Some toxic effects of lead, other metals and antibacterial agents on the nervous system--animal experiment models

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.