Morell P, Toews A D, Wagner M, Goodrum J F
Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill 27599-7250.
Neurotoxicology. 1994 Spring;15(1):171-80.
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 metabolic specificity is often complicated by: (1) secondary responses in the affected cells, (2) involvement of other functionally-related cell types, and (3) the presence of compensatory and/or regenerative responses. In this context we study tellurium, which systemically blocks cholesterol biosynthesis at the squalene epoxidase step. Because of the high demand in developing peripheral nerves for newly synthesized cholesterol required for myelin assembly, this metabolic block leads to demyelination of the sciatic nerve. This insult is confounded by the fact that the myelin-forming Schwann cells do not upregulate their cholesterol 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 block. The shortage of cholesterol in Schwann cells results in an immediate secondary response down-regulation of steady-state mRNA levels for specific myelin proteins. Remyelination occurs after cessation of tellurium exposure. This model of primary demyelination allows study of Schwann-cell specific responses during the processes of myelin breakdown and subsequent steps leading to remyelination, without the complications of axonal degeneration and regeneration. Because tellurium specifically blocks the synthesis of a major required membrane component, it is also well suited for examining the coordinate control of membrane synthesis and assembly at the genomic level.
一种化合物可能具有“发育性神经毒性”，因为它干扰了特定类型神经细胞在发育过程中专门或优先表达的代谢步骤。最初的代谢特异性常常因以下情况而变得复杂：（1）受影响细胞中的次级反应，（2）其他功能相关细胞类型的参与，以及（3）代偿性和/或再生性反应的存在。在此背景下，我们研究碲，它在角鲨烯环氧化酶步骤系统性地阻断胆固醇生物合成。由于发育中的外周神经对髓鞘组装所需的新合成胆固醇有很高需求，这种代谢阻断导致坐骨神经脱髓鞘。这种损伤因形成髓鞘的施万细胞不上调其胆固醇生物合成途径这一事实而变得复杂。这与预期相反；肝脏（神经系统外许多组织胆固醇的主要来源）上调胆固醇合成并克服代谢阻断。施万细胞中胆固醇的短缺导致特定髓鞘蛋白稳态mRNA水平立即出现次级反应下调。碲暴露停止后会发生髓鞘再生。这种原发性脱髓鞘模型允许研究髓鞘破坏过程中施万细胞特异性反应以及随后导致髓鞘再生的步骤，而不会出现轴突变性和再生的复杂情况。由于碲特异性阻断主要所需膜成分的合成，它也非常适合在基因组水平研究膜合成和组装的协调控制。
