Journal Article

Differing Effects of Toxicants (Methylmercury, Inorganic Mercury, Lead, Amyloid β, and Rotenone) on Cultured Rat Cerebrocortical Neurons: Differential Expression of Rho Proteins Associated With Neurotoxicity

Masatake Fujimura and Fusako Usuki

in Toxicological Sciences

Volume 126, issue 2, pages 506-514
Published in print April 2012 | ISSN: 1096-6080
Published online January 2012 | e-ISSN: 1096-0929 | DOI: http://dx.doi.org/10.1093/toxsci/kfr352
Differing Effects of Toxicants (Methylmercury, Inorganic Mercury, Lead, Amyloid β, and Rotenone) on Cultured Rat Cerebrocortical Neurons: Differential Expression of Rho Proteins Associated With Neurotoxicity

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Methylmercury (MeHg), inorganic mercury (IHg), lead (Pb), amyloid-β peptide (Aβ), and rotenone (RTN) are well-known toxicants. Here, we demonstrate that these five toxicants exhibit differing effects on cerebrocortical neurons. The concentration responsible for 30% loss of viability (EC30) values 3 days after exposure was approximately 100nM for MeHg, IHg, and RTN and 10μM for Aβ. Neuritic degeneration and subsequent apoptotic cell death were observed in these toxicant-treated cells. In contrast, the EC30 value 3 days after exposure to Pb was > 10μM. We clarified the differential expression of Ras homolog gene (Rho) family proteins (Ras-related C3 botulinum toxin substrate 1 [Rac1], cell division cycle 42, and Ras homolog gene family, member A [RhoA]) upon exposure to these five toxicants. Exposure to 100nM MeHg, IHg, or RTN downregulated the expression of Rac1, related to neuritic extension, but did not affect RhoA, related to retraction. At a higher concentration (1μM), IHg and RTN also acted through the suppression of Rac1, whereas increased MeHg toxicity was not associated with the expression of Rho family proteins. On the other hand, Pb and Aβ showed no effects on the expression of Rho proteins. Modification of the balance of neuritic extension and retraction by the suppression of Rho A rescued the neurotoxicity of 100nM MeHg, IHg, and RTN. The results indicate that the imbalance of neuritic extension and retraction by the suppression of Rac1 by 100nM MeHg, IHg, and RTN causes cerebrocortical neuron axonal degeneration and cell death. By contrast, the neurotoxicities of Pb, Aβ, and MeHg (at higher concentrations) are conferred by other toxic mechanisms.

Keywords: neurotoxicity; mercury; lead; amyloid-β; rotenone; Rho family proteins

Journal Article.  4100 words.  Illustrated.

Subjects: Medical Toxicology ; Toxicology (Non-medical)

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