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The toxicity of tricresyl phosphate towards cultured nerve cells and isolated nerve
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The toxicity of tricresyl phosphate towards cultured nerve cells and isolated nerve
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The toxicity of tricresyl phosphate towards cultured nerve cells and isolated nerve
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Dissertation
The toxicity of tricresyl phosphate towards cultured nerve cells and isolated nerve
2000
Overview
The aim of this work was to study the effects of tricresyl phosphate (TCP; mixed isomers), triorthocresyl phosphate (TOCP), triparacresyl phosphate (TPCP) and one of the metabolites of TOCP, cyclic phenyl saligenin phosphate (CPSP), on the outgrowth of neurites by differentiating mouse N2a neuroblastoma and rat C6 glioma cells. At a concentration of 1 μg/ml (2.7 μM) TCP inhibited the outgrowth of axon-like processes in differentiating N2a cells. By contrast, TCP had no effect on the production of extensions by C6 glioma cells induced to differentiate by the addition of sodium butyrate suggesting a selective effect on neuronal cells under these conditions. Further work showed that 1 μg/ml TCP, TOCP (2.7μM) and 1 μ/ml CPSP (3.8 μM) inhibit the outgrowth of axon-like processes by N2a for up to 48 hours, whilst 1 μg/ml TPCP (2.7μM) demonstrates a transient inhibition at 24 hours which diminishes after 48 horns. Inhibition of axon outgrowth was also seen with TOCP and CPSP after 4 hours exposure whereas no inhibitory effects were seen with TCP or TPCP at this time point. It was found that TCP and TOCP but not TPCP could be microsomally activated into a form that caused greater inhibition of axon outgrowth than seen in the corresponding control situations after 4 hours of exposure. The Western blot data has showed that inhibited axon outgrowth was associated with cytoskeletal changes, consistently involving a reduction in neurofilament heavy chain (NF-H) phosphorylation and sometimes associated with a reduction in the levels of NF- H, tubulin and GAP-43. The inhibitory effects of these OPs on differentiating N2a cells were shown to be attenuated in the presence of conditioned medium from rat C6 glioma cells, which are known to produce neurotrophic factors. This protective effect was observed at all time points. Preliminary studies showed that the effects of OPs on pre-differentiated cells mirrored the principal effect seen on the typical differentiating N2a cellular system, with a reduction in the number of pre-formed axons. Taken together, the findings from this in vitro cellular system indicate that TOCP and its metabolite, which are both strongly neuropathic in vivo, cause selective inhibition of the outgrowth of axon-like processes by differentiating N2a cells, and that this effect is associated with cytoskeletal changes, notably in NFs. These in vitro patterns of toxicity agree with those observed in vivo, indicating that differentiating N2a cells represent a useful cellular system for studying the neurodegenerative effects of OPs and other similar compounds.
