Heavy metal neurotoxicity : On trimethyltin-, methylmercury- and cadmium-induced disturbances of neurotransmitter systems and neurotrophins
Abstract: - Organic and inorganic metal compounds produced by human activities oftenreach the environment where they are associated with a plethora of potential health hazards.Of particular concern is the risk for CNS disturbances during development or in the adult.While considerable documentation exists concerning lead compounds, methodology needs tobe developed to better understand the mechanisms of actions of many other heavy metalcompounds. The present work studies the effects of tin, mercury and cadmium compounds inthe developing and adult rat. Trimethyltin (TMT) was chosen as a model organic metalcompound with a specific neurotoxic profile in adult rats. Its actions were characterized us-ing histological, histochemical, in situ hybridization, receptor binding and biochemicalmethods. A single injection causes neurodegenerative changes in the limbic system includinga severe transient gliosis, neuronal degeneration, selective losses of NMDA and kainatereceptors, an early transient decrease of BDNF followed by an up-regulation of BDNF andthe immediate-early gene c-fos and hsp70 concomitant with a decrease in the BDNF trkB re-ceptor mRNA. Astrocytes also show increased GABA immunoreactivity and an increase ofthe glial glutamate transporter mRNA, perhaps reflecting enhanced glial glutamate uptake.TMT also caused decreases of serotonin and noradrenalin levels in several brain regionswhile dopamine appeared not to be affected. Reduced levels of 5-HT were paralleled by re-duced 5-HT nerve terminal densities in hippocampus and cortex. Attempting to block and/orcounteract TMT toxicity, it was found that the non-NMDA antagonist DNQX was able toprotect selected animals, and that PBN, a spin-trapping agent, offered partial protection,while the NMDA antagonist MK-801 and the GABA function enhancer chlormethiazolewere without effects. Subtoxic doses of methylmercury (MeHg) caused specific decreases ofhippocampal BDNF mRNA levels within hours, recovering after three days. The related neu-rotrophin NT-3 and trkB did not show mRNA changes. C-fos mRNA increased in a specifichippocampal cell population and in cerebral cortex and cerebellum even after very low dosesof MeHg. The changes of BDNF mRNA expression were unlike those caused by many otherCNS perturbations in which BDNF is up-regulated, and were not associated with major neu-ronal or glial damage at the chosen doses. Finally, long-term low-level exposure to mercuryand cadmium during development was studied. MeHg exposure via the dams and the dietleading to brain concentrations of <1.5 mg Hg/kg caused no general toxic effects in neurons,and no changes of GFAP-immunoreactive astrocytes. However, significant changes of cere-bellar noradrenaline were found, underlining the importance of detailed and multifacetedbiochemical and morphological analysis to detect possible negative effects of long-term lowdosage exposure. Exposure to 5 ppm cadmium chloride in the drinking water during devel-opment led to significant changes of serotonin and noradrenalin levels in the cerebral cortex.BDNF mRNA was increased in cerebral cortex, while trkB mRNA was decreased in hippo-campus. Hence, chronic exposure to very low levels of cadmium chloride during develop-ment led to complex neurochemical disturbances of neurotransmitters as well as neurotroph-ins. It is concluded that morphological and biochemical analyses of brain tissue usingmarkers of neurons and glial cells including transmitter systems, neurotrophic systems andimmediate-early genes, together constitute a sensitive battery of techniques able to detectbrain disturbances caused by very low level exposure of animals to heavy metals in caseswhere the use of a single technique is likely to miss the neurotoxic damage. Applying theseand similar methods to rodents constitutes a general system capable of generating earlywarnings about the potential neurotoxic hazards of xenobiotics.Keywords - neurotoxicity, trimethyltin, methylmercury, cadmium, development, GFAP, GABA,noradrenalin, BDNF, c-fos, hsp70, glial glutamate transporter
This dissertation MIGHT be available in PDF-format. Check this page to see if it is available for download.