Olson L, Björklund H, Henschen A, Palmer M, Hoffer B
Acta Neurol Scand Suppl. 1984;100:77-87.
Modern man is chronically exposed to lead levels in the biosphere, several times higher than the natural level that once existed. There is much concern about the possible adverse effects of this population-wide low-level lead exposure, particularly on the developing organism, where the central nervous system may be a primary target for lead. We have developed animal test systems which permit temporal and spatial discrimination of possible effects of lead and other potentially neurotoxic agents in the environment on the developing central nervous system, as well as on different types of peripheral nerves in the adult individual. In one experimental design, defined areas of the fetal rat brain are grafted to the anterior chamber of the eye of adult rat recipients which are exposed to lead (1% PbAc in drinking water). Such grafts will become vascularized from the host iris and continue their development in oculo. Thus the grafted brain tissue and the host brain will share circulation and therefore be exposed to exactly the same amounts of lead simultaneously. Studies of cerebellar grafts revealed that although there was a normal gross cytological development in the presence of lead, there was a severe, permanent impairment of the spontaneous discharge rates of the grafted Purkinje neurons as observed with electrophysiological techniques long after cessation of the lead treatment. The host Purkinje neurons were not affected. A similar, although less dramatic, impairment of cerebellar function could then be demonstrated in intact animals when newborn rats were given lead (8 mg PbAc/kg i.p.) during the first 20 days of life and then studied as adults. In other areas of the fetal central nervous system grafted to the eye, lead caused disturbed growth (substantia nigra, cortex cerebri). A screening technique for potentially harmful effects on autonomic and sensory nerve terminals in adult rats makes use of intraocular injections of agents to be tested. Morphological and histochemical changes of the innervation apparatus of the iris are then studied in iris whole-mount preparations. Lead causes an adrenergic hyperinnervation of the iris. Computer-based image analysis revealed severe degenerative effects by hexachlorophene and chlorhexidine. These studies demonstrate the usefulness of the intraocular grafts and the intraocular injection technique and the need to apply both structural and functional techniques in order to detect possible neurotoxic actions of xenobiotics. The techniques have revealed hitherto unknown toxic actions of lead on cerebellar function.
现代人长期暴露于生物圈中的铅含量之下，这一含量比曾经存在的自然水平高出数倍。人们非常关注这种全人群低水平铅暴露可能产生的不良影响，尤其是对发育中的生物体，其中中枢神经系统可能是铅的主要靶器官。我们已经开发出动物测试系统，该系统能够在时间和空间上区分环境中的铅及其他潜在神经毒性物质对发育中的中枢神经系统以及成年个体不同类型外周神经可能产生的影响。在一个实验设计中，将胎鼠大脑的特定区域移植到成年大鼠受体的眼前房，受体大鼠饮用含铅（饮用水中含1%醋酸铅）的水。这样的移植物会从宿主虹膜获得血管供应，并在眼内继续发育。因此，移植的脑组织和宿主大脑将共享血液循环，从而同时暴露于完全相同剂量的铅。对小脑移植物的研究表明，尽管在有铅存在的情况下总体细胞学发育正常，但在停止铅处理很长时间后，用电生理技术观察发现，移植的浦肯野神经元的自发放电率出现了严重的永久性损伤。宿主的浦肯野神经元未受影响。当新生大鼠在出生后的前20天腹腔注射铅（8毫克醋酸铅/千克），然后作为成年大鼠进行研究时，在完整动物中也能证明小脑功能有类似的、尽管不太明显的损伤。在移植到眼睛的胎儿中枢神经系统的其他区域，铅导致生长紊乱（黑质、大脑皮层）。一种用于筛选对成年大鼠自主神经和感觉神经末梢潜在有害影响的技术利用了眼内注射待测试的物质。然后在虹膜整装标本中研究虹膜神经支配装置的形态学和组织化学变化。铅会导致虹膜肾上腺素能神经支配过度。基于计算机的图像分析显示，六氯酚和洗必泰有严重的退行性影响。这些研究证明了眼内移植和眼内注射技术的实用性，以及为检测外源性物质可能的神经毒性作用而应用结构和功能技术的必要性。这些技术揭示了铅对小脑功能迄今未知的毒性作用。
