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.
Highlights
tetrachloro dibenzo dioxin (TCDD) is an ubiquitous and most notorious environmental pollutant that accumulates in the brain as well as other organs (Kakeyama et al, 2003)
The results suggest that the translocation of protein kinase C (PKC)-α and -ε is mediated via the aryl hydrocarbon receptor (AhR)-dependent and the AhR-independent pathways, respectively, and that TCDD does not directly activate verapamil-sensitive calcium channels
Since extracellular calcium is an important factor on [3H]phorbol 12 (PDBu) binding in the cerebellar granule cells, we examined a potential route of calcium influx via the NMDA receptor, which is known to mediate calcium entry
Summary
TCDD is an ubiquitous and most notorious environmental pollutant that accumulates in the brain as well as other organs (Kakeyama et al, 2003). Recent studies indicated that low-dose exposure to environmental agents, such as dioxin and PCBs during the period of rapid brain growth, known as the "brain growth spurt" in neonatal mice can lead to disruption of the adult brain function, and to an increased susceptibility to toxic agents at adult ages (Eriksson, 1997; 2000). These effects are manifested as deranged spontaneous behavior, e.g. hyperactivity, and altered behavioral response to the cholinergic agent, nicotine (Viberg et al, 2002).
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