title: Low-concentration tributyltin perturbs inhibitory synaptogenesis and induces neuronal death in immature but not mature neurons.
abstract: Tributyltin (TBT) has harmful effects on invertebrates. Reports indicate that intoxication of humans with organotin compounds could be associated with neurological symptoms such as epilepsy and amnesia; however, the toxicity mechanisms in mammals are unknown. TBT acts as a Cl(-)/OH(-) antiporter, and likely affects the GABAergic system by disturbing Cl(-) homeostasis. This study aimed to elucidate neurotoxic actions of TBT on mouse neocortical neurons during development. From 4 days in vitro (4 DIV) or 14 DIV in culture, cortical neurons were exposed to TBT continuously for 3 days. TBT-induced neuronal death at 30nM during DIV 4-6, and at 50nM during DIV 14-16. To further characterize this age-dependent cytotoxicity, miniature postsynaptic currents (mPSCs) were analyzed by whole-cell patch-clamp. The frequency of mPSCs was significantly reduced by treatment with 30nM TBT during DIV 4-6, but not DIV 14-16. After TBT treatment during DIV 4-6, GABA(A) receptor-mediated reversal potentials (E(GABA)) were significantly shifted negatively. The TBT-induced E(GABA) shift and neuronal death were reversed by increment of extracellular Cl(-) concentration, suggesting that disruption of Cl(-) homeostasis underlies the disturbance of neuronal ontogeny induced by TBT. These data indicate that the TBT may affect synaptogenesis and neuronal survival, particularly in early development.
authors.affiliation: Department of Neurophysiology, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan. jyamada@cc.hirosaki-u.ac.jp
authors.forename: Junko
authors.initials: J
authors.lastname: Yamada
authors.forename: Koichi
authors.initials: K
authors.lastname: Inoue
authors.forename: Tomonori
authors.initials: T
authors.lastname: Furukawa
authors.forename: Atsuo
authors.initials: A
authors.lastname: Fukuda
mesh_terms: D000818:Animals; D017920:Antiporters / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects* / Q000196:embryology / Q000378:metabolism; D002712:Chlorides / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D055724:Electrophysiological Phenomena; D047108:Embryonic Development / Q000187:drug effects; D004785:Environmental Pollutants / Q000633:toxicity*; D005865:Gestational Age; D051379:Mice; D008813:Mice, Inbred ICR; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018408:Patch-Clamp Techniques; D011963:Receptors, GABA-A / Q000378:metabolism; D055366:Synaptic Potentials / Q000187:drug effects; D009435:Synaptic Transmission / Q000187:drug effects*; D014220:Trialkyltin Compounds / Q000633:toxicity*
chemical_list: D017920:Antiporters; D002712:Chlorides; D004785:Environmental Pollutants; D011963:Receptors, GABA-A; D014220:Trialkyltin Compounds; C093920:chloride-base exchanger; C011559:tributyltin