Methylmercury (MeHg) is a significant environmental contaminant that continues to pose a great risk to human health. Considerable attention in the scientific and health policy fora is focused on the question of whether MeHg intake from a diet high in fish is associated with aberrant CNS function. A number of recent studies (Kjellstrom et al., 1986, 1989; McKeon-Eyssen et al., 1983; Grandjean et al., 1997) suggest that fetal exposure at levels attained by mothers eating fish regularly during pregnancy are associated with neurological deficits in their offspring. Astrocytes play a key role in MeHg-induced excitotoxicity. [1] MeHg preferentially accumulates in astrocytes. [2] MeHg potently and specifically inhibits glutamate uptake in astrocytes. [3] Neuronal function is secondary to disturbances in astrocytes. [4] co-application of nontoxic concentrations of mercury and glutamate leads to the typical appearance of neuronal lesions associated with excitotoxic stimulation. [5] MeHg induces swelling in astrocytes. These observations are fully consistent with MeHg-induced dysregulation of excitatory amino acid homeostasis, and indicate that a glutamate-mediated excitotoxic mechanism is involved. The working hypotheses of the proposal outline a number of critical target sites for MeHg-induced neurotoxicity.
In Specific Aim 1. 0 we will test the hypothesis that activation of the astrocyte-specific enzyme, cytosolic phospholipase A2 (cPLA2) and the ensuing hydrolysis and release of arachidonic acid (AA) are mediators of glutamate release upon exposure to MeHg. We will investigate the lipase(s) involved, and determine the relationship between cPLA2 activation, regulatory volume decrease (RVD), and glutamate release.
In specific Aim 2. 0, we will test the hypothesis that MeHg-induced increased extracellular glutamate concentrations will competitively inhibit cystine transport into astrocytes, leading to diminished supply of cysteine for neuronal glutathione (GSH) synthesis.
In Specific Aim 3. 0, we will test the hypothesis that modification of cysteine residues by MeHg is associated with altered glutamate transport, and that it is regulated by the chemical redox-state of reactive cysteine residues in the astrocyte-specific glutamate transporters, GLAST and GLT1. The studies will be carried out in rat primary cultures of neurons and astrocytes, as well as Chinese hamster ovary (CHO-K1) cells (where transporters can be over expressed in cells that lack the endogenous glutamate transporter). Our approach will encompass a broad array of methods, including molecular biology, electrophysiology, radiolabel trans-membrane fluxes, and electrical impedance measurements of cell volume.
| Peres, Tanara V; Arantes, Leticia P; Miah, Mahfuzur R et al. (2018) Role of Caenorhabditis elegans AKT-1/2 and SGK-1 in Manganese Toxicity. Neurotox Res : |
| Meng, Qingtao; Wu, Shenshen; Wang, Yajie et al. (2018) MPO Promoter Polymorphism rs2333227 Enhances Malignant Phenotypes of Colorectal Cancer by Altering the Binding Affinity of AP-2?. Cancer Res 78:2760-2769 |
| Ke, Tao; Gonçalves, Filipe Marques; Gonçalves, Cinara Ludvig et al. (2018) Post-translational modifications in MeHg-induced neurotoxicity. Biochim Biophys Acta Mol Basis Dis : |
| Rohn, Isabelle; Marschall, Talke Anu; Kroepfl, Nina et al. (2018) Selenium species-dependent toxicity, bioavailability and metabolic transformations in Caenorhabditis elegans. Metallomics 10:818-827 |
| Pinkas, Adi; Cunha Martins Jr, Airton; Aschner, Michael (2018) C. elegans-An Emerging Model to Study Metal-Induced RAGE-Related Pathologies. Int J Environ Res Public Health 15: |
| Unoki, Takamitsu; Akiyama, Masahiro; Kumagai, Yoshito et al. (2018) Molecular Pathways Associated With Methylmercury-Induced Nrf2 Modulation. Front Genet 9:373 |
| Wu, Shenshen; Meng, Qingtao; Zhang, Chengcheng et al. (2018) DR4 mediates the progression, invasion, metastasis and survival of colorectal cancer through the Sp1/NF1 switch axis on genomic locus. Int J Cancer 143:289-297 |
| da Silveira, Tássia Limana; Zamberlan, Daniele Coradine; Arantes, Leticia Priscilla et al. (2018) Quinolinic acid and glutamatergic neurodegeneration in Caenorhabditis elegans. Neurotoxicology 67:94-101 |
| Ruszkiewicz, Joanna A; Pinkas, Adi; Miah, Mahfuzur R et al. (2018) C. elegans as a model in developmental neurotoxicology. Toxicol Appl Pharmacol 354:126-135 |
| Culbreth, Megan; Zhang, Ziyan; Aschner, Michael (2017) Methylmercury augments Nrf2 activity by downregulation of the Src family kinase Fyn. Neurotoxicology 62:200-206 |
Showing the most recent 10 out of 111 publications
