Exp Mol Med.  2005 Feb;37(1):58-64.

Neurotoxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin in cerebellar granule cells

• Kim SY
• Yang JH

Abstract

An environmental pollutant, tetrachloro dibenzo dioxin (TCDD) is known to illicit the cognitive disability and motor dysfunction in the developing brain. TCDD induced effects leading to neurodevelopmental and neurobehavioral deficit may have been defined, however underlying molecular mechanism and possible intracellular targets remain to be elucidated. In this study, we attempted to analyze TCDD-induced neurotoxic effects in the granule cells from cerebellum where certain cognitive abilities and motor function command are known to be excuted. [3H]PDBu, (phorbol 12,13-dibutyrate) binding assay indicated that TCDD induced a dose-dependent increase of total PKC activity and its induction was the aryl hydrocarbon receptor (AhR) dependent and N-methyl-D-aspartate receptor (NMDAR) independent. TCDD also caused the translocation of both PKC-alpha and -epsilon in a dose-dependent manner but associated with different receptors; PKC-alpha via AhR but not PKC-epsilon indicating an isozyme-specific pattern of the induction. Increase of the ROS formation was also observed in the cells treated with TCDD in a dose-dependent and an AhR-dependent manner. The treatment of the cells with the diamino dicyano-bis(2-aminophenylthio) butadiene (U0126, MEK-1/2 inhibitor), dizocilpine maleate (MK-801, non-competitive N-methyl-D-aspartate glutamate receptor antagonist) and vitamin E attenuated the TCDD-induced ROS production indicating that TCDD-induced ROS formation may be associated with activation of ERK-1/2 in the MAP kinase pathway or the NMDA receptor. TCDD also increased [Ca2+]i, which is associated with ROS formation and PKC activation in the cerebellar granule cells. It is suggested that TCDD activates the NMDA receptor, which may induce a sustained increase of [Ca2+]i in neurons followed by the ROS formation. Our findings may contribute to understanding the mechanism of TCDD-related neurotoxicity, thereby improving the health risk assessment of neurotoxic compounds in humans.

Keyword

cerebellar granule cells; neurotoxicity; PKC; ROS; TCDD

MeSH Terms

Animals
Binding, Competitive
Butadienes/pharmacology
Carcinogens/pharmacology
Cerebellum/cytology/*drug effects/enzymology
Dizocilpine Maleate/pharmacology
Environmental Pollutants/*toxicity
Enzyme Activation/drug effects
Enzyme Inhibitors/pharmacology
Mitogen-Activated Protein Kinases/antagonists & inhibitors/metabolism
Neuroprotective Agents/pharmacology
Nitriles/pharmacology
Phorbol 12,13-Dibutyrate/pharmacology
Protein Kinase C/*metabolism
Protein Transport
Rats
Rats, Sprague-Dawley
Reactive Oxygen Species/metabolism
Receptors, Aryl Hydrocarbon/metabolism
Receptors, N-Methyl-D-Aspartate/metabolism
Research Support, Non-U.S. Gov't
Tetrachlorodibenzodioxin/*toxicity