Document Detail

CS2-mediated cross-linking of erythrocyte spectrin and neurofilament protein: dose response and temporal relationship to the formation of axonal swellings.
MedLine Citation:
PMID:  9007038     Owner:  NLM     Status:  MEDLINE    
Using model proteins, a mechanism for CS2-mediated covalent cross-linking of proteins has been demonstrated previously. The biologic importance of CS2-promoted protein cross-linking is apparent as a possible dosimeter of CS2 exposure and as a potential mechanism to account for the identical neuropathies produced by 2,5-hexanedione and CS2. The present investigation examines the utility of erythrocyte spectrin cross-linking as a biomarker of effect for inhalation exposure to CS2 and examines the ability of CS2 to cross-link neurofilament proteins, a potential neurotoxic target. Rats were exposed to CS2 via inhalation at control, 50-, 500-, and 800-ppm levels for 2, 4, 8, and 13 weeks and spectrin dimer formation was quantified using denaturing gel electrophoresis and densitometry. Neurofilament preparations were also obtained from spinal cords and examined for cross-linking using Western blotting methods. The results obtained for protein cross-linking were compared to morphologic changes in the cervical and lumbar spinal cord using light and electron microscopy. The spectrin dimer exhibited a cumulative dose response and was detectable at both the 50-ppm level employed that did not produce axonal swellings and prior to the development of axonal swellings for the 500- and 800-ppm levels used. Neurofilament protein cross-linking involved all three subunits and the temporal relationship of cross-linking was consistent with a contributing role in the development of axonal swellings. These results establish the sensitivity of spectrin cross-linking for evaluating inhalation exposures and extend the similarities observed for 2,5-hexanedione and CS2 in both clinical settings and in vitro models to their effects exerted on neurofilaments in the axon.
W M Valentine; V Amarnath; D G Graham; D L Morgan; R C Sills
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Toxicology and applied pharmacology     Volume:  142     ISSN:  0041-008X     ISO Abbreviation:  Toxicol. Appl. Pharmacol.     Publication Date:  1997 Jan 
Date Detail:
Created Date:  1997-02-24     Completed Date:  1997-02-24     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  0416575     Medline TA:  Toxicol Appl Pharmacol     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  95-105     Citation Subset:  IM    
Department of Pathology, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.
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MeSH Terms
Administration, Inhalation
Air Pollutants / administration & dosage,  pharmacology*
Axons / drug effects*,  ultrastructure
Biological Markers
Body Weight / drug effects
Carbon Disulfide / administration & dosage,  pharmacology*
Cross-Linking Reagents / administration & dosage,  pharmacology*
Dose-Response Relationship, Drug
Erythrocytes / drug effects
Neurofilament Proteins / drug effects*
Rats, Inbred F344
Spectrin / drug effects*
Spinal Cord / chemistry,  drug effects,  ultrastructure
Time Factors
Grant Support
Reg. No./Substance:
0/Air Pollutants; 0/Biological Markers; 0/Cross-Linking Reagents; 0/Neurofilament Proteins; 12634-43-4/Spectrin; 75-15-0/Carbon Disulfide

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