Ž . Molecular Brain Research 49 1997 113–119 Research report Tellurium causes dose-dependent coordinate down-regulation of myelin gene expression Arrel D. Toews a,c, ) , Elaine B. Roe c , J.F. Goodrum b,c , T.W. Bouldin b,c , J. Weaver c , N.D. Goines c , P. Morell a,c a Department of Biochemistry and Biophysics, UniÕersity of North Carolina, Chapel Hill, NC 27599-7260, USA b Department of Pathology, UniÕersity of North Carolina, Chapel Hill, NC 27599-7525, USA c Neuroscience Center, UniÕersity of North Carolina, Chapel Hill, NC 27599-7250, USA Accepted 25 March 1997 Abstract Exposure of developing rats to a diet containing elemental tellurium systemically inhibits cholesterol synthesis at the level of squalene Ž . epoxidase. At high tellurium exposure levels )0.1% in the diet , there is an associated segmental demyelination of the PNS. Low levels Ž . 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 Ž increasing down-regulation of mRNA levels for myelin P protein, ceramide galactosyltransferase rate-limiting enzyme in cerebroside 0 . Ž . 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-in- duced 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 Ž . Ž . 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. q 1997 Elsevier Science B.V. Keywords: Tellurium; Demyelination; Macrophage; NGF receptor; Peripheral neuropathy 1. Introduction Both the synthesis of new membrane and the mainte- nance of existing membrane depends on all necessary membrane components being available in their required proportions at the correct time. This suggests the need for close coordinate control of mRNA expression for various membrane components. Schwann cells of the peripheral Ž . nervous system PNS produce massive amounts of myelin membrane during the post-natal development period, mak- ) Corresponding author. Neuroscience Center, CBa7250, University of Ž . North Carolina, Chapel Hill, NC 27599-7250, USA. Fax: q1 919 966-9605; E-mail: arrel@css.unc.edu ing them a useful model system for examining gene ex- pression involved in membrane synthesis and assembly. In addition, these Schwann cells display a remarkable plastic- ity. When the sciatic nerve is crushed or cut, there is myelin breakdown secondary to axonal degeneration, and Schwann cells rapidly down-regulate gene expression for all myelin components. If axonal regeneration occurs, as after nerve crush, Schwann cells up-regulate mRNA for myelin components and remyelinate the regenerating ax- w x Ž wx . ons 9,10,14,16,33 see 7 for review . A useful model for separating events involved in de- myelinationrremyelination from those of axonal degenera- tionrregeneration involves exposure of developing rats to elemental tellurium. A metabolite of the administered tel- lurium specifically inhibits squalene epoxidase, an obligate 0169-328Xr97r$17.00 q 1997 Elsevier Science B.V. All rights reserved.