Alkyl Mercury-Induced Toxicity: Multiple Mechanisms of Action

Chapter
Part of the Reviews of Environmental Contamination and Toxicology book series (RECT, volume 240)

Abstract

There are a number of mechanisms by which alkylmercury compounds cause toxic action in the body. Collectively, published studies reveal that there are some similarities between the mechanisms of the toxic action of the mono-alkyl mercury compounds methylmercury (MeHg) and ethylmercury (EtHg). This paper represents a summary of some of the studies regarding these mechanisms of action in order to facilitate the understanding of the many varied effects of alkylmercurials in the human body. The similarities in mechanisms of toxicity for MeHg and EtHg are presented and compared. The difference in manifested toxicity of MeHg and EtHg are likely the result of the differences in exposure, metabolism, and elimination from the body, rather than differences in mechanisms of action between the two.

Keywords

Arachidonic acid Calcium homeostasis Cell cycle/division Ethylmercury Glial cells Glutamate Glutamine Glutathione (GSH) Leukotriene synthesis mechanism of toxicity Membrane permeability/integrity Methylmercury Mitochondria Neurotransmitter release nitric oxide Oxidative stress Reactive oxygen species Receptor binding ROS Thimerosal 

References

  1. Aschner M, Aschner JL (1990) Mercury neurotoxicity: mechanisms of blood-brain barrier transport. Neurosci Biobehav Rev 14(2):169–176CrossRefGoogle Scholar
  2. Atchison WD, Hare MF (1994) Mechanisms of methylmercury-induced neurotoxicity. FASEB J 8:622–629Google Scholar
  3. Bahia MO, De Amorim MI, Burbano RR, Vincent S, Dubeau H (1999) Genotoxic effects of mercury on in vitro cultures of human cells. An Acad Bras Cienc 71:437–443Google Scholar
  4. Bakir F, Damluji SF, Amin-Zaki, Murtadha M, Khalidi A, al-Rawi NY, Tikriti S, Dahahir HI, Clarkson TW, Smith JC, Doherty RA (1973) Methylmercury poisoning in Iraq. Science 181:230–241CrossRefGoogle Scholar
  5. Basu N, Scheuhammer AM, Rouvinen-Watt K, Evans RD, Grochowina N, Chan LHM (2008) The effects of mercury on muscarinic cholinergic receptor subtypes (M1 and M2) in captive mink. Neurotoxicology 29:328–334CrossRefGoogle Scholar
  6. Bearss JJ, Limke TL, Atchison WD (2001) Methylmercury (MeHg) causes calcium release from smooth endoplasmic reticulum (SER) inositol-1,4,5-triphosphate receptors in rat cerebellar granule neurons. Toxicology 60:184CrossRefGoogle Scholar
  7. Bernardi P, Petronilli V (1996) The permeability transition pore as a mitochondrial calcium release channel: a critical appraisal. J Bioenerg Biomembr 28:131–138CrossRefGoogle Scholar
  8. Bernardi P, Veronese P, Petronilli V (1993) Modulation of the mitochondrial cyclosporine A-sensitive permeability transition pore. I. Evidence for two separate Me2+ binding sites with opposing effects on the pore opening probability. J Biol Chem 268:1005–1010Google Scholar
  9. Bernardi P, Vassanelli S, Veronese P, Colonna R, Szabo I, Zorati M (1992) Modulation of the mitochondrial permeability transition pore. Effect of protons and divalent cations. J Biol Chem 267:2934–2939Google Scholar
  10. Budd SL, Nicholls DG (1996) A reevaluation of the role of mitochondrial in neuronal Ca2+ homeostasis. J Neurochem 66:403–411CrossRefGoogle Scholar
  11. Bultynck G, Szlufcik K, Nadif Kasri N, Assefa Z, Callewaert G, Missiaen L, Parys JB, De Smedt H (2004) Thimerosal stimulates Ca2+ flux through inositol 1,4,5-trisphosphate receptor type 1 but not type 3 via modulation of an isoform-specific Ca2+-dependent intramolecular interaction. Biochem J (published 11 Mar 2004 as ms BJ20040072):1–37Google Scholar
  12. Burke K, Cheng Y, Li B, Petrov A, Joshi P, Bermqn R, Reuhl K, DiCicco-Bloom E (2006) Methylmercury elicits rapid inhibition of cell proliferation in the developing brain and decreases cell cycle regulator, cyclin e. Neurotoxicology 27(6):970–981Google Scholar
  13. Carocci A, Rovito N, Sinicropi MS, Gehchi G (2014) Mercury toxicity and neurodegenerative effects. Rev Environ Contam Toxicol 229:1–18Google Scholar
  14. Castoldi AF, Barni S, Turin I, Gandini C, Manzo L (2000) Early acute necrosis, delayed apoptosis and cytoskeletal breakdown in cultured cerebellar granule neurons exposed to methylmercury. J Neurosci Res 59:775–787CrossRefGoogle Scholar
  15. CDC (2015) Centers for Disease Control and Prevention. Vaccines do not cause autism. http://www.cdc.gov/vaccinesafety/concerns/autism.html
  16. Chen YJ, Jiang H, Quilley J (2003) The nitric oxide- and prostaglandin-independent component of the renal vasodilator effect of thimerosal is mediated by epoxyeicosatrienoic acids. J Pharmacol Exp Ther 304(3):1292–1298CrossRefGoogle Scholar
  17. Chilton FH, Fonteh AN, Surette ME, Triggiani M, Winklaer JD (1996) Control of arachidonate levels within inflammatory cells. Biochim Biophys Acta 1299:1–15CrossRefGoogle Scholar
  18. Choi BH, Yee S, Robles M (1996) The effects of glutathione glycoside in methylmercury poisoning. Toxicol Appl Pharmacol 141(2):357–364CrossRefGoogle Scholar
  19. Chuu J-J, Hsu C-J, Lin-Shiau S-Y (2001) Abnormal auditory brainstem responses for mice treated with mercurial compounds: involvement of excessive nitric oxide. Toxicology 162:11–22CrossRefGoogle Scholar
  20. Clarkson TW (1995) Environmental contaminants in the food chain. Am J Clin Nutr 61(3):682s–686sGoogle Scholar
  21. Clarkson TW (1992) Mercury: major issues in environmental health. Environ Health Perspect 100:31–38CrossRefGoogle Scholar
  22. Clarkson TW, Magos L (2006) The toxicology of mercury and its chemical compounds. Crit Rev Toxicol 36(8):609–662CrossRefGoogle Scholar
  23. Clarkson TW, Vyas JB, Ballatori N (2007) Mechanisms of mercury disposition in the body. Am J Ind Med 50:757–764 (Review article)CrossRefGoogle Scholar
  24. Coccini T, Randine G, Candura SM, Nappi RE, Prockop LD, Manzo L (2000) Low-level exposure to methylmercury modifies muscarinic cholinergic receptor binding characteristics in rat brain and lymphocytes: physiologic implications and new opportunities in biologic monitoring. Environ Health Perspect 108(10):29–33CrossRefGoogle Scholar
  25. Cooper JR, Bloom FE, Roth RH (eds) (2003) The biochemical basis of neuropharmacology, 8th edn. Oxford University Press, OxfordGoogle Scholar
  26. Cossaboon JM, Ganguli PM, Flegal AR (2015) Mercury offloaded in Northern elephant seal hair affects coastal seawater surrounding rookery. Proc Natl Acad Sci U S A 112(39):12058–12052CrossRefGoogle Scholar
  27. Dey PM, Gochfeld M, Reuhl KR (1999) Developmental methylmercury administration alters cerebellar PSA-NCAM expression and Golgi sialyltransferase activity. Brain Res 845:139–151CrossRefGoogle Scholar
  28. Dreiem A, Seegal RF (2007) Methylmercury-induced changes in mitochondrial function in striatal synaptosomes are calcium-dependent and ROS-independent. Neurotoxicology 28:720–726CrossRefGoogle Scholar
  29. Driscoll CT, Mason RP, Chan HM, Jacob DJ, Pironne N (2013) Mercury as a global pollutant: sources, pathways, and effects. Environ Sci Technol 47:4967–4983CrossRefGoogle Scholar
  30. Eager KR, Dulhunty AF (1999) Cardiac ryanodine receptor activity is altered by oxidizing reagents in either luminal or cytoplasmic solution. J Membr Biol 167:205–214CrossRefGoogle Scholar
  31. Elferink JGR (1999) Thimerosal: a versatile sulfhydryl reagent, calcium mobilize, and cell function-modulating agent. Gen Pharmacol 33:1–6CrossRefGoogle Scholar
  32. Eskes C, Honegger P, Juillerat-Jeanneret L, Monett-Tschudi F (2002) Microglial reaction induced by noncytotoxic methylmercury treatment leads to neuroprotein via interactions with astrocytes and IL-6 release. Glia 37:43–52CrossRefGoogle Scholar
  33. Farina M, Frizzo MES, Soares FAA, Schwalm FD, Detrich MO, Zeni G, Rocha JBT, Souza DO (2003a) Ebselen protects against methylmercury-induced inhibition of glutamate uptake by cortical slices from adult mice. Toxicol Lett 144:351–357CrossRefGoogle Scholar
  34. Farina M, Dahm KCS, Schwalm FD, Brusque AM, Frizzo MES, Zeni G, Souza DO, Rocha JBT (2003b) Methylmercury increases glutamate release from brain synaptosomes and glutamate uptake by cortical slices from suckling rat pups: modulatory effect of ebselen. Toxicol Sci 73:135–140CrossRefGoogle Scholar
  35. Faro LRF, do Nascimento JLM, Campos F, Vidal L, Alfonso M, Duran R (2005) Protective effects of glutathione and cysteine on the methylmercury-induced striatal dopamine release in vivo. Life Sci 77:444–451CrossRefGoogle Scholar
  36. Faro LRF, do Nascimento JLM, Alfonso M, Duran R (2002) Mechanism of action of methylmercury on in vivo striatal dopamine release: possible involvement of dopamine transporter. Neurochem Int 40:455–465CrossRefGoogle Scholar
  37. Faro LR, do Nascimento JL, San Jose JM, Alfonso M, Durán R (2000) Intrastriatal administration of methylmercury increases in vivo dopamine release. Neurochem Res 25:225–229CrossRefGoogle Scholar
  38. Faustman EM, Ponce RA, Ou YC, Mendoza MAC, Lewandowski TL, Kavanagh T (2002) Investigations of methylmercury-induced alterations in neurogenesis. Environ Health Perspect 110(Suppl 5):859–864CrossRefGoogle Scholar
  39. Fonfria E, Rodrigues-Farre E, Sunol C (2001) Mercury interaction with the GABAA receptor modulates the benzodiazepine binding site in primary cultures of mouse cerebellar granule cells. Neuropharmacology 41:819–833CrossRefGoogle Scholar
  40. Franco JL, Teixeira A, Meotti FC, Ribas CM, Stringari J, Pomblum SCG, Moro AM, Bohrer D, Bairos AV, Dafre AL, Santos ARS, Farina M (2006) Cerebellar thiol status and motor deficit after lactational exposure to methylmercury. Environ Res 102:22–28CrossRefGoogle Scholar
  41. Gao Y, Ding W, Shi R, Tian Y (2008) Effects of methylmercury on postnatal neurobehavioral development in mice. Neurotoxicol Teratol 30(6):462–467CrossRefGoogle Scholar
  42. Gardner PR, Nguyen DD, White CW (1994) Aconitase is a sensitive and critical target of oxygen poisoning in cultured mammalian cells and in rat lungs. Proc Natl Acad Sci U S A 91:12248–12252CrossRefGoogle Scholar
  43. Garg TK, Chang IY (2006) Methylmercury causes oxidative stress and cytotoxicity in microglia: attenuation by 15-deoxy-delat 12, 14-prostaglandin J2. J Neuroimmunol 171(1–2):17–28CrossRefGoogle Scholar
  44. Goll DE, Thompson VF, Li H, Wei W, Cong J (2003) The caplain system. Physiol Rev 83(3):731–801CrossRefGoogle Scholar
  45. Green AK, Cobbold PH, Dixon CJ (1999) Thimerosal enhances agonist-specific differences between [Ca2+]i oscillations induced by phenylephrine and ATP in single rat hepatocytes. Cell Calcium 25:173178CrossRefGoogle Scholar
  46. Gribble EJ, Hong S-W, Faustman EM (2005) The magnitude of methylmercury-induce cytotoxicity and cell arrest is p53-dependent. Birth Def Res A Clin Mol Teratol 73(1):29–38CrossRefGoogle Scholar
  47. Guroff G (1963) A neutral calcium-activated proteinase from the soluble fraction of rat brain. J Biol Chem 239:149–155Google Scholar
  48. Haldane H, Sullivan DM (2001) DNA topoisomerase II-catalyzed DNA decantation. In: Osheroff N, Bjornsti M-A (eds) Methods of molecular biology 95: DNA topoisomerase protocols: enzymology and drugs. Humana Press Inc., Totowa, NJGoogle Scholar
  49. Halliwell B (1992) Reactive oxygen species and the central nervous system. J Neurochem 59(5):16091623CrossRefGoogle Scholar
  50. Hardin JG, Limbird LE (2001) In: Hardin JG, Limbird LE (eds) Goodman and Gilman’s the pharmacological basis of therapeutics, 10th edn. McGraw-Hill Medical Publishing Division, New YorkGoogle Scholar
  51. Hare MF, McGinnis KM, Atchison WD (1993) Methylmercury increases intracellular concentrations of Ca++ and heavy metals in NG108-15 cells. J Pharmacol Exp Ther 266(3):1626–1635Google Scholar
  52. Hasinoff BB, Wu X, Yalowich JC, Goodfellow B, Laufer RS, Adedayo O, Dmitrienko GI (2006) Kinamycins A and C, bacterial metabolites that contain an unusual diazo group, as potential new anticancer agents: antiproliferative and cell effects. Anticancer Drugs 17:825–837CrossRefGoogle Scholar
  53. Hatzelmann A, Haurand M, Ullrich V (1990) Involvement of calcium in the thimerosal-stimulated formation of leukotriene by fMLP in human polymorphonuclear leukocytes. Biochem Pharmacol 39(3):559–567CrossRefGoogle Scholar
  54. Hughes WL (1957) A physiochemical rationale for the biologic activity of mercury and its compounds. Ann N Y Acad Sci 65:454–460CrossRefGoogle Scholar
  55. Ida-Eto M, Oyabu A, Ohkawara T, Tashiro Y, Narita N, Narita M (2013) Prenatal exposure to organomercury, thimerosal, persistently impairs the serotonergic and dopaminergic systems in the rat brain: Implications for association with developmental disorders. Brain Dev 35:261–264CrossRefGoogle Scholar
  56. Ida-Eto M, Oyabu A, Ohkawara T, Tashiro Y, Narita N, Narita M (2011) Embryonic exposure to thimerosal, an organomercury compound, causes abnormal early development of serotonergic neurons. Neurosci Lett 505:61–64CrossRefGoogle Scholar
  57. Jalili HA, Abbasi AH (1961) Poisoning by ethyl mercury toluene sulfonanilide. Br J Ind Med 18:303–308Google Scholar
  58. Kaever V, Goppelt-Strube M, Resch K (1988) Enhancement of eicosanoid synthesis in mouse peritoneal macrophages by the organic mercury compound thimerosal. Prostaglandins 35(6):885–902CrossRefGoogle Scholar
  59. Kang MS, Jeong JY, Seo JH, Jeon HJ, Jung KM, Chin M-R, Moon C-K, Bonventre JV, Jung SY, Kim DK (2006) Methylmercury-induced toxicity is mediated by enhanced intracellular calcium through activation of phosphatidylcholine-specific phospholipase C. Toxicol Appl Pharmacol 216:206–215CrossRefGoogle Scholar
  60. Kim Y-J, Kim Y-S, Kim M-S, Ryu J-C (2007) The inhibitory mechanism of methylmercury on differentiation of human neuroblastoma cells. Toxicology 234(1–2):1–9CrossRefGoogle Scholar
  61. Kinoshita Y, Ohnishi A, Kohaki K, Yokota A (1999) Apparent diffusion coefficient on rat brain and nerves intoxicated with methylmercury. Environ Res 80:348–354CrossRefGoogle Scholar
  62. Kutsuna M (ed) (1968) Minamata disease. Study group of Minamata disease. Kumamatio University, Japan, pp 1–4Google Scholar
  63. Lee MS, Kwon YT, Li M, Peng J, Friedlander RM, Tsai LH (2000) Neurotoxicity induces cleavage of p35 to p25 by caplain. Nature 405:360–364CrossRefGoogle Scholar
  64. Limke TL, Heidemann SR, Atchison WD (2004a) Disruption of intraneuronal divalent cation regulation by methylmercury: Are specific targets involved in altered neuronal development and cytotoxicity in methylmercury poisoning? Neurotoxicology 25:741–760CrossRefGoogle Scholar
  65. Limke TL, Bearss JJ, Atchison WD (2004b) Acute exposure to methylmercury causes Ca2+ dysregulation and neuronal death in rat cerebellar granule cells through an M3 muscarinic receptor linked pathway. Toxicol Sci 80:60–68CrossRefGoogle Scholar
  66. Limke TL, Otero-Montanez JK, Atchison WD (2003) Evidence for interactions between intracellular calcium stores during methylmercury-induced intracellular calcium dysregulation in rat cerebellar granule neurons. J Pharmacol Exp Ther 304:949–958CrossRefGoogle Scholar
  67. Limke TL, Atchison WD (2002) Acute exposure to methylmercury opens the mitochondrial permeability transition pore in rat cerebellar granule cells. Toxicol Appl Pharmacol 178:52–61CrossRefGoogle Scholar
  68. Machaty Z, Wang WH, Day BN, Prather RS (1999) Calcium release and subsequent development induced by modification of sulfhydryl groups in porcine oocytes. Biol Reprod 61:1384–1391CrossRefGoogle Scholar
  69. Maden M, Holder N (1992) Retinoic acid and development of central nervous system. Bioessays 14:431–438CrossRefGoogle Scholar
  70. Maden M, Holder N (1991) The involvement of retinoic acid in the development of the vertebrate central nervous system. Development Suppl. 2:87–94Google Scholar
  71. Maden M, Ong DE, Chytil F (1990) Retinoid-binding protein distribution in the developing mammalian nervous system. Development 109(1):75–80Google Scholar
  72. Makino K, Okuda K, Sugino E, Nishiya T, Toyama T, Iwawaki T, Fujimura M, Kumagai Y, Uchara T (2014) Correlation between attenuation of protein disulfide isomerase activity through S-mercuration and neurotoxicity induced by methylmercury. Neurotox Res 27:99–105. doi:10.1007/s12640-014-9494-8 CrossRefGoogle Scholar
  73. Manfroi CB, Schwalm FD, Cereser V, Abreu F, Oliveira A, Bizarro L, Rocha JBT, Frizzo MES, Souza DO, Faroma M (2004) Maternal milk as methylmercury source for suckling mice: neurotoxic effects involved with the cerebellar glutamatergic system. Toxicol Sci 81:172–178CrossRefGoogle Scholar
  74. Marty MS, Atchison WD (1997) Pathways mediating Ca2+ entry in rat cerebellar granule cells following in vitro exposure to methyl mercury. Toxicol Appl Pharmacol 147:319–330CrossRefGoogle Scholar
  75. Mash DC, Flynn DD, Polter LT (1985) Loss of M2 muscarinic receptors in the cerebral cortex in Alzheimer’s disease and experimental cholinergic denervation. Science 228:1115–1117CrossRefGoogle Scholar
  76. Mason MJ, Mahaut-Smith MP (2001) Voltage-dependent Ca 2+ release in rat megakaryocytes requires functional IP3 receptors. J Physiol 533:175–183CrossRefGoogle Scholar
  77. Minnema DJ, Cooper GP, Greenland RD (1987) Effects of methylmercury on neuro-transmitter release from rat brain synaptosomes. Toxicol Appl Pharmacol 99(3):510–521CrossRefGoogle Scholar
  78. Miura K, Koide N, Himeno S, Nakagawa I, Imura N (1999) The involvement of microtubular disruption in methylmercury-induced apoptosis in neuronal and nonneuronal cell lines. Toxicol Appl Pharmacol 160:279–288CrossRefGoogle Scholar
  79. Miyamoto K, Nakanishi H, Moriguchi S, Fukuyama N, Eto K, Wakammiya J, Murao K, Arimura K, Osame M (2001) Involvement of enhanced sensitivity of N-methyl-D-aspartate receptors in vulnerability of developing cortical neurons to methylmercury neurotoxicity. Brain Res 901:252–258CrossRefGoogle Scholar
  80. Mori N, Yasutake A, Hirayama K (2007) Comparative study of activities in reactive oxygen species production/defense system in mitochondria of rat brain and liver, and their susceptibility to methylmercury toxicity. Arch Toxicol 81(11):769–778CrossRefGoogle Scholar
  81. Muller M, Westphal G, Vesper A, Bunger J, Hallier E (2001) Inhibition of the human erythrocytic glutathione-S-transferase T1 (GST T1) by thimerosal. Int J Hyg Environ Health 203(5-6):479–481CrossRefGoogle Scholar
  82. Mutkus L, Aschnr JL, Syversen T, Shanker G, Sonnewald U, Aschner M (2005) In vitro uptake of glutamate in GLAST- and GLT-1-transfected mutant CHO-K1 cells is inhibited by the ethylmercury-containing preservative thimerosal. Biol Trace Elem Res 105(1–3):71–86CrossRefGoogle Scholar
  83. Myhre O, Andersen JM, Aarnes H, Fonnum F (2003) Evaluation of the probes 2′7′-dichlorofluoresein diacetate, luminal, and lucigenin as indicators of reactive species formation. Biochem Pharmacol 65(10):1575–1582CrossRefGoogle Scholar
  84. Nath R, Davis M, Probert AW, Kupina NC, Ren X, Schielke GP, Wang KW (2000) Processing of cdk5 activator p35 to its truncated form (p25) by calpain in acutely injured neuronal cells. Biochem Biophys Res Commun 274:16–21CrossRefGoogle Scholar
  85. Ndountse LT, Chan HM (2008) Methylmercury increases N-methyl-D-aspartate receptors on human SH-SY 5Y neuroblastoma cells leading to neurotoxicity. Toxicology 249:251–255CrossRefGoogle Scholar
  86. Oppedisano F, Pochini L, Broer S, Indiveri C (2011) The BoAT1 amino acid transporter from rat kidney reconstituted in liposomes: kinetics and inactivation by methylmercury. Biochim Biophys Acta 1808:2551–2558CrossRefGoogle Scholar
  87. Oppedisano F, Galluccio M, Indiveri C (2010) Inactivation by Hg2+ and methylmercury of the glutamine/amino acid transporter (ASCT2) reconstituted in liposomes: prediction of the involvement of a CXXC motif by homology modeling. Biochem Pharmacol 80:1266–1273CrossRefGoogle Scholar
  88. Oslowski CM, Urano F (2011) Measuring ER stress and the unfolded protein response using mammalian tissue culture system. Methods Enzymol 490:71–92CrossRefGoogle Scholar
  89. Ou YC, White CC, Krejsa CM, Ponce RA, Kavanagh TJ, Faustman EM (1999a) The role of intracellular glutathione in methylmercury-induced toxicity in embryonic neural cells. Neurotoxicology 20:793–804Google Scholar
  90. Ou YC, Thompson SA, Ponce RA, Schroeder J, Kavanagh TJ, Faustman EM (1999b) Induction of the cell cycle regulatory gene p21 (WAF1, C1P1) following methylmercury exposure in vitro and in vivo. Toxicol Appl Pharmacol 157(3):203–212CrossRefGoogle Scholar
  91. Palacin M, Estevez R, Bertran J, Zorzano A (1998) Molecular biology of mammalian plasma membrane amino acid transporters. Physiol Rev 78:969–1054Google Scholar
  92. Paemeleire K, de Hemptinne A, Leybaert L (1999) Chemically, mechanically, and hyperosmolarity induced calcium responses of rat cortical capillary endothelial cells in culture. Exp Brain Res 126:473–481CrossRefGoogle Scholar
  93. Peng S, Hajela RK, Atchison WD (2002) Effects of methylmercury on human neuronal L-type calcium channels transiently expressed in human embryonic kidney cells (HEK-293). J Pharmacol Exp Ther 302(2):424–432CrossRefGoogle Scholar
  94. Perez-Castro AV, Toth-Rogler LE, Wei L-N, Nguyen-Huu MC (1989) Spatial and temporal pattern of expression of the cellular retinol-binding protein during mouse embryogenesis. Proc Natl Acad Sci U S A 86(22):8813–8817CrossRefGoogle Scholar
  95. Pochini L, Peta V, Indiveri C (2013) Inhibition of the OCTN2 carnitine transporter by HgCl(2) and methylmercury in the proteoliposome experimental model: insights in the mechanism of toxicity. Toxicol Mech Methods 23(2):68–76CrossRefGoogle Scholar
  96. Randall A, Tsien RW (1995) Pharmacological dissection of multiple types of Ca2+ channel currents in rat cerebellar granule neurons. J Neurosci 15:2995–3012Google Scholar
  97. Rodier PM, Aschner M, Sager PR (1984) Mitotic arrest in the developing CNS after prenatal exposure to methylmercury. Neurobehav Toxicol Teratol 6:379–385Google Scholar
  98. Ron D, Walter P (2007) Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol 8:519–529CrossRefGoogle Scholar
  99. Ruberte E, Friederich V, Chambon P, Morriss-Kay G (1993) Retinoic acid receptors and cellular retinoid binding proteins. III. Their differential transcript distribution during mouse nervous system development. Development 118(1):267–282Google Scholar
  100. Sakaue M, Okazaki M, Hara S (2005) Very low levels of methylmercury induce cell death of cultured rat cerebellar neurons via calpain activation. Toxicology 213:97–106CrossRefGoogle Scholar
  101. Samuelsson B (1982) From studies of biochemical mechanisms to novel biological mediators: prostaglandin endoperoxides, thromboxanes and leukotrienes. Nobel Lecture, December 8, 1982. Department of Physiological Chemistry, Karolinska Institutet, S-104 01 Stockholm, SwedenGoogle Scholar
  102. Samuelsson B (1983) Leukotrienes: mediators of immediate hypersensitivity reactions and inflammation. Science 220:568–575CrossRefGoogle Scholar
  103. Samuelsson B, Dahlen S-E, Lindgren JA, Rouzer CA, Serhan CN (1987) Leukotrienes and lipoxins: structures, biosynthesis, and biological effects. Science 237:1171–1176CrossRefGoogle Scholar
  104. Sayers LG, Brown GR, Michell RH, Michelangeli F (1993) The effects of thimerosal on calcium uptake and inositol 1,4,5-trisphosphate-induced calcium release in cerebellar microsomes. Biochem J 289:883887CrossRefGoogle Scholar
  105. Seewagen CL (2010) Threats of environmental mercury to birds: knowledge gaps and priorities for future research. Bird Conserv Int 20:112–123Google Scholar
  106. Shanker G, Matkus LS, Walker SJ, Aschner M (2002) Methylmercury enhances arachidonic acid release and cytosolic phospholipase A2 expression in primary cultures of neonatal astrocytes. Mol Brain Res 106:1–11CrossRefGoogle Scholar
  107. Sharpe MA, Livingston AD, Baskin DS (2012) Thimerosal-derived ethylmercury is a mitochondrial toxin in human astrocytes: possible role of Fenton chemistry in the oxidation and breakage of mtDNA. J Toxicol 2012: Article ID 373678Google Scholar
  108. Shinyashiki M, Kumagai Y, Nakajima H, Nagafune J, Homma-Takeda S, Sagai M, Shimojo N (1998) Differential changes in rat brain nitric oxide synthase in vivo and in vitro by methylmercury. Brain Res 798:147–155CrossRefGoogle Scholar
  109. Simmons-Willis TA, Koh AS, Clarkson TW, Ballatori N (2002) Transport of a neurotoxicant by molecular mimicry: the methylmercury-L-cysteine complex is a substrate for human L-type large neutral amino acid transporter (LAT) 1 and LAT2. Biochem J 367:239–246CrossRefGoogle Scholar
  110. Sirois JE, Atchison WD (2000) Methylmercury affects multiple subtypes of calcium channels in rat cerebellar granule cells. Toxicol Appl Pharmacol 167:1–11CrossRefGoogle Scholar
  111. Sitsapesan R, Williams AJ (2000) Do inactivation mechanisms rather than adaptation hold the key to understanding ryanodine receptor channel gating? J Gen Physiol 116:867–872CrossRefGoogle Scholar
  112. Song J, Jang YY, Shin YK, Lee MY, Lee C-S (2000) Inhibitory action of thimerosal, a sulfhydryl oxidant, on sodium channels in rat sensory neurons. Brain Res 864(1):105–113CrossRefGoogle Scholar
  113. Stuning M, Brom J, Konig W (1988) Multiple effects of ethylmercurithiosalicylate on the metabolization of arachidonic acid by human neutrophils. Prostaglandins Leukot Essent Fatty Acids 32:1–7CrossRefGoogle Scholar
  114. Szalai G, Krishnamurthy R, Hajnoczky G (1999) Apoptosis driven by IP3-linked mitochondrial calcium signals. EMBO J 18(22):6349–6361CrossRefGoogle Scholar
  115. Tornquist K, Vainio P, Titievsky A (1999) Redox modulation of intracellular free calcium concentration in thyroid FRTL-5 cells; evidence for an enhanced extrusion of calcium. Biochem J 339:621–628CrossRefGoogle Scholar
  116. Vanlingen S, Sipma H, Missianen L, De Smedt H, De Smet P, Casteels R, Parys JB (1999) Modulation of type 1, 2, and 3 inositol 1,4,5-trisphosphate receptors by cyclic ADP-ribose and thimerosal. Cell Calcium 25:107–114CrossRefGoogle Scholar
  117. Verity MA, Sarafian T, Pacifici EHK, Sevanian A (1994) Phospholipase A2 stimulation by MeHg in neuron culture. J Neurochem 62(2):705–714CrossRefGoogle Scholar
  118. Verrey F, Meier C, Rossier G, Kuhn LC (2000) Glycoprotein-associated amino acid exchangers: broadening the range of transport specificity. Plfugers Arch 440:503–512CrossRefGoogle Scholar
  119. Wall SJ, Yasuda RP, Li M, Ciesla W, Wolf BB (1992) Differential regulation of subtypes M1-M5 of muscarinic receptors in forebrain by chronic atropine administration. J Pharmacol Exp Ther 262(2):584–588Google Scholar
  120. Wang WH, Machaty Z, Abeydeera LF, Prather RS, Day BN (1999) Time course of cortical and zona reactions of pig oocytes upon intracellular calcium increase induced by thimerosal. Zygote 7:79–86CrossRefGoogle Scholar
  121. Weihe P, Grandjean P, Debes F, White R (1996) Health implications for Faroe Islanders of heavy metals and PCBs from pilot whales. Sci Total Environ 186:141–148CrossRefGoogle Scholar
  122. Wu X, Liang H, O’Hara KA, Yalowich JC, Hasinoff BB (2008) Thiol-modulated mechanisms of the cytotoxicity of thimerosal and inhibition of DNA topoisomerase H alpha. Chem Res Toxicol 21(2):483–493CrossRefGoogle Scholar
  123. Yates DE, Mayack DT, Munney K, Evers DC, Major A, Kaur T, Taylor RJ (2005) Mercury levels in mink (Mustels vison) and river otter (Lontra canadensis) from northeastern North America. Ecotoxicology 14:263–274CrossRefGoogle Scholar
  124. Yin Z, Milatovic D, Aschner JL, Syversen T, Rocha JBT, Souza DO, Sidoryk M, Albrecht J, Aschner M (2007) Methylmercury induces oxidative injury, alterations in permeability and glutamine transport in cultured astrocytes. Brain Res 1131(1):1–10CrossRefGoogle Scholar
  125. Yuan Y, Atchison WD (2003) Methylmercury differentially affects GABAA receptor-mediated spontaneous IPSCs in Purkinje and granule cells of rat cerebellar slices. J Physiol 550(1):191–204CrossRefGoogle Scholar
  126. Zarini S, Gijon MA, Folco G, Murphy RC (2006) Effect of arachidonic acid reacylation on leukotriene biosynthesis in human neutrophils stimulated with granulocyte-macrophage colony stimulating factor and formyl-methionyl-leucyl-phenylalanine. J Biol Chem 281(15):10134–10142CrossRefGoogle Scholar
  127. Zhang J (1984) Clinical observations in ethyl mercury chloride poisoning. Am J Ind Med 8:251–258CrossRefGoogle Scholar

Copyright information

© Springer 2016

Authors and Affiliations

  1. 1.Division of Toxicology and Human Health SciencesAgency for Toxic Substances and Disease RegistryAtlantaUSA

Personalised recommendations