Abstract

The neurotoxic organometal, trimethyltin (TMT), was administered to rats on postnatal day (PND)5. Neurotoxicity was assessed throughout subsequent development using morphological, biochemical and functional endpoints. These consisted of brain weight measures and histology (morphology), assays of nervous system-specific proteins (biochemistry) and neurobehavioral indices of activity and learning (function). All three indices were affected. TMT caused dose-related decreases in brain weights at all ages examined, PND13, 22 and 66, with the hippocampus being the most severely reduced. Histological examination of the hippocampus revealed loss of pyramidal neurons in CA3 to CA4. Exposure to TMT was followed by dose- and age-dependent reductions in synapsin I, a neuron-specific phosphoprotein associated with synaptic vesicles; these effects of TMT were greater in hippocampus than in forebrain. TMT did not alter the concentration or protein composition of isolated myelin. The ontogeny of locomotion was altered in a dose- and time-dependent manner; TMT induced hypoactivity early in development (PND13) and hyperactivity by weaning (PND21); hyperactivity was also observed in the adult. Finally, TMT also affected learning ability throughout development. Deficits were observed in: acquisition and retention of an instrumental alleyway response; acquisition of a step-through passive avoidance response; and radial-arm maze performance. These results demonstrate the use of a multi-endpoint, multi-timepoint strategy for the detection and characterization of neurotoxicity.