Methylmercury-induced decrement in neuronal migration may involve cytokine-dependent mechanisms: a novel method to assess neuronal movement in vitro.

A major toxic effect associated with methylmercury (MeHg) exposure in developing humans is damage to the nervous system, which involves inhibition of cell migration, particularly in the cerebellum. The mechanisms by which MeHg impairs neural migration are not fully known, especially at low doses. In this paper we report on a novel method for observing and quantitating the movement of individual cells in primary cultures of murine neonatal cerebellar cells, which offers an opportunity to assess the role of endogenous and exogenous factors on neural migration. We have used this system to test the hypothesis that treatment with methylmercury would inhibit movement of granule cell neurons, possibly via a cytokine-mediated mechanism. We demonstrate that LPS (50 ng/ml) increases movement of neurons, concomitant with increased levels of TNF-alpha and IL-6 secreted protein, and IL-1alpha mRNA. Treatment with LPS did not increase the number of neurons that moved, but, of the cells that did move, exposure to LPS significantly increased the total distances moved. Treatment with methylmercury (0.1 microM) decreased the number of moving cells and inhibited overall distance traveled by granule cells.

[1]  E. Cano,et al.  Tumor Necrosis Factor‐α (TNF‐α), Interferon‐γ, and Interleukin‐6 but Not TNF‐β Induce Differentiation of Neuroblastoma Cells: The Role of Nitric Oxide , 1994 .

[2]  R. Zinkernagel,et al.  On the cellular source and function of interleukin 6 produced in the central nervous system in viral diseases , 1989, European journal of immunology.

[3]  H. Cui,et al.  Potassium chloride inhibits proliferation of cerebellar granule neuron progenitors. , 1998, Brain research. Developmental brain research.

[4]  P. Moszczyński.  Mercury compounds and the immune system: a review. , 1997, International journal of occupational medicine and environmental health.

[5]  H. Cui,et al.  Methylmercury antagonizes the survival-promoting activity of insulin-like growth factor on developing cerebellar granule neurons. , 1998, Toxicology and applied pharmacology.

[6]  T. Burbacher,et al.  Changes in the number of astrocytes and microglia in the thalamus of the monkey Macaca fascicularis following long-term subclinical methylmercury exposure. , 1996, Neurotoxicology.

[7]  K. Reuhl,et al.  Altered sensitivity of posttranslationally modified microtubules to methylmercury in differentiating embryonal carcinoma-derived neurons. , 1997, Toxicology and applied pharmacology.

[8]  C. Regan.  Regulation of neural cell adhesion molecule sialylation state. , 1991, The International journal of biochemistry.

[9]  M. Mehler,et al.  Hematolymphopoietic and inflammatory cytokines in neural development , 1997, Trends in Neurosciences.

[10]  M. Monestier,et al.  Cytokine regulation of a rodent model of mercuric chloride-induced autoimmunity. , 1999, Environmental health perspectives.

[11]  J. Satoh,et al.  Cytokine‐lnduced Expression of Intercellular Adhesion Molecule‐1 (ICAM‐1) in Cultured Human Oligodendrocytes and Astrocytes , 1991, Journal of neuropathology and experimental neurology.

[12]  Roberta F. White,et al.  Milestone development in infants exposed to methylmercury from human milk. , 1995, Neurotoxicology.

[13]  D W Dickson,et al.  Cytokine production by human fetal microglia and astrocytes. Differential induction by lipopolysaccharide and IL-1 beta. , 1993, Journal of immunology.

[14]  Thomas M. Jessell,et al.  Chemotropic guidance of developing axons in the mammalian central nervous system , 1988, Nature.

[15]  U. Otten,et al.  Identification of interleukin-6 (IL-6)-expressing neurons in the cerebellum and hippocampus of normal adult rats , 1994, Neuroscience Letters.

[16]  M. Kunimoto,et al.  Migration of granule neurons in cerebellar organotypic cultures is impaired by methylmercury , 1997, Neuroscience Letters.

[17]  L. Lapham,et al.  ABNORMAL NEURONAL MIGRATION, DERANGED CEREBRAL CORTICAL ORGANIZATION, AND DIFFUSE WHITE MATTER ASTROCYTOSIS OF HUMAN FETAL BRAIN: A MAJOR EFFECT OF METHYLMERCURY POISONING IN UTERO , 1978, Journal of neuropathology and experimental neurology.

[18]  D. Giulian,et al.  Interleukin-1 is an astroglial growth factor in the developing brain , 1988, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[19]  W. Sheng,et al.  Tumor necrosis factor-alpha production by human fetal microglial cells: regulation by other cytokines. , 1995, Developmental neuroscience.

[20]  U. Otten,et al.  Neurotrophins: signals between the nervous and immune systems. , 1994, Progress in brain research.

[21]  K. Reuhl,et al.  Effects of methyl mercury on the microtubule system of mouse lymphocytes. , 1988, Toxicology and applied pharmacology.

[22]  J. Olmsted,et al.  Interaction of methylmercury with microtubules in cultured cells and in vitro. , 1983, Experimental cell research.

[23]  T. Hirano,et al.  Induction of neuronal differentiation in PC12 cells by B-cell stimulatory factor 2/interleukin 6 , 1988, Molecular and cellular biology.

[24]  K. Reuhl,et al.  Pathological effects of in utero methylmercury exposure on the cerebellum of the golden hamster. 1. Early effects upon the neonatal cerebellar cortex. , 1981, Environmental research.

[25]  K. Reuhl,et al.  Developmental methylmercury administration alters cerebellar PSA–NCAM expression and Golgi sialyltransferase activity , 1999, Brain Research.

[26]  V. Mareš,et al.  The cellular kinetics of the developing mouse cerebellum. I. The generation cycle, growth fraction and rate of proliferation of the external granular layer. , 1970, Brain research.

[27]  K. Reuhl,et al.  Pathological effects of in utero methylmercury exposure on the cerebellum of the golden hamster. II. Residual effects on the adult cerebellum. , 1981, Environmental research.

[28]  E. Benveniste,et al.  Adhesion molecule expression and regulation on cells of the central nervous system , 1999, Journal of Neuroimmunology.

[29]  F. Piva,et al.  Immortalized luteinizing hormone-releasing hormone neurons show a different migratory activity in vitro. , 2000, Endocrinology.

[30]  B. Weiss,et al.  Methylmercury developmental neurotoxicity: a comparison of effects in humans and animals. , 1990, Neurotoxicology and teratology.

[31]  U. Otten,et al.  Expression of interleukin-6 (IL-6) and interleukin-6 receptor (IL-6R) mRNAs in rat brain during postnatal development , 1994, Brain Research.

[32]  D. Mergler,et al.  Methylmercury exposure affects motor performance of a riverine population of the Tapajós river, Brazilian Amazon , 2000, International archives of occupational and environmental health.

[33]  P. Hultman,et al.  Methyl mercury-induced autoimmunity in mice. , 1999, Toxicology and applied pharmacology.

[34]  P. Rodier,et al.  Effects of methylmercury on developing mouse cerebellar cortex , 1982, Experimental Neurology.

[35]  D. Balomenos,et al.  The prototypic Th2 autoimmunity induced by mercury is dependent on IFN-gamma and not Th1/Th2 imbalance. , 1998, Journal of immunology.

[36]  T. Shirao,et al.  The effects of neurotrophin-3 and brain-derived neurotrophic factor on cerebellar granule cell movement and neurite extension in vitro , 2000, Neuroscience.

[37]  R. Novak,et al.  Developmental changes in the cellular distribution of glutathione and glutathione S-transferases in the murine nervous system. , 1995, Neurotoxicology.

[38]  I. Autenrieth,et al.  Early gamma interferon mRNA expression is associated with resistance of mice against Yersinia enterocolitica , 1994, Infection and immunity.

[39]  J. Merrill,et al.  Interactions of the nervous and immune systems in development, normal brain homeostasis, and disease 1 , 1995, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[40]  P. Sager.  Selectivity of methyl mercury effects on cytoskeleton and mitotic progression in cultured cells. , 1988, Toxicology and applied pharmacology.

[41]  J. P. Schwartz,et al.  Involvement of cytokines in normal CNS development and neurological diseases: Recent progress and perspectives , 1998, Journal of neuroscience research.

[42]  E. Coligan.  Current protocols in immunology , 1991 .

[43]  C. Regan.  Neural cell adhesion molecules, neuronal development and lead toxicity. , 1993, Neurotoxicology.

[44]  J. Pounds,et al.  Absorption and disposition of 203Hg in the pregnant and nonpregnant hamster following oral administration of [203Hg]methylmercuric chloride. , 1981, Environmental research.

[45]  Louis W. Chang,et al.  Effects of methylmercury on the development of the nervous system: A review , 1979 .

[46]  Immunization.,et al.  MERCURY EXPOSURE AND MURINE RESPONSE TO PLASMODIUM YOELIZ , 2000 .

[47]  T Takeuchi,et al.  FETAL MINAMATA DISEASE: A NEUROPATHOLOGICAL STUDY OF TWO CASES OF INTRAUTERINE INTOXICATION BY A METHYL MERCURY COMPOUND , 1965, Journal of neuropathology and experimental neurology.

[48]  M. Aschner,et al.  Persistent, differential alterations in developing cerebellar cortex of male and female mice after methylmercury exposure. , 1984, Brain research.

[49]  Roberta F. White,et al.  Cognitive deficit in 7-year-old children with prenatal exposure to methylmercury. , 1997, Neurotoxicology and teratology.

[50]  J. Merrill,et al.  Tumor necrosis factor alpha, interleukin 1 and related cytokines in brain development: normal and pathological. , 1992, Developmental neuroscience.

[51]  Choi Bh.  Methylmercury poisoning of the developing nervous system: I. Pattern of neuronal migration in the cerebral cortex. , 1986 .

[52]  E. Laws,et al.  Mechanisms of C6 glioma cell and fetal astrocyte migration into hydrated collagen I gels , 1992, Brain Research.

[53]  M. Shamy,et al.  Neuroimmunotoxicology: humoral assessment of neurotoxicity and autoimmune mechanisms. , 1999, Environmental health perspectives.