Contact Info:Email: atchiso1@msu.edu Phone: (517) 353-4947 Fax: (517) 353-8915

Research Synopsis

The nervous system has long been recognized as one of the most susceptible organ systems to insult from toxic environmental contaminants due to its limited capacity to repair tissue damage. Unlike other tissues such as liver, kidney or skin, for which cellular repair occurs readily, toxicity to the nervous system is generally irreversible. During the last few years, interest has focused on the study of neurotoxicology. This is due to the heightened awareness of society to the potential for neurotoxicity following disastrous or potentially disastrous episodes of contamination seen with agents such as methylmercury in Japan and Iraq, polychlorinated and polybrominated biphenyls in Taiwan and here in the U.S.A., and insecticides such as mirex and kepone. Historically, most neurotoxicology studies have focused on pathological descriptions of the lesions observed clinically in affected individuals. Few mechanistic studies at the cellular level have been undertaken, so the toxic mechanisms of action of these agents remain largely unknown.

My research interest is the study of effects of chemicals on the nervous system, particularly those chemicals which act directly on the synapse. My primary research interest is in the cellular mechanism of action of chemicals which disrupt Ca2+-dependent processes at the membrane and intracelluarly. A variety of techniques including electrophysiological recordings of ion channel activity (patch-voltage clamp) and synaptic transmission (intracellular and extracellular microelectrode recording techniques), neurochemical analysis of synaptic function and fluorescent microscopy and digital imaging of intracellular ion concentrations using fluorescent probes such as Fura-2. Toxicological research interests are presently focused on the effects of heavy metals such as methylmercury, many of which exert potent toxic actions at chemical synapses, and on the mechanism of delayed neurotoxicity caused by certain sulfur-containing agents. A second area of interest in my laboratory is the pharmacology and physiology of neurotransmitter release in the peripheral and central nervous system, especially identifying the molecular entities involved in Ca2+-dependent neurosecretion.

Selected Achievements since 2001

Editorial Boards
Neurotoxicology, 1986-present; Associate Editor, 1989-present

Journal of Pharmacology and Experimental Therapeutics, 1988-2001

National & International Society Committees
Myasthenia Gravis Association, Medical Advisory Board, 1990-1991 (Member); 1991-present (Chair)

Society of Toxicology, Neurotoxicology Specialty Section, Secretary/Treasurer; 1998-1999; Vice-President, 1999-2000; President, 2000-2001; Past President, 2001-2002

American Society of Pharmacology and Experimental Therapeutics (ASPET), Neuropharmacology Division, Nominating Committee, 2001-2002

Selected Samples of Publications Since 2001

Audesirk G, Armstrong D, van den Maagdenberg AMJM, Atchison W, Shafer T, Fletcher C: Calcium channels: Critical targets of toxicants and diseases. Environ. Hlth. Perspect. 108(12): 1215-1218, 2001. (Review)

Heidemann SR, Lamoreaux P, Atchison WD: Inhibition of axonal morphogenesis by nonlethal, submicromolar concentrations of methylmercury. Toxicol. Appl. Pharmacol. 174(1): 49-59, 2001.

Limke TL, Atchison WD: Acute exposure to methylmercury opens the mitochondrial permeability transition pore in rat cerebellar granule cells. Toxicol. Appl. Pharmacol. 178(1); 52-61, 2002.

Peng SQ, Hajela RK, Atchison WD: Effects of methylmercury on human neuronal high voltage-activated calcium channels transiently expressed in cultures of human embryonic kidney cells (HEK-293). J. Pharmacol. Exp. Ther. 302(2): 424-432, 2002.

Flink MT, Atchison WD: Passive transfer to mice of Lambert-Eaton Myasthenic Syndrome induces dihydropyridine sensitivity of neuromuscular transmission. J. Physiol. (Lond.) 543(Pt 2): 567-576, 2002.

Xu Y-F, Autio D, Rheuben MB, Atchison WD: Impairment of synaptic vesicle exocytosis and trafficking at motor nerve terminals of mice during dithiobiuret-induced muscle weakness. J. Neurophysiol. 88: 3243-3258, 2002.

Peng SQ, Hajela RK, Atchison WD: Characteristics of block by Pb2+ of function of human neuronal L-, N- and R-type Ca2+ channels transiently expressed in human embryonic kidney 293 cells. Molec. Pharmacol. 6296); 1418-1430, 2002.

Limke TL, Otero-Montañez JKL, Atchison WD: Evidence for interaction between intracellular calcium stores during methylmercury-induced intracellular calcium dysregulation in rat cerebellar granule neurons. J. Pharmacol. Exp. Ther. 304(3); 949-958, 2003.

Yuan Y, Atchison WD: Methylmercury differentially affects GABAA receptor-mediated spontaneous IPSCs in Purkinje and granule cells of rat cerebellar slices. J. Physiol. (Lond.) 550: 191-204, 2003.

Flink MT, Atchison WD: Iberiotoxin-induced block of Ca2+-activated K+ channels induces dihydropyridine sensitivity of ACh release from mammalian motor nerve terminals. J. Pharmacol. Exp. Ther. 305(2): 646-652, 2003.
Hajela RK, Peng S, Atchison WD: Comparative effects of methylmercury and Hg2+ on human neuronal N- and R-type high voltage activated calcium channels transiently expressed in human embryonic kidney cells (HEK293). J. Pharmacol. Exp. Ther. 306(3): 1129-1136, 2003.

Atchison WD: Effects of toxic environmental contaminants on voltage-gated calcium channel function: From past to present. J. Biomembr. Bioenerget. 35(6): 507-532, 2003.

Flink MT, Atchison WD: Ca2+ channels as targets of neurological disease: Lambert-Eaton Syndrome and other Ca2+ channelopathies. J. Bioenerget. Biomembr. 35(6): 697-718, 2003.

Atchison WD: Neurotoxicants and synaptic function: Session VII-B Summary and research needs. Neurotoxicology 25(4): 515-519, 2004.

Rheuben MW, Autio D, Xu Y-F, Atchison WD: Morphometric characterization of the neuromuscular junction of rodents intoxicated with 2,4-dithiobiuret: Evidence that nerve terminal recycling processes contribute to muscle weakness. Toxicol. Appl. Pharmacol. 196(2): 266-286, 2004.

Limke TL, Bearss JJ, Atchison WD: 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(1): 60-68, 2004.

Limke TL, Heidemann SR, Atchison WD: Disruption of intraneuronal divalent cation regulation by methylmercury: Are specific targets involved in altered neuronal development and cytotoxicity in methylmercury poisoning? Neurotoxicology 25(5): 741-760, 2004.

Is chemical neurotransmission altered specifically during methylmercury-induced cerebellar
dysfunction? William D. Atchison Trends Pharmacol Sci. 2005 Sep 23; [Epub ahead of print]

Yuan Y, Otero-Montanez JK, Yao A, Herden CJ, Sirois JE, Atchison WD.
Inwardly rectifying and voltage-gated outward potassium channels exhibit low sensitivity to methylmercury. Neurotoxicology. 2005 Jun;26(3):439-54.

Peng SQ, Hajela RK, Atchison WD. Fluid flow-induced increase in inward Ba2+ current expressed in HEK293 cells transiently transfected with human neuronal L-type Ca2+ channels. Brain Res. 2005 May 31;1045(1-2):116-23.

Yuan Y, Atchison WD. Methylmercury induces a spontaneous, transient slow inward chloride current in Purkinje cells of rat cerebellar slices. J Pharmacol Exp Ther. 2005 May;313(2):751-64