Caenorhabditis elegans: A Novel Chronic Exposure Model to Evaluate Microcystins’ Interference With NeurodevelopmentEPA Grant Number: FP917356
Title: Caenorhabditis elegans: A Novel Chronic Exposure Model to Evaluate Microcystins’ Interference With Neurodevelopment
Investigators: Moore, Caroline E
Institution: University of California - Davis
EPA Project Officer: Klieforth, Barbara I
Project Period: September 1, 2011 through August 31, 2014
RFA: STAR Graduate Fellowships (2011) RFA Text | Recipients Lists
Research Category: Fellowship - Pesticides and Toxic Substances , Academic Fellowships
Chronic exposure to the potentially life threatening, ubiquitous microcystins (MCs) may interfere with neurodevelopment. Because MCs are acutely hepatotoxic and inhibit protein phosphatases in vitro and in vivo, MCs have a high potential to interfere with the regulation of normal neuronal function. The proposed research study will utilize a novel model system using Caenorhabditis elegans (C. elegans) to evaluate in vivo effects of chronic MC exposure on neurodevelopment.
To test the hypothesis that chronic exposure to MCs produces behavioral changes indicative of neurotoxicity in C. elegans by covalently binding protein phosphatases, the study will first determine if protein phosphatase (PP) activity is inhibited after chronic exposure of C. elegans to MCs and if levels of PP1, PP2A and PP2B are altered. PP1 and PP2A are known targets for MCs, while TAX-6, the sole calcineurin A subunit in C. elegans, shares high homology with human PP2B and is a potential indirect target if MCs alter intracellular calcium levels. Secondly, the study will determine if chronic exposure to MCs decreases chemotaxis similar to acute exposure, and evaluate several other behavioral endpoints. Thirdly, the study will screen protein phosphatase mutants for altered behavior and determine if chronic MC exposure exacerbates or ameliorates these protein phosphatase mutant strains’ phenotypes to begin determining which protein phosphatases are targeted in C. elegans.
Exposure to MCs from egg to adult will cause neurological defects in C. elegans by targeting protein phosphatases, resulting in decreased levels of overall protein phosphatase activity but not altered expression of PP1, PP2A or PP2B. This will lead to a more pronounced decrease in chemotaxis behavior than noted in acute MC exposure due to prolonged alterations in sensory neuron signaling pathways. Along with the additional decrease in olfaction, hypersensitivity to osmotic changes and a loss of adaptation also are expected in chronically exposed C. elegans. As a result of defects in the regulation of serotonin-mediated reproduction pathways, the exposed strains will have a small body size and brood size, and a higher generation time and rate of egg laying in liquid compared to N2s. Exposed nematodes will be uncoordinated and have difficulties sensing changes in food availability or environment.
Potential to Further Environmental/ Human Health Protection
The protein phosphatases found as targets in C. elegans can be compared to homologous protein phosphatases of humans, leading to advances in MC neurotoxicity mechanisms. Exposing an in vivo model through its entire lifetime will represent a realistic exposure model of underrepresented populations continuously exposed from lakes and rivers with toxic blooms. If chronic exposure to MCs alters neurodevelopment in vivo, the accepted level of MCs in drinking water should be re-evaluated.