Chronic exposure to high concentrations of manganese (Mn) results in adverse neurological health effects commonly referred to as manganism. Manganese neurotoxicity is a significant toxicological problem resulting from the use of manganese as a gasoline additive, and in welding, metal industries, pesticide manufacturing, pharmaceutical preparations, infant food formulations, and battery production. Manganese predominantly accumulates in the basal ganglia structures and causes mitochondrial dysfunction, oxidative stress, and apoptosis. However, cellular and molecular mechanisms underlying manganese neurotoxicity are poorly understood. We have been studying mitochondrial-dependent apoptotic signaling in manganese neurotoxicity and found that protein kinase C-delta (PKCd), a member of the novel PKC isoform family, is persistently activated by caspase-3 to promote apoptosis during manganese exposure. While studying the apoptotic signaling pathway in cell culture models of manganese neurotoxicity, we also unexpectedly identified that PKCd is upregulated both in protein and mRNA levels during manganese treatment. Further analysis of the PKCd promoter revealed that two key transcription factors, NFkB and SP1, regulate PKCd gene expression. Thus, our competitive renewal proposal aims to systematically characterize this gene-environment interaction by studying novel molecular mechanisms underlying manganese-induced upregulation of the proapoptotic PKCd gene. We propose to complete the study by pursuing the following specific aims: i) To characterize upregulation of an oxidative stress-sensitive proapoptotic kinase PKCd in mouse primary neuronal cultures and animal models following manganese exposure, ii) To investigate molecular mechanisms of manganese-induced upregulation of PKCd by examining its transcriptional regulation of a PKCd promoter, and iii) To further define the functional role of NFkB and SP1-dependent PKCd upregulation in manganese-induced neuronal damage during chronic manganese exposure. Cellular, molecular, and neurochemical approaches in relevant cell cultures and animal models of manganese neurotoxicity will be used. We anticipate that the proposed study will provide comprehensive information about how environmental exposure to manganese can alter the expression of the key proapoptotic gene PKCd to augment manganese neurotoxicity, and this knowledge may advance the development of novel translational approaches for the treatment of manganese neurotoxicity.

Public Health Relevance

Environmental exposure to excessive manganese impairs basal ganglia function, resulting in a neurological disorder relatively similar to Parkinsonism commonly known as Manganism. Manganese exposure is of serious concern due to the increased incidences of extrapyramidal neurological symptoms among miners and industrial workers, including welders. Manganese predominantly accumulates in the basal ganglia structures and causes mitochondrial dysfunction, oxidative stress, and apoptosis. However, cellular and molecular mechanisms underlying manganese neurotoxicity are poorly understood. The proposed study will elucidate the neurotoxic mechanisms underlying manganese induced upregulation of a proapoptotic kinase PKCd and its functional relevance to manganese neurotoxicity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES010586-12
Application #
8318602
Study Section
Special Emphasis Panel (ZRG1-IFCN-C (04))
Program Officer
Lawler, Cindy P
Project Start
2000-08-05
Project End
2016-03-31
Budget Start
2012-05-01
Budget End
2013-03-31
Support Year
12
Fiscal Year
2012
Total Cost
$323,165
Indirect Cost
$98,165
Name
Iowa State University
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
005309844
City
Ames
State
IA
Country
United States
Zip Code
50011
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