Methylmercury (MeHg) is a persistent environmental toxin that selectively disrupts development of the fetal brain. Human exposure to MeHg, which occurs predominantly through fish consumption, contributes to an estimated 6% of women of child-bearing age in the U.S. having blood mercury levels at or above the reference dose set by the EPA. Children born to mothers having elevated blood mercury levels show cognitive deficits. Despite the ongoing health risks posed by MeHg the discrete mechanisms that make the developing nervous system most sensitive to MeHg toxicity are not clear. As well, factors that confer resistance to MeHg intoxication are not fully understood. In this proposal we will investigate how MeHg interferes with the earliest events in neurogenesis. Our overall hypothesis is that MeHg acts specifically in the nervous system by overcoming endogenous defense mechanisms to alter activity of cell signaling pathways. Using the Drosophila (fruit fly) model, we have discovered that MeHg can activate Notch receptor signaling, a highly conserved pathway required for normal neurogenesis in flies and humans. We also find overall resistance to MeHg is achieved by upregulation of glutathione synthesis specifically in the nervous system. We will therefore investigate how these fundamental mechanisms operate to disrupt, and alternatively protect, nervous system development with three Aims. First, we will characterize three distinct cell differentiation events in embryonic neurogenesis where Notch signaling is potentially perturbed by MeHg. Second, we will identify and characterize direct interactions of MeHg with protein targets in the Notch pathway. Finally, we will identify gene products that confer MeHg resistance by artificial selection and expression profiling. These data will advance our understanding of the fundamental molecular mechanisms dictating the susceptibility of the embryonic nervous system to MeHg toxicity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES015550-05
Application #
8016683
Study Section
Neurotoxicology and Alcohol Study Section (NAL)
Program Officer
Kirshner, Annette G
Project Start
2007-04-20
Project End
2012-09-01
Budget Start
2011-02-01
Budget End
2012-09-01
Support Year
5
Fiscal Year
2011
Total Cost
$276,677
Indirect Cost
Name
University of Vermont & St Agric College
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
066811191
City
Burlington
State
VT
Country
United States
Zip Code
05405
Engel, Gregory L; Rand, Matthew D (2014) The Notch target E(spl)mδ is a muscle-specific gene involved in methylmercury toxicity in motor neuron development. Neurotoxicol Teratol 43:11-8
Jebbett, Nathan J; Hamilton, Joshua W; Rand, Matthew D et al. (2013) Low level methylmercury enhances CNTF-evoked STAT3 signaling and glial differentiation in cultured cortical progenitor cells. Neurotoxicology 38:91-100
Rand, Matthew D; Lowe, Jessica A; Mahapatra, Cecon T (2012) Drosophila CYP6g1 and its human homolog CYP3A4 confer tolerance to methylmercury during development. Toxicology 300:75-82
Mahapatra, Cecon T; Rand, Matthew D (2012) Methylmercury tolerance is associated with the humoral stress factor gene Turandot A. Neurotoxicol Teratol 34:387-94
Engel, G L; Delwig, A; Rand, M D (2012) The effects of methylmercury on Notch signaling during embryonic neural development in Drosophila melanogaster. Toxicol In Vitro 26:485-92
Mahapatra, Cecon T; Bond, Jeffrey; Rand, David M et al. (2010) Identification of methylmercury tolerance gene candidates in Drosophila. Toxicol Sci 116:225-38
Rand, Matthew D (2010) Drosophotoxicology: the growing potential for Drosophila in neurotoxicology. Neurotoxicol Teratol 32:74-83
Rand, Matthew D; Kearney, Alison L; Dao, Julie et al. (2010) Permeabilization of Drosophila embryos for introduction of small molecules. Insect Biochem Mol Biol 40:792-804
Rand, Matthew D; Dao, Julie C; Clason, Todd A (2009) Methylmercury disruption of embryonic neural development in Drosophila. Neurotoxicology 30:794-802
Delwig, A; Rand, M D (2008) Kuz and TACE can activate Notch independent of ligand. Cell Mol Life Sci 65:2232-43