VACCINE

Example Of A Current Research Study In Progress • January 2016
NIHJ Research Portfolio Online Reporting Tools
RePORT
Project Number:
1R15ES012209-01
Contact PI / Project Leader:
Kiningham, Kinsley K.
Title:
Mechanism Of Thimerosal Induced Neurotoxicity
Awardee Organization:
Marshall University
Abstract Text:
DESCRIPTION (provided by applicant):
Mercurials are potent neurotoxins, which localize to both neurons and glia within the central
nervous system and elicit a range of deleterious actions. Sodium ethylmercurithiosalicylate (thimerosal)
is a widely used ethyl mercury containing preservative used in over-the-counter medications,
cleaners and cosmetics. Recent concern has been raised on the use of thimerosal in over 30
vaccines licensed in the United States. With the addition of several important vaccines over the
last few years, exposure to mercury has increased among infants, leading some investigators to
suggest an association between thimerosal exposure and autism. There is limited toxicological information
regarding ethyl mercury; therefore, estimates of health risks from thimerosal exposure
have been based on mechanistic studies of methyl mercury, a close chemical relative about which
much is known. These estimates may actually underestimate the toxicity of ethyl mercury containing
agents. The wide use of thimerosal makes understanding the mechanism(s) of its toxicity a
significant human health issue. The overall goal of this project is to investigate the mechanism by
which thimerosal causes neuronal cell death. The hypothesis to be tested is that thimerosal results
in dose-dependent activation of specific signaling molecules and redox-sensitive transcription
factors known to activate pro-death genes in neurons. If this hypothesis is correct then pharmacological
intervention should attenuate toxicity as a result of thimerosal exposure. Using a human
neuroblastoma cell line, SK-N-SH, this project will test the hypothesis in four specific aims. Aim
1 will identify in a dose-dependent manner the predominant cell death pathway (apoptotic versus
necrotic) associated with thimerosal exposure and to determine if it is associated with an increase
in reactive oxygen species and caspase-3 dependent. Aim 2 will determine if cell death is mediated
through an AP-1-dependent pathway. In addition, this specific aim will establish the role of
c-Jun-N-terminal kinase; an enzyme, which phosphorylates and activates AP-1, in thimerosalmediated
neuronal death. Aim 3 will determine if the cell death pathway is mediated through an
NFkappaB-dependent mechanism. Aim 4 will determine if thimerosal toxicity can be attenuated
by the administration of S-adenosylmethionine, an enzyme which increases endogenous levels of
glutathione. This project will generate mechanistic data on thimerosal neurotoxicity and potentially
identify specific targets for pharmacological intervention.
“This project
will generate mechanistic data
on thimerosal neurotoxicity and
potentially identify specific targets
for pharmacological intervention.”
https://projectreporter.nih.gov/project_info_description.cfm?projectnumber=1R15ES012209-01