Tellurium causes dose-dependent coordinate down-regulation of myelin gene expression.
Exposure of developing rats to a diet containing elemental tellurium systemically inhibits cholesterol synthesis at the level of squalene epoxidase. At high tellurium exposure levels (> 0.1% in the diet), there is an associated segmental demyelination of the PNS. Low levels of dietary tellurium (0.0001%) led to in vivo inhibition of squalene epoxidase activity in sciatic nerve, and inhibition increased with increasing exposure levels. With increasing dose and increasing exposure times, there was an increasing degree of demyelination and increasing down-regulation of mRNA levels for myelin P0 protein, ceramide galactosyltransferase (rate-limiting enzyme in cerebroside synthesis), and HMG-CoA reductase (rate-limiting enzyme in cholesterol synthesis). Because these were all down-regulated in parallel, we conclude there is coordinate regulation of the entire program for myelin synthesis in Schwann cells. An anomaly was that at early time points and low tellurium levels, mRNA levels for HMG-CoA reductase were slightly elevated, presumably in response to tellurium-induced sterol deficits. We suggest the eventual down-regulation relates to a separate mechanism by which Schwann cells regulate cholesterol synthesis, related to the need for coordinate synthesis of myelin components. Levels of mRNA for the low-affinity nerve growth factor receptor (indicator of alterations in axon-Schwann cell interactions) and for lysozyme (marker for phagocytic macrophages) were both up-regulated in a dose- and time-dependent manner which correlated with the presence of segmental demyelination. Levels of mRNA coding for myelin-related proteins were down-regulated at low tellurium exposure levels, without demyelination or up-regulation of nerve growth factor receptor. This suggests the down-regulation is related to the tellurium-induced cholesterol deficit, and not to the loss of axonal contact associated with early stages of demyelination or to the entry of activated macrophages.
Toews
A D
AD
Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill 27599-7260, USA. arrel@css.unc.edu
Roe
E B
EB
Goodrum
J F
JF
Bouldin
T W
TW
Weaver
J
J
Goines
N D
ND
Morell
P
P
D000085:Acetates / Q000378:metabolism; D000821:Animal Feed; D000818:Animals; D002784:Cholesterol / Q000096:biosynthesis; D005786:Gene Expression Regulation / Q000187:drug effects*; D006903:Hydroxymethylglutaryl CoA Reductases / Q000096:biosynthesis; D007700:Kinetics; D008297:Male; D018993:Myelin P0 Protein / Q000096:biosynthesis*; D009185:Myelin Proteins / Q000096:biosynthesis*; D010105:Oxygenases / Q000037:antagonists & inhibitors; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D012583:Schwann Cells / Q000187:drug effects / Q000378:metabolism*; D012584:Sciatic Nerve / Q000187:drug effects / Q000378:metabolism*; D013185:Squalene / Q000378:metabolism; D050603:Squalene Monooxygenase; D013691:Tellurium / Q000008:administration & dosage / Q000494:pharmacology*; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects
D000085:Acetates; D018993:Myelin P0 Protein; D009185:Myelin Proteins; D012333:RNA, Messenger; D013185:Squalene; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases; D010105:Oxygenases; D050603:Squalene Monooxygenase; D013691:Tellurium