Concerns over the health risks associated with polybrominated diphenyl ethers (PBDEs) have been raised, especially given their ubiquitous environmental persistence and appreciable increases in their levels, both in the environment and human tissue. The penta-PBDE mixture, DE 71 has been demonstrated to inhibit the sequestration of dopamine by the vesicular monoamine transporter 2 (VMAT2) and generate oxidative stress. VMAT2 is a key mediator of cytosolic dopamine, regulating the accumulation and metabolism to neurotoxic reactive species. It has been well established that enhanced oxidative stress contributes to Parkinson's disease (PD) pathogenesis. Although the etiology of PD is unknown, epidemiological evidence has demonstrated a strong association between the environment and the development of PD. As DE 71 alters dopamine storage, this suggests that VMAT2 may be a putative target for DE 71 neurotoxicity. As our knowledge of the role that the environment plays in PD grows it will be important to gain a better understanding of the molecular mechanisms within the brain that are affected by environmental compounds. This proposal will examine the influence that disruption of dopamine handling by alteration of the VMAT2 has on DE 71-mediated degeneration of dopamine neurons. Furthermore, it will examine potential mechanism(s) by which DE 71 disrupts VMAT2. Completion of this project will be achieved through the candidate's involvement in a rigorous research environment where he will interact with his mentor and co-mentor, which will be critical to his acquisition of progressive experimental techniques and understanding of the daily responsibilities of a successful principle investigator. The comprehensive knowledge of toxicology and neuroscience, research techniques, laboratory management, and the commitment needed to succeed in academia that he will gain as a trainee will be immediately applied as he undertake the task of establishing his own laboratory. Not only will these skills facilitate a seemless transition to independence, they will also augment the candidate's ability to supervise a successful laboratory with the goal of elucidating the role of the environment in neurodegenerative disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Transition Award (R00)
Project #
5R00ES017477-05
Application #
8282930
Study Section
Special Emphasis Panel (NSS)
Program Officer
Kirshner, Annette G
Project Start
2010-09-03
Project End
2013-08-31
Budget Start
2012-06-01
Budget End
2013-08-31
Support Year
5
Fiscal Year
2012
Total Cost
$242,276
Indirect Cost
$85,969
Name
Emory University
Department
Public Health & Prev Medicine
Type
Schools of Public Health
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
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Wilson, W Wyatt; Onyenwe, Wellington; Bradner, Joshua M et al. (2014) Developmental exposure to the organochlorine insecticide endosulfan alters expression of proteins associated with neurotransmission in the frontal cortex. Synapse 68:485-97
Bradner, Joshua M; Suragh, Tiffany A; Caudle, W Michael (2013) Alterations to the circuitry of the frontal cortex following exposure to the polybrominated diphenyl ether mixture, DE-71. Toxicology 312:48-55
Bradner, Joshua M; Suragh, Tiffany A; Wilson, W Wyatt et al. (2013) Exposure to the polybrominated diphenyl ether mixture DE-71 damages the nigrostriatal dopamine system: role of dopamine handling in neurotoxicity. Exp Neurol 241:138-47
Caudle, W Michael; Guillot, Thomas S; Lazo, Carlos R et al. (2012) Industrial toxicants and Parkinson's disease. Neurotoxicology 33:178-88