Michael Aschner
Michael Aschner received a Ph.D. degree from the Department of Anatomy and Neurobiology, School of Medicine and Dentistry, University of Rochester, in 1985. He is currently the Gray E. B. Stahlman Professor of Neuroscience in the Department of Pediatrics at the Vanderbilt University Medical Center in Nashville, Tenn. He also holds joint appointments at the Kennedy Center and in the Department of Pharmacology. Dr. Aschner's research interests are in the neurobiology and physiology of astrocytes and the mechanisms of central nervous system injury. Dr. Aschner has been particularly interested in metal uptake and distribution in the brain, devoting the last 20 years of his research to the mechanisms of transport of methylmercury, manganese, and uranium across the endothelium composing the blood-brain barrier, as well as their cellular and molecular mechanisms of neurotoxicity. His current studies address gene environment interactions in mercury and manganese induced neurotoxicity, and are carried out in C. elegans, rats. The impact of manganese on neurodevelopment is assessed in human neonates by means of MRI. Dr. Aschner has served on numerous national and international toxicology panels (Institute of Medicine, EPA, CDC), and served and chaired the ALTX-3 NIH study section. He has authored about 250 peer-reviewed manuscripts and chapters in the area of neurotoxicology. He serves as an Associate Editor for a number of journals, including Neurotoxicology and Toxicological Sciences. He is the PI on DoD grants and NIH grants. He is a member of SOT since 1985 and ATS since 1997. In the past, he chaired the Placement Committee of the SOT, and held the presidency of the International Neurotoxicology Association (ASN).
Biography Updated on 13 January 2008
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Articles in Scholarly Journals [Incomplete List]
- Methylmercury induces oxidative injury, alterations in permeability and glutamine transport in cultured astrocytes
Brain Research, vol. 1131, pp. 1–10, 2007 - Neuroprotection by tamoxifen in focal cerebral ischemia is not mediated by an agonist action at estrogen receptors but is associated with antioxidant activity
Experimental Neurology, vol. 204, no. 2, pp. 819–827, 2007 - Down-regulation of early ionotrophic glutamate receptor subunit developmental expression as a mechanism for observed plasticity deficits following gestational exposure to benzo(a)pyrene
NeuroToxicology, vol. 28, no. 5, pp. 965–978, 2007 - Modulation of cholinergic systems by manganese
NeuroToxicology, vol. 28, no. 5, pp. 1003–1014, 2007 - Neuronal oxidative injury and dendritic damage induced by carbofuran: Protection by memantine?
Toxicology and Applied Pharmacology, vol. 219, no. 2-3, pp. 97–105, 2007 - Manganese: Recent advances in understanding its transport and neurotoxicity
Toxicology and Applied Pharmacology, vol. 221, no. 2, pp. 131–147, 2007 - Role of glutathione in determining the differential sensitivity between the cortical and cerebellar regions towards mercury-induced oxidative stress
Toxicology, vol. 230, no. 2-3, pp. 164–177, 2007 - Manganese neurotoxicity: A focus on the neonate
Pharmacology & Therapeutics, vol. 113, no. 2, pp. 369–377, 2007 - Manganese Inhalation by Rhesus Monkeys is Associated with Brain Regional Changes in Biomarkers of Neurotoxicity
Toxicological Sciences, vol. 97, no. 2, pp. 459–466, 2007 - Manganese Induces Oxidative Impairment in Cultured Rat Astrocytes
Toxicological Sciences, vol. 98, no. 1, pp. 198–205, 2007 - Polymorphic ventricular tachycardia and abnormal Ca2+ handling in very-long-chain acyl-CoA dehydrogenase null mice
AJP: Heart and Circulatory Physiology, vol. 292, no. 5, pp. H2202–H2211, 2007 - Putative proteins involved in manganese transport across the blood-brain barr 1ier
Human & Experimental Toxicology, vol. 26, no. 4, pp. 295–302, 2007 - Involvement of glutamate and reactive oxygen species in methylmercury neurotoxicity
Brazilian Journal of Medical and Biological Research, vol. 40, no. 3, 2007 - Mercuric Chloride Inhibits the In Vitro Uptake of Glutamate in GLAST- and GLT-1-Transfected Mutant CHO-K1 Cells
Biological Trace Element Research, vol. 109, no. 3, pp. 267–280, 2006 - Neurotoxicity of Depleted Uranium: Reasons for Increased Concern
Biological Trace Element Research, vol. 110, no. 1, pp. 1–18, 2006 - Depleted Uranium Is Not Toxic to Rat Brain Endothelial (RBE4) Cells
Biological Trace Element Research, vol. 110, no. 1, pp. 61–72, 2006 - Brain Accumulation of Depleted Uranium in Rats Following 3- or 6-Month Treatment With Implanted Depleted Uranium Pellets
Biological Trace Element Research, vol. 111, no. 1-3, pp. 185–198, 2006 - Alterations of Oxidative Stress Biomarkers Due to In Utero and Neonatal Exposures of Airborne Manganese
Biological Trace Element Research, vol. 111, no. 1-3, pp. 199–216, 2006 - A Manganese-Enhanced Diet Alters Brain Metals and Transporters in the Developing Rat
Toxicological Sciences, vol. 92, no. 2, pp. 516–525, 2006 - Iron Deficient and Manganese Supplemented Diets Alter Metals and Transporters in the Developing Rat Brain
Toxicological Sciences, vol. 95, no. 1, pp. 205–214, 2006 - Determining the oxidation states of manganese in NT2 cells and cultured astrocytes
Neurobiology of Aging, vol. 27, no. 12, pp. 1816–1826, 2006 - The effects of manganese on glutamate, dopamine and ?-aminobutyric acid regulation
Neurochemistry International, 2006 - Manganese in the shower: Mere speculation over an invalidated public health danger
Medical Hypotheses, vol. 66, no. 1, pp. 200–201, 2006 - Growth hormone administration to aged animals reduces disulfide glutathione levels in hippocampus
Mechanisms of Ageing and Development, vol. 127, no. 1, pp. 57–63, 2006 - Characteristics of manganese (Mn) transport in rat brain endothelial (RBE4) cells, an in vitro model of the blood–brain barrier
NeuroToxicology, vol. 27, no. 1, pp. 60–70, 2006 - Increased manganese uptake by primary astrocyte cultures with altered iron status is mediated primarily by divalent metal transporter
NeuroToxicology, vol. 27, no. 1, pp. 125–130, 2006 - The transport of manganese across the blood–brain barrier?
NeuroToxicology, vol. 27, no. 3, pp. 311–314, 2006 - Glutathione modulation influences methyl mercury induced neurotoxicity in primary cell cultures of neurons and astrocytes
NeuroToxicology, vol. 27, no. 4, pp. 492–500, 2006 - The use of magnetic resonance imaging (MRI) in the study of manganese neurotoxicity
NeuroToxicology, vol. 27, no. 5, pp. 798–806, 2006 - Speciation of manganese in cells and mitochondria: A search for the proximal cause of manganese neurotoxicity
NeuroToxicology, vol. 27, no. 5, pp. 765–776, 2006 - Effects of inhaled manganese on biomarkers of oxidative stress in the rat brain
NeuroToxicology, vol. 27, no. 5, pp. 788–797, 2006 - Cultured lymphocytes from autistic children and non-autistic siblings up-regulate heat shock protein RNA in response to thimerosal challenge
NeuroToxicology, vol. 27, no. 5, pp. 685–692, 2006 - Nutritional aspects of manganese homeostasis
Molecular Aspects of Medicine, vol. 26, no. 4-5, pp. 353–362, 2005 - Determining the oxidation states of manganese in PC12 and nerve growth factor-induced PC12 cells
Free Radical Biology and Medicine, vol. 39, no. 2, pp. 164–181, 2005 - Interactions between excessive manganese exposures and dietary iron-deficiency in neurodegeneration
Environmental Toxicology and Pharmacology, vol. 19, no. 3, pp. 415–421, 2005 - Manganese accumulation in striatum of mice exposed to toxic doses is dependent upon a functional dopamine transporter
Environmental Toxicology and Pharmacology, vol. 20, no. 3, pp. 390–394, 2005 - Manganese transport by rat brain endothelial (RBE4) cell-based transwell model in the presence of astrocyte conditioned media
Journal of Neuroscience Research, vol. 81, no. 2, pp. 235–243, 2005 - Modulatory effect of glutathione status and antioxidants on methylmercury-induced free radical formation in primary cultures of cerebral astrocytes
Molecular Brain Research, vol. 137, no. 1-2, pp. 11–22, 2005 - The importance of glutamate, glycine, and ?-aminobutyric acid transport and regulation in manganese, mercury and lead neurotoxicity
Toxicology and Applied Pharmacology, vol. 204, no. 3, pp. 343–354, 2005 - Manganese Dosimetry: Species Differences and Implications for Neurotoxicity
Critical Reviews in Toxicology, vol. 35, no. 1, pp. 1–32, 2005 - Effects of Methylmercury on Primary Brain Cells in Mono- and Co-culture
Toxicological Sciences, vol. 87, no. 1, pp. 169–175, 2005 - Methylmercury
Therapeutic Drug Monitoring, vol. 27, no. 3, pp. 278–283, 2005 - Acrylamide Stimulates Glutamine Uptake in Fischer 344 Rat Astrocytes by a Mechanism Involving Upregulation of the Amino Acid Transport System N
Annals of the New York Academy of Sciences, vol. 1053, no. 1, pp. 435–443, 2005 - Effects of Acrylamide on Primary Neonatal Rat Astrocyte Functions
Annals of the New York Academy of Sciences, vol. 1053, no. 1, pp. 444–454, 2005 - Persistent Alterations in Biomarkers of Oxidative Stress Resulting from Combined In Utero and Neonatal Manganese Inhalation
Biological Trace Element Research, vol. 104, no. 2, pp. 151–164, 2005 - The In Vitro Uptake of Glutamate in GLAST and GLT-1 Transfected Mutant CHO-K1 Cells Is Inhibited by Manganese
Biological Trace Element Research, vol. 107, no. 3, pp. 221–230, 2005 - Methylmercury Alters the In Vitro Uptake of Glutamate in GLAST- and GLT-1-Transfected Mutant CHO-K1 Cells
Biological Trace Element Research, vol. 107, no. 3, pp. 231–246, 2005 - Manganese Neurotoxicity
Annals of the New York Academy of Sciences, vol. 1012, no. 1, pp. 115–128, 2004 - DEVELOPMENTAL NEUROPATHOLOGY OF ENVIRONMENTAL AGENTS
Annual Review of Pharmacology and Toxicology, vol. 44, no. 1, pp. 87–110, 2004 - Manganese exposure and induced oxidative stress in the rat brain
Science of The Total Environment, vol. 334-335, pp. 409–416, 2004 - Free radical formation in cerebral cortical astrocytes in culture induced by methylmercury
Molecular Brain Research, vol. 128, no. 1, pp. 48–57, 2004 - Manganese-Induced Cytotoxicity in Dopamine-Producing Cells*1
NeuroToxicology, vol. 25, no. 4, pp. 543–553, 2004 - Methylmercury Stimulates Arachidonic Acid Release and Cytosolic Phospholipase A2 Expression in Primary Neuronal Cultures
NeuroToxicology, vol. 25, no. 3, pp. 399–406, 2004 - Globus pallidus: a target brain region for divalent metal accumulation associated with dietary iron deficiency
The Journal of Nutritional Biochemistry, vol. 15, no. 6, pp. 335–341, 2004 - Brain barrier systems: a new frontier in metal neurotoxicological research
Toxicology and Applied Pharmacology, vol. 192, no. 1, pp. 1–11, 2003 - Oxidative Stress Is Induced in the Rat Brain Following Repeated Inhalation Exposure to Manganese Sulfate
Biological Trace Element Research, vol. 93, no. 1-3, pp. 113–126, 2003 - Astrocyte-Mediated Methylmercury Neurotoxicity
Biological Trace Element Research, vol. 95, no. 1, pp. 1–10, 2003 - Methylmercury-induced reactive oxygen species formation in neonatal cerebral astrocytic cultures is attenuated by antioxidants
Molecular Brain Research, vol. 110, no. 1, pp. 85–91, 2003 - Use of Microarray Technologies in Toxicology Research
NeuroToxicology, vol. 24, no. 3, pp. 321–332, 2003 - Developmental Aspects of Blood–Brain Barrier (BBB) and Rat Brain Endothelial (RBE4) Cells as in vitro Model for Studies on Chlorpyrifos Transport
NeuroToxicology, vol. 24, no. 4-5, pp. 741–745, 2003 - Effect of methylmercury on glutamate metabolism in cerebellar astrocytes in culture
Neurochemistry International, vol. 43, no. 4-5, pp. 411–416, 2003 - Manganese neurotoxicity and glutamate-GABA interaction
Neurochemistry International, vol. 43, no. 4-5, pp. 475–480, 2003 - The Consequences of Methylmercury Exposure on Interactive Functions between Astrocytes and Neurons
NeuroToxicology, vol. 23, no. 6, pp. 755–759, 2002 - Open Issues from the 15th International Conference on Manganese
NeuroToxicology, vol. 23, no. 2, pp. 123–125, 2002 - Manganese Causes Differential Regulation of Glutamate Transporter (GLAST) Taurine Transporter and Metallothionein in Cultured Rat Astrocytes
NeuroToxicology, vol. 23, no. 4-5, pp. 595–602, 2002 - Effects of Manganese (Mn) on the Developing Rat Brain: Oxidative-Stress Related Endpoints
NeuroToxicology, vol. 23, no. 2, pp. 169–175, 2002 - Chronic Ethanol Produces Increased Taurine Transport and Efflux in Cultured Astrocytes
NeuroToxicology, vol. 23, no. 6, pp. 693–700, 2002 - Effects of Manganese on Oxidative Stress in CATH.a Cells
NeuroToxicology, vol. 23, no. 2, pp. 159–164, 2002 - XANES Spectroscopy: A Promising Tool for Toxicology: A Tutorial
NeuroToxicology, vol. 23, no. 2, pp. 127–146, 2002 - Glutamate/Aspartate Transporter (GLAST), Taurine Transporter and Metallothionein mRNA Levels are Differentially Altered in Astrocytes Exposed to Manganese Chloride, Manganese Phosphate or Manganese Sulfate
NeuroToxicology, vol. 23, no. 3, pp. 281–288, 2002 - The Uptake of Manganese in Brain Endothelial Cultures
NeuroToxicology, vol. 23, no. 2, pp. 165–168, 2002 - Eighth Meeting of the International Neurotoxicology Association
NeuroToxicology, vol. 23, no. 6, pp. 657–658, 2002 - Neurotoxic mechanisms of fish-borne methylmercury
Environmental Toxicology and Pharmacology, vol. 12, no. 2, pp. 101–104, 2002 - The neuropathogenesis of mercury toxicity
Molecular Psychiatry, vol. 7, no. s2, pp. S40–S41, 2002 - Methylmercury enhances arachidonic acid release and cytosolic phospholipase A2 expression in primary cultures of neonatal astrocytes
Molecular Brain Research, vol. 106, no. 1-2, pp. 1–11, 2002 - Pharmacology and Toxicology of Astrocyte-Neuron Glutamate Transport and Cycling
Journal of Pharmacology and Experimental Therapeutics, vol. 301, no. 1, pp. 1–6, 2002 - Manganese Accumulates in Iron-Deficient Rat Brain Regions in a Heterogeneous Fashion and Is Associated with Neurochemical Alterations
Biological Trace Element Research, vol. 87, no. 1-3, pp. 143–156, 2002 - Mercury toxicity
Journal of Pediatrics, vol. 138, no. 3, pp. 450–451, 2001 - Selected Presentations and General Discussion: Session IX Summary and Research Needs
NeuroToxicology, vol. 22, no. 6, pp. 849–852, 2001 - Transendothelial permeability of chlorpyrifos in RBE4 monolayers is modulated by astrocyte-conditioned medium
Molecular Brain Research, vol. 97, no. 1, pp. 43–50, 2001 - Roles of the metallothionein family of proteins in the central nervous system
Brain Research Bulletin, vol. 55, no. 2, pp. 133–145, 2001 - Aspartate and Glutamate Transport in Acutely and Chronically Ethanol Exposed Neonatal Rat Primary Astrocyte Cultures
NeuroToxicology, vol. 22, no. 5, pp. 601–605, 2001 - Roles of Glia in Developmental Neurotoxicity: Session VI Summary and Research Needs
NeuroToxicology, vol. 22, no. 5, pp. 567–573, 2001 - Mercuric chloride, but not methylmercury, inhibits glutamine synthetase activity in primary cultures of cortical astrocytes
Brain Research, vol. 891, no. 1-2, pp. 148–157, 2001 - Methylmercury inhibits the in vitro uptake of the glutathione precursor, cystine, in astrocytes, but not in neurons
Brain Research, vol. 894, no. 1, pp. 131–140, 2001 - Ethanol-induced swelling in neonatal rat primary astrocyte cultures
Brain Research, vol. 900, no. 2, pp. 219–226, 2001 - The uptake of cysteine in cultured primary astrocytes and neurons
Brain Research, vol. 902, no. 2, pp. 156–163, 2001 - Methylmercury-mediated inhibition of 3H-?-aspartate transport in cultured astrocytes is reversed by the antioxidant catalase
Brain Research, vol. 902, no. 1, pp. 92–100, 2001 - Methylmercury has a selective effect on mitochondria in cultured astrocytes in the presence of [U-13C]glutamate
Brain Research, vol. 908, no. 2, pp. 149–154, 2001 - Methylmercury inhibits cysteine uptake in cultured primary astrocytes, but not in neurons
Brain Research, vol. 914, no. 1-2, pp. 159–165, 2001 - Identification and characterization of uptake systems for cystine and cysteine in cultured astrocytes and neurons: Evidence for methylmercury-targeted disruption of astrocyte transport
Journal of Neuroscience Research, vol. 66, no. 5, pp. 998–1002, 2001 - Foreign metallothionein-I expression by transient transfection in MT-I and MT-II null astrocytes confers increased protection against acute methylmercury cytotoxicity
Brain Research, vol. 855, no. 1, pp. 32–38, 2000 - Dopamine toxicity in neuroblastoma cells: role of glutathione depletion by ?-BSO and apoptosis
Brain Research, vol. 858, no. 1, pp. 1–8, 2000 - Methylmercury alters glutamate transport in astrocytes
Neurochemistry International, vol. 37, no. 2-3, pp. 199–206, 2000 - Metallothioneins Attenuate Methylmercury-Induced Neurotoxicity in Cultured Astrocytes and Astrocytoma Cells
Annals of the New York Academy of Sciences, vol. 890, no. 1 NEUROPROTECTI, pp. 223–226, 1999 - Transfection and overexpression of metallothionein-I in neonatal rat primary astrocyte cultures and in astrocytoma cells increases their resistance to methylmercury-induced cytotoxicity
Brain Research, vol. 818, no. 2, pp. 414–420, 1999 - Alteration of iron homeostasis following chronic exposure to manganese in rats
Brain Research, vol. 833, no. 1, pp. 125–132, 1999 - Manganese Homeostasis in the CNS,
Environmental Research, vol. 80, no. 2, pp. 105–109, 1999 - Dimethyl sulfoxide, but not acidosis-induced metallothionein mRNA expression in neonatal rat primary astrocyte cultures is inhibited by the bioflavonoid, quercetin
Brain Research, vol. 794, no. 2, pp. 304–308, 1998 - Methylmercury-induced astrocytic swelling is associated with activation of the Na+/H+ antiporter, and is fully reversed by amiloride
Brain Research, vol. 799, no. 2, pp. 207–214, 1998 - Methylmercury-induced inhibition of regulatory volume decrease in astrocytes: characterization of osmoregulator efflux and its reversal by amiloride
Brain Research, vol. 811, no. 1-2, pp. 133–142, 1998 - Induction of astrocyte metallothioneins (MTs) by zinc confers resistance against the acute cytotoxic effects of methylmercury on cell swelling, Na+ uptake, and K+ release
Brain Research, vol. 813, no. 2, pp. 254–261, 1998 - Immune and inflammatory responses in the CNS: modulation by astrocytes
Toxicology Letters, vol. 102-103, no. 1-2, pp. 283–287, 1998 - Astrocyte Metallothioneins (MTs) and Their Neuroprotective Role
Annals of the New York Academy of Sciences, vol. 825, no. 1 Neuroprotecti, pp. 334–347, 1997 - Induction of metallothionein-I (MT-I) mRNA in primary astrocyte cultures is mediated by hypotonicity and not ethanol (EtOH) per se
Brain Research, vol. 770, no. 1-2, pp. 289–293, 1997 - Metallothionein induction protects swollen rat primary astrocyte cultures from methylmercury-induced inhibition of regulatory volume decrease
Brain Research, vol. 738, no. 2, pp. 213–221, 1996 - Metallothionein induction by bismuth in neonatal rat primary astrocyte cultures
Brain Research, vol. 732, no. 1-2, pp. 106–112, 1996 - Inhibition of regulatory volume decrease in swollen rat primary astrocyte cultures by methylmercury is due to increased amiloride-sensitive Na+ uptake
Brain Research, vol. 732, no. 1-2, pp. 169–178, 1996 - Detection of Metallothionein (MT) Proteins with Radiolabeled [14C]Iodoacetamide
Toxicology Mechanisms and Methods, vol. 6, no. 3, pp. 149–155, 1996 - Cadmium chloride (CdCl2)-induced metallothionein (MT) expression in neonatal rat primary astrocyte cultures
Brain Research, vol. 678, no. 1-2, pp. 91–98, 1995 - Adenosine modulates methylmercuric chloride (MeHgCl)-inducedd-aspartate release from neonatal rat primary astrocyte cultures
Brain Research, vol. 689, no. 1, pp. 1–8, 1995 - The role of -SH groups in methylmercuric chloride-induced d-aspartate and rubidium release from rat primary astrocyte cultures
Brain Research, vol. 641, no. 1, pp. 1–9, 1994 - The role of sulfhydryl groups ind-aspartate and rubidium release from neonatal rat primary astrocyte cultures
Brain Research, vol. 648, no. 1, pp. 16–23, 1994 - Manganese (Mn) transport across the rat blood-brain barrier: Saturable and transferrin-dependent transport mechanisms
Brain Research Bulletin, vol. 33, no. 3, pp. 345–349, 1994 - Astrocytes as Mediators of Methylmercury Neurotoxicity: Effects on D-Aspartate and Serotonin Uptake
Developmental Neuroscience, vol. 16, no. 3-4, pp. 222–231, 1994 - Lead increases inositol 1,4,5-triphosphate levels but does not interfere with calcium transients in primary rat astrocytes
Brain Research, vol. 618, no. 1, pp. 9–18, 1993 - Methylmercury-induced alterations in excitatory amino acid transport in rat primary astrocyte cultures
Brain Research, vol. 602, no. 2, pp. 181–186, 1993 - The role of sulfhydryl groups and calcium in the mercuric chloride-induced inhibition of glutamate uptake in rat primary astrocyte cultures
Brain Research, vol. 607, no. 1-2, pp. 249–254, 1993 - Glial-Neuronal Interactions: Relevance to Neurotoxic Mechanisms
Toxicology and Applied Pharmacology, vol. 118, no. 2, pp. 141–158, 1993 - Stimulation of ?-aspartate efflux by mercuric chloride from rat primary astrocyte cultures
Developmental Brain Research, vol. 75, no. 2, pp. 261–268, 1993 - Manganese Uptake and Efflux in Cultured Rat Astrocytes
Journal of Neurochemistry, vol. 58, no. 2, pp. 730–735, 1992 - Interactions of methylmercury with rat primary astrocyte cultures: methylmercury efflux
Brain Research, vol. 554, no. 1-2, pp. 10–14, 1991 - Manganese neurotoxicity: Cellular effects and blood-brain barrier transport
Neuroscience & Biobehavioral Reviews, vol. 15, no. 3, pp. 333–340, 1991 - Uptake of methylmercury in the rat brain: effects of amino acids
Brain Research, vol. 462, no. 1, pp. 31–39, 1988 - Distribution of mercury 203 in pregnant rats and their fetuses following systemic infusions with thiol-containing amino acids and glutathione during late gestation
Teratology, vol. 38, no. 2, pp. 145–155, 1988 - Mercury 203 distribution in pregnant and nonpregnant rats following systemic infusions with thiol-containing amino acids
Teratology, vol. 36, no. 3, pp. 321–328, 1987 - Increased axonal transport in the rat optic system after systemic exposure to methylmercury: differential effects in local vs systemic exposure conditions
Brain Research, vol. 401, no. 1, pp. 132–141, 1987 - Reduction of axonal transport in the rat optic system after direct application of methylmercury
Brain Research, vol. 381, no. 2, pp. 244–250, 1986 - Persistent, differential alterations in developing cerebellar cortex of male and female mice after methylmercury exposure
Developmental Brain Research, vol. 12, no. 1, pp. 1–11, 1984