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ToxSci Advance Access published online on April 20, 2005
Toxicological Sciences, doi:10.1093/toxsci/kfi175
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Toxicological Sciences © The Author 2005. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org
Received February 8, 2005
Accepted April 13, 2005

Neurotoxicology

EFFECTS OF THIMEROSAL ON NGF SIGNAL TRANSDUCTION AND CELL DEATH IN NEUROBLASTOMA CELLS

Damani K. Parran 1, Angela Barker 1, and Marion Ehrich 1*

1 Virginia-Maryland Regional College of Veterinary Medicine, Laboratory for Neurotoxicity Studies, Virginia Tech, 1 Duckpond Drive, Blacksburg, VA 24061-0442

* To whom correspondence should be addressed.
Marion Ehrich, E-mail: marion{at}vt.edu


  Abstract

Signaling through neurotrophic receptors is necessary for differentiation and survival of the developing nervous system. The present study examined the effects of the organic mercury compound thimerosal on nerve growth factor signal transduction and cell death in a human neuroblastoma cell line (SH-SY5Y cells). Following exposure to 100 ng/ml NGF and increasing concentrations of thimerosal (1 nM - 10 µM), we measured the activation of TrkA, MAPK and PKC-{delta}. In controls, the activation of TrkA MAPK and PKC-{delta} peaked after 5 minutes of exposure to NGF and then decreased but was still detectable at 60 minutes. Concurrent exposure to increasing concentrations of thimerosal and NGF for 5 minutes resulted in a concentration-dependent decrease in TrkA and MAPK phosphorylation, which was evident at 50 nM for TrkA and 100 nM for MAPK. Cell viability was assessed by the LDH assay. Following 24 hr exposure to increasing concentrations of thimerosal, the EC50 for cell death in the presence or absence of NGF was 596 nM and 38.7 nM, respectively. Following 48 hr exposure to increasing concentrations of thimerosal, the EC50 for cell death in the presence and absence of NGF was 105 nM and 4.35 nM, respectively. This suggests that NGF provides protection against thimerosal cytotoxicity. To determine if apoptotic versus necrotic cell death was occurring, oligonucleosomal fragmented DNA was quantified by ELISA. Control levels of fragmented DNA were similar in both the presence and absence of NGF. With and without NGF, thimerosal caused elevated levels of fragmented DNA appearing at 0.01 µM (apoptosis) to decrease at concentrations > 1 µM (necrosis). These data demonstrate that thimerosal could alter NGFinduced signaling in neurotrophin-treated cells at concentrations lower than those responsible for cell death.

Keywords: signal transduction; neurotrophin; mercury compound.
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