GENE-EXPRESSION DURING TELLURIUM-INDUCED PRIMARY DEMYELINATION

A compound may be ''developmentally neurotoxic'' because it interferes with a metabolic step exclusively or preferentially expressed during development in a particular class of neural cells. The initial metabol ic specificity is often complicated by: (1) secondary responses in the affected cells, (2) involvement of other functionally-related cell ty pes, and (3) the presence of compensatory and/or regenerative response s. In this context we study tellurium, which systemically blocks chole sterol biosynthesis at the squalene epoxidase step. Because of the hig h demand in developing peripheral nerves for newly synthesized cholest erol required for myelin assembly, this metabolic block leads to demye lination of the sciatic nerve. This insult is confounded by the fact t hat the myelin-forming Schwann cells do not upregulate their cholester ol biosynthetic pathway. This is contrary to expectations; liver (the main source of cholesterol for many tissues outside the nervous system ) upregulates synthesis of cholesterol and overcomes the metabolic blo ck. The shortage of cholesterol in Sch wann cells results in an immedi ate secondary response down-regulation of steady-state mRNA levels for specific myelin proteins. Remyelination occurs after cessation of tel lurium exposure. Th is model of primary demyelination allows study of Schwann-cell specific responses during the processes of myelin breakdo wn and subsequent steps leading to remyelination, without the complica tions of axonal degeneration and regeneration. Because tellurium speci fically blocks the synthesis of a major required membrane component, i t is also well suited for examining the coordinate control of membrane synthesis and assembly at the genomic level. (C) 1994 Intox Press, In c.