Science Inventory



Parran, D. K., S Barone, T. R. Ward, AND W R. Mundy. METHYLMERCURY EFFECTS ON NEUROTROPHIN SIGNALING IN PC12 CELLS. Presented at Society of Toxicology, San Francisco, CA, March 25-29, 2001.


Exposure to methylmercury (CH 3 Hg) can cause disruption in the development of the nervous system but the underlying mechanism of action is unclear. Previous in vivo studies in our laboratory have shown that developmental exposure to CH 3 Hg resulted in changes in neurotrophic factor signaling that were associated with altered morphology of the neocortex. Because neurotrophin signaling through Trk receptors is important for differentiation and survival in the developing nervous system, we examined the hypothesis that CH 3 Hg could disrupt differentiation via actions on the neurotrophin signal transduction cascade. The present study examined the effects of CH 3 Hg on NGF-stimulation of the Trk A receptor, mitogen activated protein kinase (MAPK), and neurite outgrowth in an in vitro model of differentiation. Exposure to NGF for 24 hr stimulated neurite outgrowth in primed PC12 cells and was inhibited by CH3Hg with an EC 50 of 0.03 m M, a concentration which did not affect cell viability. Whole cell binding assays using radiolabeled NGF reveal a single binding site with an affinity of approximately 2 nM. A 1 hr exposure of PC12 cells to 0.01-3 m M CH 3 Hg did not affect specific binding of I 125 -NGF to the Trk A receptor. Activation of Trk A and the MAPK cascade were monitored by measuring the phosphorylated, active forms following NGF stimulation. NGF stimulation caused in a time-dependent activation of both Trk A and MAPK with a peak activation of both at 5 min. Activation decreased over time but remained significantly elevated at 60 min. Concurrent exposure to CH 3 Hg resulted in a concentration-dependent decrease in MAPK activation after 60 min of NGF stimulation but not after 5min. This data suggests that CH 3 Hg may cause a disruption in differentiation of PC12 cells by inhibiting the neurotrophin signal transduction cascade, but not at the site of NGF binding to the Trk receptor. (DKP was supported by NIEHS Training Grant T32ES07126. This abstract does not necessarily reflect EPA policy)

Record Details:

Product Published Date: 03/27/2001
Record Last Revised: 06/06/2005
Record ID: 60774