Methylmercury (MeHg) is a potent neurotoxin. We hypothesize that under conditions of MeHg-induced oxidative stress, Nrf2 coordinates the upregulation of cytoprotective genes that combat MeHg- induced oxidative injury, and that genetic and biochemical changes that negatively impact upon Nrf2 function increase MeHg's neurotoxicity. Corollaries of this hypothesis imply (i) that genetic susceptibility to MeHg-induced neurotoxicity correlates with Nrf2 expression levels and activation of downstream genes associated with antioxidant activity, and (ii) the degree of Nrf2 upregulation represents a critical determinant of cell-specific (astrocytes vs. neurons) adaptive responses to MeHg. The approach to testing these hypotheses includes biochemical and molecular characterization of Nrf2 signaling both in vivo and in vitro (primary astrocytes and neurons), and genetic correlates of neurobiological phenotypes (biochemical, morphological and neurobehavioral endpoints), taking full advantage of the unique BXD recombinant inbred (RI) mice.
Specific Aim 1 will determine if MeHg exposure in cultured murine primary cerebellar astrocytes and neurons, and during development in vivo induces oxidative stress that correlates with Nrf2 transcriptional activation.
Specific Aim 2 will evaluate whether the phosphatidylinositol 3-kinase (PI3K)-serine/threonine protein kinase Akt-mediated cell survival pathway is essential for Nrf2-dependent protection against MeHg.
Specific Aim 3 will test the role of Nrf2 heritability in modulating MeHg susceptibility in BXD RI mouse strains.
These specific aims hold the promise of delineating common initiator signals for the modulation of MeHg neuroprotection, shedding light on neurotoxic mechanisms and susceptibility associated with exposure to this metal.
The proposed studies will provide novel and innovative information on (1) the role of transcriptional modifications by MeHg of the Nrf2 signaling pathway and its associated networks in modulating neurodevelopmental toxicity and neuroprotection;(2) functional domains that may underlie broad points of interaction of MeHg with biological systems;(3) the role of genetic traits of susceptibility in mediating molecular mechanisms of MeHg injury;and (4) gene-environment interactions within and across species in the integrated systems response to MeHg.
|Nguyen, Thuy T; Aschner, Michael (2014) F3 -Isoprostanes as a Measure of in vivo Oxidative Damage in Caenorhabditis elegans. Curr Protoc Toxicol 62:11.17.1-11.17.13|
|da Silva Santos, Vivian; Bisen-Hersh, Emily; Yu, Yingchun et al. (2014) Anthocyanin-rich açaí (Euterpe oleracea Mart.) extract attenuates manganese-induced oxidative stress in rat primary astrocyte cultures. J Toxicol Environ Health A 77:390-404|
|Bisen-Hersh, Emily B; Farina, Marcelo; Barbosa Jr, Fernando et al. (2014) Behavioral effects of developmental methylmercury drinking water exposure in rodents. J Trace Elem Med Biol 28:117-24|
|Martinez-Finley, Ebany J; Chakraborty, Sudipta; Slaughter, James C et al. (2013) Early-life exposure to methylmercury in wildtype and pdr-1/parkin knockout C. elegans. Neurochem Res 38:1543-52|
|Farina, Marcelo; Avila, Daiana Silva; da Rocha, Joao Batista Teixeira et al. (2013) Metals, oxidative stress and neurodegeneration: a focus on iron, manganese and mercury. Neurochem Int 62:575-94|
|Caito, Samuel W; Zhang, Yaofang; Aschner, Michael (2013) Involvement of AAT transporters in methylmercury toxicity in Caenorhabditis elegans. Biochem Biophys Res Commun 435:546-50|
|Martinez-Finley, Ebany J; Caito, Samuel; Slaughter, James C et al. (2013) The Role of skn-1 in methylmercury-induced latent dopaminergic neurodegeneration. Neurochem Res 38:2650-60|