Heavy metal neurotoxicity : on trimethyltin-, methylmercury- and cadmium-induced disturbances of neurotransmitter systems and neurotrophins

Sammanfattning: Organic and inorganic metal compounds produced by human activities often reach 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 to be developed to better understand the mechanisms of actions of many other heavy metal compounds. 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 metal compound with a specific neurotoxic profile in adult rats. Its actions were characterized using histological, histochemical, in situ hybridization, receptor binding and biochemical methods. A single injection causes neurodegenerative changes in the limbic system including a severe transient gliosis, neuronal degeneration, selective losses of NMDA and kainate receptors, an early transient decrease of BDNF followed by an up-regulation of BDNF and the immediate-early gene c-fos and hsp70 concomitant with a decrease in the BDNF trkB receptor mRNA. Astrocytes also show increased GABA immunoreactivity and an increase of the glial glutamate transporter mRNA, perhaps reflecting enhanced glial glutamate uptake. TMT also caused decreases of serotonin and noradrenalin levels in several brain regions while dopamine appeared not to be affected. Reduced levels of 5-HT were paralleled by reduced 5-HT nerve terminal densities in hippocampus and cortex. Attempting to block and/or counteract TMT toxicity, it was found that the non-NMDA antagonist DNQX was able to protect selected animals, and that PBN, a spin-trapping agent, offered partial protection, while the NMDA antagonist MK-801 and the GABA function enhancer chlormethiazole were without effects. Subtoxic doses of methylmercury (MeHg) caused specific decreases of hippocampal BDNF mRNA levels within hours, recovering after three days. The related neurotrophin NT-3 and trkB did not show mRNA changes. C-fos mRNA increased in a specific hippocampal cell population and in cerebral cortex and cerebellum even after very low doses of MeHg. The changes of BDNF mRNA expression were unlike those caused by many other CNS perturbations in which BDNF is up-regulated, and were not associated with major neuronal or glial damage at the chosen doses. Finally, long-term low-level exposure to mercury and cadmium during development was studied. MeHg exposure via the dams and the diet leading 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 cerebellar noradrenaline were found, underlining the importance of detailed and multifaceted biochemical and morphological analysis to detect possible negative effects of long-term low dosage exposure. Exposure to 5 ppm cadmium chloride in the drinking water during development 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 development led to complex neurochemical disturbances of neurotransmitters as well as neurotrophins. It is concluded that morphological and biochemical analyses of brain tissue using markers of neurons and glial cells including transmitter systems, neurotrophic systems and immediate-early genes, together constitute a sensitive battery of techniques able to detect brain disturbances caused by very low level exposure of animals to heavy metals in cases where the use of a single technique is likely to miss the neurotoxic damage. Applying these and similar methods to rodents constitutes a general system capable of generating early warnings about the potential neurotoxic hazards of xenobiotics.