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.