TELLURIUM CAUSES DOSE-DEPENDENT COORDINATE DOWN-REGULATION OF MYELIN GENE-EXPRESSION

Exposure of developing rats to a diet containing elemental tellurium s ystemically inhibits cholesterol synthesis at the level of squalene ep oxidase. At high tellurium exposure levels (> 0.1% in the diet), there is an associated segmental demyelination of the PNS. Low levels of di etary tellurium (0.0001%) led to in vivo inhibition of squalene epoxid ase activity in sciatic nerve, and inhibition increased with increasin g exposure levels. With increasing dose and increasing exposure times, there was an increasing degree of demyelination and increasing down-r egulation of mRNA levels for myelin P-0 protein, ceramide galactosyltr ansferase (rate-limiting enzyme in cerebroside synthesis), and HMG-CoA reductase (rate-limiting enzyme in cholesterol synthesis). Because th ese were all down-regulated in parallel, we conclude there is coordina te regulation of the entire program for myelin synthesis in Schwann ce lls. 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 even tual down-regulation relates to a separate mechanism by which Schwann cells regulate cholesterol synthesis, related to the need for coordina te synthesis of myelin components. Levels of mRNA for the low-affinity nerve growth factor receptor (indicator of alterations in axon-Schwan n cell interactions) and for lysozyme (marker for phagocytic macrophag es) were both up-regulated in a dose-and time-dependent manner which c orrelated with the presence of segmental demyelination. Levels of mRNA coding for myelin-related proteins were down-regulated at low telluri um exposure levels, without demyelination or up-regulation of nerve gr owth factor receptor. This suggests the down-regulation is related to the tellurium-induced cholesterol deficit, and not to the loss of axon al contact associated with early stages of demyelination or to the ent ry of activated macrophages. (C) 1997 Elsevier Science B.V.