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Grantee Research Project Results

Grantee Research Project Results

Mechanisms of Methylmercury-induced Cellular Stress in Caenorhabditis elegans

EPA Grant Number: FP917150
Title: Mechanisms of Methylmercury-induced Cellular Stress in Caenorhabditis elegans
Investigators: VanDuyn, Natalia M
Institution: Indiana University
EPA Project Officer: Cobbs-Green, Gladys M.
Project Period: September 1, 2010 through August 31, 2013
Project Amount: $111,000
RFA: STAR Graduate Fellowships (2010)
Research Category: Fellowship - Pesticides and Toxic Substances , Academic Fellowships

Description:

Objective:

Methylmercury (MeHg) is a ubiquitous environmental contaminant that poses a considerable threat to public health. MeHg easily crosses the blood brain barrier and the placenta, leading to developmental deficits and neuropathology. Although MeHg poisonings have been studied for decades, the molecular basis for the toxicity remains largely unknown. My objective is to identify and characterize the cellular and molecular components involved in MeHg toxicity.

Synopsis:

Methylmercury (MeHg) is a ubiquitous environmental toxicant that can result in severe neurological and developmental defects. Although MeHg has been studied for decades, the molecular basis for the toxicity remains largely unknown. My project utilizes the nematode C. elegans, a small worm whose genes and cellular response to stress are very similar to those of humans, to identify and characterize the molecular pathways involved in MeHg-induced developmental defects and neuropathology.

Approach:

I will utilize a novel C. elegans model for MeHg toxicity to identify and characterize the molecular pathways involved in MeHg toxicity. I will generate transgenic C. elegans animals and incorporate biochemical and genetic analysis to identify MeHg sensitive cells, and determine if the stress-responsive proteins GSTs, MAPKs, and SKN-1 may modulate toxicant-induced cellular vulnerability. I will also incorporate a reverse genetic screen to identify proteins involved in MeHg toxicity.

Expected Results:

I have recently shown that the expression of particular GSTs and SKN-1 is involved in inhibiting MeHg-induced cellular stress. I expect that these proteins and their downstream targets will modulate DA and GABAergic neuronal vulnerabilities to the toxicant. GSTs and members of the MAPKs also likely play a role in the MeHg-induced developmental deficits and neurodegeneration, and I expect that decreases in gene expression will increase cellular stress and cellular dysfunction. Furthermore, the incorporation of the reverse genetic screen will likely identify novel regulators of the MeHg induced cellular stress and neuron degeneration.

Potential to Further Environmental/Human Health Protection:

The cellular and molecular basis for MeHg-induced toxicity and developmental defects are largely unknown. This proposal will likely elucidate cellular sensitivities and novel molecular pathways involved in the toxicant-induced pathology. The identification of genes and molecules involved in the toxicity may provide novel MeHg-associated therapeutic targets. Furthermore, these studies may identify early molecular markers of MeHg-induced pathology that may be utilized to determine specific toxicant-associated exposures.

Supplemental Keywords:

methylmercury, neurodevelopment, oxidative stress,

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The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Conclusions drawn by the principal investigators have not been reviewed by the Agency.

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