Along with a number of associated genetic factors, a large body of data indicates that environmental agents, especially neurotoxic metals, may play a role in the etiology of neurobehavioral disorders. Exposure to manganese (Mn), a well-known neurotoxicant, is widespread in the general population from gasoline additives, fossil fuel combustion, and accumulates at high levels in workers exposed to welding fumes. Overt Mn neurotoxicity (manganism or Mn-induced parkinsonism) causes symptoms that are similar to Parkinson's disease, and studies with """"""""asymptomatic"""""""" welders suggest an association between exposure to Mn-containing metal fumes and subclinical neurobehavioral deficits. A link between low levels of Mn and neurological disorders is suspected, but weakened by both the lack of an in vivo objective marker of Mn dose to the human brain, and from insufficient data on how this correlates with functional impairment. Divalent Mn (Mn2+) is paramagnetic and causes a reduction in T1 relaxation time that is significantly greater than for all other metals, particularly the metals contained in welding fumes. Thus, magnetic resonance imaging (MRI) T1 relaxation time and T1 contrast changes of magnetic resonance imaging (MRI) may reflect Mn accumulation in the brain tissue of welders with adequate specificity. Historically, the pallidal index has served as an MRI measure for overt Mn poisoning. Its utility has been questioned because regions other than the globus pallidus (GP) have been neglected for study, and the pallidal index may not be sensitive to low levels of exposure. Supported by preliminary data in human subjects, we propose to test the central hypothesis that, relative to matched controls, """"""""asymptomatic"""""""" welders will have significantly higher Mn accumulation in specific brain regions [e.g., olfactory bulbs (OB), basal ganglia (BG: i.e., caudate, putamen &GP), frontal lobe (FL: i.e., frontal gray (FGM) and white matter (FWM) &prefrontal cortex (including the orbital frontal cortex)] that correlate with airborne Mn exposure and region-specific neurobehavioral changes. We propose a study of 40 welders (boilermakers/pipefitters) and 40 matched controls (electricians/sprinkler fitters) with both retrospective and prospective environmental exposure measurements, neuropsychological tests, blood metal (Fe and Mn) assessment, and state-of-the-art MRI estimates of both Mn (with rapid T1 mapping) and Fe [with Susceptibility Weighted Images (SWI)]. Via this study, we shall develop an important clinical tool to bridge the gap between basic and applied research in this area that will lead to a better understanding of the role that neurotoxic metals play in the development of neurobehavioral disorders. This will be accomplished through the following specific aims:
Aim 1 will validate that the MRI T1 measurements provide a reliable biomarker of Mn exposure in specific brain regions [e.g., OB, BG and FL, etc.] in humans.
Aim 2 will delineate the functional consequences of region-specific Mn accumulation in the brain.
Aim 3 will explore Fe-Mn interactions in brain and their functional consequences.

Public Health Relevance

Manganese (Mn), a well-known neurotoxicant that is ubiquitous in the environment from gasoline additives, the combustion of fossil fuels, as well as being particularly concentrated in welding fumes, may play a role in neurodegenerative processes. The basic and epidemiological studies in this area, however, are marred by the lack of an objective marker(s) of metal deposition in the human brain and how this correlates directly with neurobehavioral impairment. The proposed study will use the improved, state-of-the-art MRI techniques to reflect regional brain Mn deposition in response to environmental exposure, delineate its functional correlations, and will lead to a better understanding of the role of environmental neurotoxicants in the development of neurobehavioral disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
1R01ES019672-01A1
Application #
8185903
Study Section
Acute Neural Injury and Epilepsy Study Section (ANIE)
Program Officer
Lawler, Cindy P
Project Start
2011-08-16
Project End
2015-04-30
Budget Start
2011-08-16
Budget End
2012-04-30
Support Year
1
Fiscal Year
2011
Total Cost
$651,673
Indirect Cost
Name
Pennsylvania State University
Department
Neurology
Type
Schools of Medicine
DUNS #
129348186
City
Hershey
State
PA
Country
United States
Zip Code
17033
Lee, Eun-Young; Eslinger, Paul J; Flynn, Michael R et al. (2017) Association of neurobehavioral performance with R2* in the caudate nucleus of asymptomatic welders. Neurotoxicology 58:66-74
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Lee, Eun-Young; Flynn, Michael R; Lewis, Mechelle M et al. (2017) Welding-related brain and functional changes in welders with chronic and low-level exposure. Neurotoxicology :
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Lee, Eun-Young; Flynn, Michael R; Du, Guangwei et al. (2016) Increased R2* in the Caudate Nucleus of Asymptomatic Welders. Toxicol Sci 150:369-77
Lewis, Mechelle M; Flynn, Michael R; Lee, Eun-Young et al. (2016) Longitudinal T1 relaxation rate (R1) captures changes in short-term Mn exposure in welders. Neurotoxicology 57:39-44

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