Toxicology Division Research Highlights

Neurotoxicology

• Evaluation of oxidative stress mechanisms of the combined paraquat + maneb exposure model of the Parkinson's disease phenotype.
  
  
• A pesticide based developmental model of Parkinson's disease, postnatal paraquat + maneb, produces significant elevation in lipid peroxidation levels even 6 months post exposure, suggesting ongoing elevation in oxidative stress state. 
  
  
• Development of a double-mutant alpha-synuclein transgenic model of the Parkinson's Disease phenotype that enhances vulnerability to the pesticides paraquat and maneb in a gene-environment interaction model.
  
  
• Laser capture microdissection of nigral dopaminergic neurons from postnatal saline and paraquat + maneb exposed mice for microarray analysis to determine gene-related changes associated with these early exposures.
  
  
• Exploration of gender associated differences and their role in neuroprotection following exposure to paraquat and maneb, given the apparent protection of females
  
  
• Determination of mechanism of enhanced vulnerability to paraquat following prenatal exposure to maneb.
  
  
• The neurotransmitter dopamine contributes to the degeneration of the nigral dopaminergic neurons following exposure to mitochondrial poisons.
  
  
• The toxicity of manganese to dopaminergic neurons differs from that produced by mitochondrial poisons.
  
  
• Adenosine A2a antagonists protect against toxicity produced by intrastriatal mitochondrial impairment via receptors located outside of the striatum.
  
  
• Established a chronic in vitro model of mitochondrial dysfunction to study cellular mechanisms underlying degeneration of dopamine neurons as may occur in neurodegenerative diseases such as Parkinson's disease.
  
  
• Showed that dopamine could inhibit respiration by both monoamine oxidase-dependent and independent mechanisms.
  
  
• Demonstrated that oxidative stress increased glutaredoxin catalyzed glutathione-protein-mixed disulfide formation in mesencephalic neurons and that this correlated with neuroprotection.
  
  
• First to demonstrate functional glutaredoxin activity in brain mitochondria.
  
  
• Demonstrated that intracellular glutathione could be elevated in neurons with glutathione-ethyl ester treatment and that this protected cells against oxidative stress or mitochondrial dysfunction.
  
  
• Perinatal exposure of mice to lead reduces striatal dopamine content in adult female offspring.
  
  
• Demonstration of significant interactions between Pb exposure and environmental stress that result in permanently altered stress responsivity of offspring.
  
  
• Documented permanent changes in corticosterone levels and HPA axis function in response to maternal only exposures to Pb with lifetime consequences for offspring.
  
  
• Studies on the neurotoxicity of atrazine and its ability to kill dopaminergic neurons.
  
  
• Role of environmental metal exposures in autism
  
  
• Neuroprotective mechanisms of estradiol against oxidative stress includes the induction of antioxidant enzymes.
  
  
• Studies on the role of free radicals in mediating paraquat-induced toxicity in lung and brain tissue
  
  
• Studies using in vivo gene delivery with regulatable lentivirus for assessment of dopamine-mediated behaviors with a long-term plan of altering sensitivity to toxicants.
  
  
• Ongoing studies using nanofiber matrix to enhance dopamine neurite outgrowth in culture with a long-term plan of enhancing stem cell growth and survival in vivo.
  

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