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Manganese Research

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Manganese has been found in at least 603 of 1,467 National Priorities List sites identified by the Environmental Protection Agency (EPA).

Research studies indicate that there may be a substantial increased risk of a Parkinson's like Disease from exposure to fumes during the welding process. Fumes produced during the welding of certain hard surface rods or stainless steel contain high levels of manganese. Manganese may cause the development of a Parkinson's like Disease at ages much younger than normally associated with the disease.

Parkinson's Disease Research at NIEHS

In keeping with its public health mission, the NIEHS focuses on preventing development of PD by identifying environmental triggers of this disease and identifying how individuals differ in their susceptibility to these triggers. Additional research is directed toward defining the biochemical pathways of early PD development. Findings from such work could potentially lead to therapeutic interventions.

1. An NIEHS-supported study at Wayne State University and the Henry Ford Hospital in Detroit has shown that long-term, occupational exposure to certain combinations of metals is significantly associated with acquiring PD. Mixtures of lead, copper and iron posed a greater risk than exposure to any of these metals singly. This is the first study to link long-term (20 or more years) occupational exposure to heavy metals with a chronic neurodegenerative disorder.

2. NIEHS-supported researchers at Vanderbilt University are attempting to identify endogenous factors that start the neurodegenerative cascade leading to PD. These researchers hypothesize that heavy metal exposure could lead to oxidation of cathecholamines through a brain-specific pathway that produces a compound that is subsequently harmful to neurons.

3. Under an NIEHS grant, researchers at the Parkinson's Institute are investigating the role of a natural protein, alpha-synuclein, on neurodegeneration. Using a transgenic mouse that overexpresses this protein, these researchers will examine if overexpression of this protein leads to neurodegeneration over time or if overexpression of this protein can lead to enhanced vulnerability to neurotoxic injury. They are also investigating biological pathways by which overexpression occurs. These experiments might also reveal clues about the role of aging in neurodegeneration because they will be conducted in mice of different ages

4. The NIEHS is investigating the possibility of using its Agricultural Health Study to define environmental risks of PD. This study, done in collaboration with the National Cancer Institute, is a large cohort of farmers and pesticide applicators and their families. The NIEHS has worked with Dr. Tanner at the Parkinson's Institute to incorporate screening questions that could identify people in this cohort who should be further studied as potential PD cases. If a large enough subset is identified within this cohort, it could lead to important insight into environmental triggers of PD.

5. An NIEHS grant awarded to researchers at the University of at Los Angeles is being used to test the hypothesis that PD results from pesticide exposure(s) coupled with genetic susceptibility. Study subjects will be comprised of newly diagnosed PD cases and controls from three rural counties, Kern, Fresno , and Tulare . Environmental and occupational pesticide exposure estimates for each subject will be derived using pesticide-use reporting (PUR) data and information about pesticide application on crops in combination with crop patterns shown in satellite images and aerial photographs; in addition, extensive exposure interviews will be conducted with all study subjects. A variety of genetic analyses will be conducted to investigate the interaction between environmental and occupational pesticide exposure and genetic variation.

6. University of Washington researchers are conducting an NIEHS-sponsored study to investigate the association of PD with variations in a number of genes that play a role in activation and/or detoxification of environmental agents. The unifying hypothesis tested by these studies is that chemicals that induce oxidative stress reactions will destroy dopamine neurons preferentially among persons with genetically defined susceptibilities. Exposures of greatest priority interest are industrial solvents, heavy metals, and pesticides. This project may ultimately serve as a model approach for investigating the complex interplay between environmental exposures and host factors on risk for neurodegenerative disorders.

7. The NIEHS supports research at the Mayo Clinic in Rochester New York to study the association of PD with susceptibility genes previously found to be associated with novelty seeking behavior, substance use (tobacco, alcohol, and caffeine), and anxiety and depressive disorders. The initial efforts are focusing on testing association with nine candidate susceptibility genes including three detoxification genes, three dopaminergic genes, and three serotonergic genes. Additionally, a large DNA bank for rapid and efficient testing of new genetic hypothesis for PD is being established as a resource for future studies.

8. The NIEHS sponsors research from the University of Southern to assess the importance of environmental risk factors for PD in a population-based sample of 50,000 Swedish twin pairs over the age of 55 years who will be screened for PD. The zygosity of the affected twin pairs will be determined in the individuals who screen positive for PD. Information about environmental exposures which either protect or put one at risk for PD will be obtained from interviews with and archived information about those twins in which only one is affected (discordant pairs). This twin study provides a powerful tool for assessing the relative contribution of genetic and environmental determinants to PD.

9. NIEHS is sponsoring work at the University of Texas at Austin that seeks to understand the role of organochlorine pesticides in PD by studying the effects of these pesticides on signal transduction in dopamine neurons. Of primary interest are two proteins involved in cellular uptake and storage of dopamine, the dopamine transporter (DAT) and the vesicular monoamine transporter (VMAT-2). DAT can act as a molecular gateway for a number of toxic substances to enter dopamine cells, and recent findings by these researchers indicate that organochlorine pesticides cause more DATs to be expressed, providing a potential mechanism by which pesticides could increase the vulnerability of these neurons to other environmental toxicants.

10. NIEHS sponsors research at the Winifred Masterson Burke Medical Research Institute to establish molecular indicators and appropriate model systems to assess the pathological processes triggered by developmental exposure to environmental neurotoxicants. The foundation for this work is the hypothesis that exposure to environmental neurotoxicants during dopaminergic development enhances the susceptibility to accelerated dopaminergic cell death during aging. To test this hypothesis, these researchers have adopted a newly established, unique model system of in vitro SN dopaminergic development using an embryonic dopaminergic progenitor cell line. The feasibility of this in vitro model system to monitor various pathological molecular indicators during distinct developmental stage is being pilot tested using both known and the potential dopaminergic environmental neurotoxicants.

11. Iowa State University of Science and Technology researchers, using a grant from the NIEHS, are characterizing the dopaminergic neurotoxicity of the gasoline additive methylcyclopentadienyl manganese tricarbonyl (MMT) in several in vitro models of PD. Ongoing studies include evaluating the effects of MMT on oxidative stress and Ca2+ load and cell death pathways. In addition, these researchers are testing the ability of genetic or pharmacologic intervention to reduce MMT neurotoxicity. This systematic approach should lead to significant advances in our understanding of the causative role of MMT in selective dopaminergic neurodegeneration.

12. NIEHS is sponsoring a study at the University of New Mexico at Albuerque to investigate the mechanisms by which inhaled neurotoxicants implicated in PD, such as manganese, enter the central nervous system through the olfactory eipthelium and target dopaminergic systems. The results of these studies should clarify factors controlling CNS entry of inhaled toxicants, interactions of environmental exposures in potentially sensitive subsets of individuals; and the relationship to neurodegeneration. Ultimately, such approaches should help to identify markers of sensitive sub-populations or periods of sensitivity to inhaled neurotoxicants.

13. Investigators at St. Jude Children's Research Hospital , using a grant from the NIEHS, are exploiting the observation that MPTP toxicity is genetically determined in mice to characterize a novel molecular signaling pathway in astrocytes that links this xenobiotic to neuronal death and several of the pathological hallmarks of PD. These researchers are using a novel chimeric primary culture paradigm where isolated astrocytes or neurons from resistant or sensitive strains of mice are co-cultured in different combinations; in this paradigm, the genetic susceptibility to MPTP is conferred by astrocytes. Use of the murine MPTP model enables dissection of the interaction between a prototypic exogenous neurotoxicant and genetic risk factors that may contribute to the pathogenesis of PD.

14. NIEHS supports research at the University of North Carolina at Chapel Hill to understand the biological mechanisms underlying the epidemiological observation that exposure to the herbicide paraquat increases risk of PD. The guiding hypothesis is that paraquat-induced reactive oxygen species lead to formation of Lewy bodies, abnormal protein aggregates found in the cells of the substantia nigra in PD. The in vitro studies being conducted focus on the reactive oxygen species, hydrogen peroxide, and its interaction with two proteins found in Lewy bodies, cytochrome C and alpha-synuclein.

15. Texas Tech University Health Science Center researchers, using a grant awarded by the NIEHS, are testing the hypothesis that the toxicity of two naturally occurring isoquinolines (IsoQ) and two classes of pesticides, an organochlorine and a dithiocarbamate, alone or in combination, disrupts mitochondrial dysfunction in the dopaminergic neurons of the substantia nigra. The investigators also are exploring whether the activation of nicotinic alpha-7 receptors attenuates pesticide and IsoQ toxicities, consistent with the apparent neuroprotective effects of cigarette smoking. Taken together, these studies will evaluate the mechanisms by which environmental and endogenous toxins act as risk factors in PD, and the potential benefit derived from nicotinic alpha-7-receptor activation.

16. Research supported by the NIEHS at Rush-Presbyterian-St Lukes Medical Center is exploring whether fetal infections can increase the risk for developing PD later in life. The investigators hypothesize that gram (-) infection during pregnancy attenuates dopaminergic neuron development leaving the offspring with fewer dopaminergic neurons at birth and therefore at increased risk for PD in later life.

17. Research being conducted at the University of Rochester is exploring whether combined exposures to environmental chemicals is a more realistic exposure model for humans risk for developing PD. Preliminary evidence has shown that the combined exposure in mice to the pesticide, paraquat (PQ), and the fungicide, maneb (MB), potentiated the effects on dopaminergic function and associated behaviors, than did either compound administered alone and that these effects result in specific degeneration of the cells in the substantia nigra. These findings with combined PQ and MB raise concerns about the adequacy of current risk assessment standards based on exposures to single compounds and emphasize the need to obtain data on human exposures to the classes of agents used in the same geographic area.

18. The NIEHS sponsors work at the Parkinson's Institute to understand how environmental agents (i.e. metals and pesticides) might interact with proteins (i.e. alpha-synuclein) in brain cells and how such interactions could lead to protein aggregation and neuronal degeneration in PD using mice that over express alpha-synuclein. The possibility that metals and pesticides (or combinations of agents) are capable of affecting the rate of alpha-synuclein aggregation is the focus of these experiments. The results obtained are likely to clarify the mechanisms of alpha-synuclein aggregation and its role in Lewy body formation and further our understanding of the relationship between inclusion bodies, dopaminergic degeneration and metals and pesticides, both of which have been implicated in the etiology of idiopathic PD.

19. Work being supported by an NIEHS grant to researchers at Beth Israel Deaconess Hospital , Boston , MA is testing the hypothesis that accumulation of somatic mutations in mitochondrial (mt) DNA in critical cell types in the brain is one of the conditions necessary for the progression of some neurodegenerative processes. Preliminary findings showed that 1) individual pigmented neurons in substantia nigra accumulate very high levels of mtDNA deletions compromising the cell's resistance to various stresses and that 2) these cells with a heavy mutational load are the first to die in Parkinson's brain. Efforts will be focused first on PD patients and pigmented neurons of substantia nigra in the hopes that understanding the mechanisms of somatic mutation may help to find ways to make these processes even slower, moving the onset of these debilitating diseases outside the normal human lifespan.

20. Research supported by the NIEHS is being conducted at the University of Southern to test the hypotheses that an increase in the levels of nitric oxide stimulates both dopamine autoxidation and mitochondrial oxidant production resulting in an increased oxidative load in the dopaminergic cell. The results in this study will help elucidate the mechanisms by which nitric oxide induces autoxidation of dopamine and leads to the impairment of mitochondrial functions associated with PD. Understanding these mechanisms is an indispensable step in developing therapeutic interventions.

21. A Wake Forest University study sponsored by the NIEHS is focusing on the brain transport kinetics of manganese phosphate and manganese sulfate, and the findings will be correlated with the transport kinetics of manganese chloride, a model manganese (Mn) compound that has been previously studied. The objective of this work is to identify the transport mechanism(s) of Mn (in its various forms) across the blood-brain barrier (BBB) under the hypothesis that the rate and extent of Mn transport across the BBB will ultimately affect its toxicity. This research will demonstrate the mechanism(s) by which Mn enters the brain both in vitro and in vivo, and lays the foundation for mechanistically based therapies for manipulating transport in conditions of Mn intoxication.

22. NIEHS-sponsored research at the University of Rochester is focused on the loss of dopamine in the striatum and the destruction of cells in the globus pallidus (GP) from the toxic effect of manganese exposure. The research is examining the relation of Mn speciation using X-ray near edge structure (XANES) spectroscopy on DA loss and how altered Ca2+ metabolism leads to mitochondrial disintegration and apoptosis in the GP.

23. An NIEHS grant awarded to researchers at the University of Wisconson is being used to examine the mechanism by which the induction of an enzyme involved in antioxidant defense, NAD(P)H:quinone oxidoreductase (QR), by tert-butylhydroquinone (tBHQ) can protect against the neurotoxicity of glutamate. Preliminary studies in human neuroblastoma cells and primary glial cell cultures have shown that tBHQ increases QR through activation of its antioxidant response element (ARE). Elucidating the molecular mechanisms (s) regulating ARE genes in brain, therefore, may be crucial for developing therapeutic approaches to mitigate, or prevent, neurotoxicity.

24. NIEHS-sponsored research at the William Beaumont Hospital is determining the relevance of Nocardia asteroides (NA) infection as an animal model for PD and a potential causative agent of PD. NA-infected mice have a loss of nigrostriatal dopaminergic neurons, decreased striatal dopamine concentration, and movement abnormalities including head shaking and slowness of movement. Moreover, NA can survive long-term in the brain as an L-form, suggesting that chronic, subclinical infection could result in neurodegeneration. An understanding of the process by which experimental NA infection causes loss of dopaminergic neurons and motor abnormalities may be relevant to preventing this process in PD.

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