1):22-8.
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Links
Type II glucocorticoid receptors are involved in neuronal death and astrocyte activation induced by trimethyltin in the rat hippocampus.Imai H, Nishimura T, Sadamatsu M, Liu Y, Kabuto M, Kato N.Regional Environment Division, National Institute for Environmental Studies, Tsukuba, Ibaraki, 305-0053, Japan. imahide@nies.go.jpAccording to our previous study, trimethyltin (TMT), a neurotoxicant, induces the loss of pyramidal neurons in the rat hippocampus, which is preceded by a transient increase in plasma corticosterone concentration. To address whether this transient activation of the hypothalamopituitary-adrenocortical axis is related to neuronal loss in the hippocampus, we evaluated the effects of bilateral adrenalectomy (ADX) and the chronic supplemental treatment of glucocorticoid receptor agonists after ADX on TMT-induced hippocampal damage. Peroral administration of a single dose of TMT (9 mg/kg body wt) induced the extensive loss of CA3 pyramidal neurons and reactive astrocytosis in the hippocampus, as evidenced by results of vimentin and glial fibrillary acidic protein immunohistochemistry, and the effects were profoundly exacerbated by bilateral adrenalectomy. Prolonged administration of corticosterone not only attenuated the exacerbating effects of adrenalectomy but also partially reversed the TMT-induced neuronal loss and reactive astrocytosis. Dexamethasone, but not aldosterone, could be substituted for corticosterone, suggesting a novel neuroprotective action of type II glucocorticoid receptors in the hippocampus.
2: Brain Res. 1988 Sep 20;460(2):346-51.
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Links
Parallel changes in operant behavioral adaptation and hippocampal corticosterone binding in rats treated with trimethyltin.Gerbec EN, Messing RB, Sparber SB.Department of Pharmacology, University of Minnesota Medical School, Minneapolis 55455.Rats were given water vehicle or trimethyltin (TMT; 3.0, 6.0 or 7.5 mg/kg, p.o.). ...........Corticosterone binding to hippocampal cytosolic protein was maximally reduced for the group given 6.0 mg TMT/kg. The greatest reduction in hippocampal weight resulted from injection of 7.5 mg TMT/kg, but a smaller reduction in [3H]corticosterone binding (i.e. 22%) was observed for this group. In the absence of an effect of 3.0 mg TMT/kg upon weight of hippocampus, there also was a reduction in steroid binding, indicating the sensitivity of this parameter for TMT toxicity. The results support the notion that hippocampal corticosteroid receptors are important for behavioral adaptation, and rats given moderate doses of TMT may be useful for studying functions of corticosterone receptors.Publication Types:
3: Neurosci Res. 2005 Mar;51(3):319-27.
Related Articles,
Links
Corrected and republished from:
Neurosci Res. 2004 Oct;50(2):209-17. Cytokines participate in neuronal death induced by trimethyltin in the rat hippocampus via type II glucocorticoid receptors.Liu Y, Imai H, Sadamatsu M, Tsunashima K, Kato N.Department of Neuropsychiatry, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. liuying-tky@umin.ac.jpWe investigated the role of IL-1alpha and IL-1beta expressed in the reactive gliosis following hippocampal damage induced by trimethyltin (TMT). IL-1alpha immunoreactivity was expressed earlier in small glial cells on day 4 post-TMT, while IL-1beta expression was obvious in large swollen glial cells on day 14 post-TMT. Both IL-1alpha and IL-1beta immunoreactivities were double-labeled with astrocyte marker, vimentin, but not with a microglia marker, OX-42. The expression of both IL-1alpha/beta was enhanced by adrenalectomy (ADX) prior to TMT administration. Corticosterone (CORT) or dexamethasone (DEX) supplementation not only cancelled effects of ADX, but also partially reversed TMT-induced enhancement of IL-1alpha/beta expressions. These changes coincided with TMT-induced neuronal death in CA3 pyramidal cells of the hippocampus. It is suggested that IL-1alpha/beta expressed in reactive astrocytes participate in TMT neurotoxicity via type II glucocorticoid receptors.
Related Articles,
Links
Type II glucocorticoid receptors are involved in neuronal death and astrocyte activation induced by trimethyltin in the rat hippocampus.Imai H, Nishimura T, Sadamatsu M, Liu Y, Kabuto M, Kato N.Regional Environment Division, National Institute for Environmental Studies, Tsukuba, Ibaraki, 305-0053, Japan. imahide@nies.go.jpAccording to our previous study, trimethyltin (TMT), a neurotoxicant, induces the loss of pyramidal neurons in the rat hippocampus, which is preceded by a transient increase in plasma corticosterone concentration. To address whether this transient activation of the hypothalamopituitary-adrenocortical axis is related to neuronal loss in the hippocampus, we evaluated the effects of bilateral adrenalectomy (ADX) and the chronic supplemental treatment of glucocorticoid receptor agonists after ADX on TMT-induced hippocampal damage. Peroral administration of a single dose of TMT (9 mg/kg body wt) induced the extensive loss of CA3 pyramidal neurons and reactive astrocytosis in the hippocampus, as evidenced by results of vimentin and glial fibrillary acidic protein immunohistochemistry, and the effects were profoundly exacerbated by bilateral adrenalectomy. Prolonged administration of corticosterone not only attenuated the exacerbating effects of adrenalectomy but also partially reversed the TMT-induced neuronal loss and reactive astrocytosis. Dexamethasone, but not aldosterone, could be substituted for corticosterone, suggesting a novel neuroprotective action of type II glucocorticoid receptors in the hippocampus.
2: Brain Res. 1988 Sep 20;460(2):346-51.
Related Articles,
Links
Parallel changes in operant behavioral adaptation and hippocampal corticosterone binding in rats treated with trimethyltin.Gerbec EN, Messing RB, Sparber SB.Department of Pharmacology, University of Minnesota Medical School, Minneapolis 55455.Rats were given water vehicle or trimethyltin (TMT; 3.0, 6.0 or 7.5 mg/kg, p.o.). ...........Corticosterone binding to hippocampal cytosolic protein was maximally reduced for the group given 6.0 mg TMT/kg. The greatest reduction in hippocampal weight resulted from injection of 7.5 mg TMT/kg, but a smaller reduction in [3H]corticosterone binding (i.e. 22%) was observed for this group. In the absence of an effect of 3.0 mg TMT/kg upon weight of hippocampus, there also was a reduction in steroid binding, indicating the sensitivity of this parameter for TMT toxicity. The results support the notion that hippocampal corticosteroid receptors are important for behavioral adaptation, and rats given moderate doses of TMT may be useful for studying functions of corticosterone receptors.Publication Types:
3: Neurosci Res. 2005 Mar;51(3):319-27.
Related Articles,
Links
Corrected and republished from:
Neurosci Res. 2004 Oct;50(2):209-17. Cytokines participate in neuronal death induced by trimethyltin in the rat hippocampus via type II glucocorticoid receptors.Liu Y, Imai H, Sadamatsu M, Tsunashima K, Kato N.Department of Neuropsychiatry, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. liuying-tky@umin.ac.jpWe investigated the role of IL-1alpha and IL-1beta expressed in the reactive gliosis following hippocampal damage induced by trimethyltin (TMT). IL-1alpha immunoreactivity was expressed earlier in small glial cells on day 4 post-TMT, while IL-1beta expression was obvious in large swollen glial cells on day 14 post-TMT. Both IL-1alpha and IL-1beta immunoreactivities were double-labeled with astrocyte marker, vimentin, but not with a microglia marker, OX-42. The expression of both IL-1alpha/beta was enhanced by adrenalectomy (ADX) prior to TMT administration. Corticosterone (CORT) or dexamethasone (DEX) supplementation not only cancelled effects of ADX, but also partially reversed TMT-induced enhancement of IL-1alpha/beta expressions. These changes coincided with TMT-induced neuronal death in CA3 pyramidal cells of the hippocampus. It is suggested that IL-1alpha/beta expressed in reactive astrocytes participate in TMT neurotoxicity via type II glucocorticoid receptors.
Glucocorticoid Receptor Toxicity
This is a blog about the effect of mitochondrial neurotoxins on glucocorticoid II receptors. It will mostly be about toxins other than the one the one I was exposed to, hexachlorophene. I have addressed that research in related blogs.
This is an attempt to raise a broader question. Besides hexachlorophene, don't other mitochondrial neurotoxins (eg trimethyltin) also cause life-long glucocorticoid receptor deficiencies that ,in turn, cause disorders of hypercortisolemia, neuroendocrine type?
Posted by rremibgooglepages.com at 1:50 PM 0 comments
This is an attempt to raise a broader question. Besides hexachlorophene, don't other mitochondrial neurotoxins (eg trimethyltin) also cause life-long glucocorticoid receptor deficiencies that ,in turn, cause disorders of hypercortisolemia, neuroendocrine type?
Posted by rremibgooglepages.com at 1:50 PM 0 comments
Glucocorticoid Receptor Toxicity
This is a blog about the effect of mitochondrial neurotoxins on glucocorticoid II receptors. It will mostly be about toxins other than the one the one I was exposed to, hexachlorophene. I have addressed that research in related blogs.
This is an attempt to raise a broader question. Besides hexachlorophene, don't other mitochondrial neurotoxins (eg trimethyltin) also cause life-long glucocorticoid receptor deficiencies that ,in turn, cause disorders of hypercortisolemia, neuroendocrine type?
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