Manganese Health Research Program: Phase 1, Core 2
Research Core Projects:
(1) Biomarkers of Early Onset of Manganese Neurotoxicities among Occupationally Exposed Chinese Workers
(2) Magnetic Resonance Imaging (MRI) and Spectroscopy (MRS) in Manganese-Exposed Smelting Workers: Relationship to External and Internal Exposure Indices
Core Principal Investigator (CPI): Wei Zheng
550 Stadium Mall Drive, CIVL 1163
Key Collaborators: Frank Rosenthal, Purdue University, email@example.com
Ulrike Dydak, Purdue University, firstname.lastname@example.org
Project started: 1 April 2005
Scheduled completion date: 31 March 2009
Completed: December 2010
Background: Exposure to excessive manganese (Mn) is known to lead to motor and psychological disorders. Understanding the vulnerability of glutamatergic and GABAergic systems to manganese (Mn) toxicity should provide insights into the mechanisms of Mn-induced neurotoxicity.
Objectives: Our goal was to study whether brain levels of gamma aminobutyric acid (GABA), glutamate and other brain metabolites in smelters were altered as a consequence of Mn exposure as compared to healthy controls, and to investigate their potential as biomarker.
Methods: High-resolution 3D MRI was used to quantify Mn deposition in the brain by the pallidal index, and the single voxel Magnetic Resonance Spectroscopy (MRS) was used to investigate brain concentrations of active metabolites in the globus pallidus, putamen, thalamus and frontal cortex of a well-established cohort of 10 male Mn-exposed smelters and 10 male age-matched control subjects. In addition, the MEGA-PRESS sequence was used to determine GABA levels in the basal ganglia.
Results: Seven out of ten exposed subjects showed clear T1-hyperintense signals in the globus pallidus. A significant increase of GABA/tCr by 82% (p<0.01) was found in the basal ganglia region due to Mn exposure and NAA/tCr was significantly decreased in the frontal cortex of exposed subjects (9%, p<0.05). Using both, the GABA level and the pallidal index, the logistic regression model allows for differentiation of the exposed from the non-exposed subjects with 91% accuracy.
Conclusions: We demonstrated for the first time that GABA levels in the human basal ganglia are elevated in Mn-exposed smelters. In combination with the pallidal index, the GABA level may be a powerful non-invasive biomarker for Mn exposure. The project was finished on 28 January 2011.
Key research accomplishments
- For the first time in literature, we proposed biological measurable values that may truly reflect Mn exposure status in humans. These values (i.e., eMIR and pMIR) are a composite of the blood index of Mn exposure and the biological consequence of such an exposure. It may be useful for clinical diagnosis of Mn intoxication as well as for risk assessment of Mn toxicity in general population.
- High-resolution 3D T1-weighted MR imaging allows to trace the regions of Mn accumulation in high detail to the most interior parts of the GP and other involved structures. Two pallidal indices, PIWM and PIMU, can be used to identify Mn-exposed subjects with 70-80% accuracy.
- We show for the first time a significant increase in GABA concentration in the thalamic regions of Mn-exposed subjects. Overall this study demonstrates the feasibility of measuring GABA in the basal ganglia of highly Mn exposed subjects.
- We found that PAS can be used to reduce brain concentrations of Mn.
- We have also developed the HPLC method for PAS quantification. This paves the way for future kinetic study to produce the parameters needed for its approval by IRB for clinical trial in the US.
- Local Chinese researchers have been trained along with the progress of this project. They have now had a better sense on the quality of data collection, proper conduct of human study, respect of subject’s privacy, and scientific and objective interpretation of data. Data safety monitoring meets the strict guideline of DoD requirement.
Peer-Reviewed Publications Supported by the DoD Fund (03/2005-01/2011)
- Jiang, Y, and Zheng, W* (2005). Cardiovascular toxicities upon manganese exposure. Cardiovasc. Toxicol. 5:345-354.
- Jiang, Y-M, Zheng, W*, Long, L-L, Zhao, W-J, Li, X-G, Mo, X-A, Lu, J-P, Fu, X, Li, W-M, Liu, S-F, Long, Q-Y, Huang, J-L, and Pira, E (2007). Brain magnetic resonance imaging and manganese concentrations in red blood cells of smelting workers: Search for biomarkers of manganese exposure. NeuroToxicology 28:126-135. (doi:10.1016/j.neuro.2006.08.005)
- Aschner, M, Nass, R, Guilarte, TR, Schneider, JS, and Zheng, W* (2007). Manganese: Recent advances in understanding its transport and neurotoxicity. Toxicol. Appl. Pharmacol. 221(2):131-147. (doi:10.1016/j.taap.2007.03.001)
- Jiang YM, Long LL, Zhu XY, Zheng H, Fu X, Ou SY, Wei DL, Zhou HL, and Zheng W* (2008). Evidence for altered hippocampal volume and metabolites in workers occupationally exposed to lead: A study by magnetic resonance imaging and 1H magnetic resonance spectroscopy. Toxicol Letters 181: 118-125. (doi: 10.1016/j.toxlet.2008.07.009)
- Aschner M, Santos AP, Erikson KM and Zheng W* (2008). Manganese transport into the brain: Putative mechanisms. Metal Ions Biol Med. 10:695-700.
- Wang, DX, Du, XQ, and Zheng, W* (2008). Alteration of saliva and serum concentrations of manganese, copper, zinc, cadmium and lead among career welders. Toxicol Letters 176:40-47. (doi:10.1016/j.toxlet.2007.10.003)
- Kalia K, Jiang W, and Zheng W* (2008). Manganese accumulates primarily in nuclei of cultured brain cells. NeuroToxicology 29(3):466-470. (DOI: 10.1016/j.neuro.2008.02.012)
- Wang XQ, Li J, and Zheng W* (2008). Efflux of iron from the cerebrospinal fluid to the blood at the blood-CSF barrier: Effect of manganese exposure. Exp Biol Med 233:1561-1571 (doi: 10.3181/0803-RM-104)
- Wang XQ, Miller DS, and Zheng W* (2008). Intracellular trafficking of metal transporters in intact rat choroid plexus following in vitro treatment of manganese or iron. Toxicol Appl Pharmacol 230:167-174. (doi:10.1016/j.taap.2008.02.024)
- Zheng W*, Jiang YM, Zhang YS, Jiang W, Wang X, and Cowan DM (2009). Chelation Therapy of manganese intoxication by para-aminosalicylic acid (PAS) in Sprague-Dawley rats. NeuroToxicology 30: 240-248 (doi:10.1016/j.neuro.2008.12.007)
- Cowan DM, Fan QY, Zou Y, Shi XJ, Chen J, Rosenthal FS, Aschner M, and Zheng W* (2009). Manganese exposure among smelting workers: Blood manganese-iron ratio as a novel tool for manganese exposure assessment. Biomarkers 14(1): 3-16. (doi:10.1080/13547500902730672)
- Cowan DM, Zheng W*, Zou Y, Shi XJ, Chen J, Rosenthal FS, and Fan QY (2009). Manganese exposure among smelting workers: Relationship between blood manganese-iron ratio and early onset neurobehavioral alternations. Neurotoxicology 30:1214-1222 (doi:10.1016/j.neuro.2009.02.005)
- Long LL, Li XR, Huang ZK, Jiang YM, and Zheng W* (2009). Brain MRI and 1H-MRS of patients with chronic hepatic diseases: Relation to the severity of liver damage and recovery after liver transplantation. Exp Biol Med 234:1075-1085. (doi: 10.3181/0903-RM-118)
- Zheng W*, Fu SX, Dydak U, and Cowan DM (2011). Biomarkers of manganese intoxication. NeuroToxicology 32(1):1-8. (doi:10.1016/j.neuro.2010.10.002)
- Hong L, Jiang W, Zheng W, and Zeng S (2011). HPLC analysis of para-aminosalicylic acid and its metabolite in plasma, cerebrospinal fluid and brain tissues. J Pharmaceut Biomed Analysis 54:1101-1109. (doi:10.1016/j.jpba.2010.11.031)
- Dydak U, Jiang YM, Long LL, Zhu H, Chen J, Li WM, Edden RAE, Hu SG, Fu X, Long ZY, Mo XA, Meier D, Harezlak J, Aschner M, Murdoch J, and Zheng W (2010). In vivo measurement of brain GABA concentrations by magnetic resonance spectroscopy in smelters occupationally exposed to manganese. Env Health Persp 119: 219-224. (doi:10.1289/ehp.1002192)
- Rutchik JS, Zheng W*, Jiang YM, and Mo X (2011). How does an occupational neurologist assess welders and steelworkers for a manganese-induced movement disorder? J Occ Env Med (in press)
Abstracts Presented and Published
- Zheng, W (2006). Discovery of biomarkers of manganese exposure in humans. Toxicol Sci suppl 90(S-1), 1847.
- Yang, LZ, Jiang, YM, and Zheng, W (2006). Erythrocytes as a useful biological matrix for assessment of manganese exposure among smelting Workers. Toxicol Sci supplement 90(S-1), 191.
- Jiang, YM, Mo, XA, Du, FQ, Gao, HY, Xie, JL, Lia, FL, Pira, E, and Zheng, W (2006). Effective treatment of manganese-induced occupational Parkinsonism with p-aminosalicylic Acid (PAS-Na): A case of 17-year follow-up study. Toxicol Sci supplement 90(S-1), 1767.
- Mo, XA Jiang, YM, Long, LL, Zhao, WJ, Li, XR, Su, SH, Zheng, W (2006). Brain magnetic resonance imaging and blood levels of trace elements among manganese-exposed steel workers. Toxicol Sci supplement 90(S-1), 191.
- Rutchik, JS, Mo, XA, Jiang, YM, and Zheng, W. (2006). Manganism or Parkinson’s disease: Indications from six cases among Chinese welders and steel workers. International Conference on Industrial Medicine, Rome, Italy.
- Zheng, W, Jiang, Y, Jiang, W, Zhang, Y, Wang, X, and Cowan, DM (2007). Chelation therapy of manganese (Mn) intoxication with p-aminosalicylic acid (PAS) in Sprague-Dawley rats. Toxicol Sci supplement 96(S-1), 1087. (Charlotte, NC)
- Zheng, W, Miller, GW, Pira, E, Rutchik, JS, and Zhang, J (2007). Advances in causation and therapy of parkinsonian diseases: Views from toxicologists and clinicians. Toxicol Sci supplement 96(S-1), 1328. (Workshop in Charlotte, NC)
- Zheng, W, and Jiang, Y (2007). Efficacy and Selectivity of Metal Chelators in Treatment of Manganese Parkinsonism. Toxicol Sci supplement 96(S-1), 1333. (Workshop in Charlotte, NC)
- Cowan, DM, Fan, Q, Shi, X, Zou, Y, Rosenthal, FS, Aschner, M, and Zheng, W (2007). Manganese (Mn) in saliva as an indicator for occupational exposure in Chinese smelting workers. Toxicol Sci supplement 96(S-1), 1086. (Charlotte, NC)
- Zheng, W, Wang, D, Du, X (2007). Alteration of manganese, copper, zinc, cadmium, and lead in saliva of career welders. The 11th International Congress of Toxicology, Montreal, Canada, July 15-19.
- Zheng, W, Pira, E, and Jiang, Y (2007). Alternation of the oxidative stress status in erythrocytes and sera among manganese-exposed smelting workers. The 11th International Neurotoxicology Association Meeting, Pacific Grove, CA, June 10-15.
- Cowan DM, Fan QY, Zou Y, Shi XJ, Rosenthal FS, Aschner M, and Zheng W (2008). Manganese exposure in 328 smelting workers: Relationship among external/internal markers and neurological/psychomotor examinations. Toxicol Sci supplement 102(1), 708. (Seattle)
- Zheng W, Zhang YS, Jiang YM, and Jiang W (2008). Removal of tissue manganese by p-aminosalicylic acid (PAS) in manganese-exposed rats in vivo. Toxicol Sci supplement 102(1), 2102. (Seattle)
- Zheng W, Cowan DM, Zou Y, Shi XJ, Chen J, and Fan QY (2008). Use of manganese-iron ratio in blood for assessment of Mn exposure among smelting workers. The 20th International Conference on Epidemiology in Occupational Health (EPICOH-2008) (June 9-11) and the 10th International Symposium on Neurobehavioral Methods and Effects in Environmental and Occupational Health (NEUREOH-2008) (June 11-13). Costa Rica June 9-13, 2008. Occ Env Med 65(Suppl): 149.
- Zheng W (2009). A single parameter combining multiple bio-indices as a new approach to discover biomarkers of metal toxicities: A case study with manganese. SOT meeting in Baltimore
- Dydak U, Jiang Y, Long L, Chen J, Li W, Murdoch J, Meier D, Aschner M, and Zheng W (2009). Assessment of manganese exposure by 3D high-resolution T1-weighted MRI. SOT meeting in Baltimore
- Cowan DM and Zheng W (2009). Relationship between blood manganese-iron ratio and early onset neurobehavioral alterations. SOT meeting in Baltimore
- Fan Q, Zou Y, Liu J, Yu C, Chen J, Shi X, Zhang Y, and Wei Zheng (2009). Decreased DMT1, TF and hepcidin gene expressions in leucocyte of manganese exposed workers. SOT meeting in Baltimore
- Dydak U, Long L, Zhu H, Li WM, Jiang Y, Chen J, Fu X, Hu S, Edden RAE, Meier D, Aschner M, Murdoch J, and Zheng W (2009). Assessment of neurotransmitter concentrations in occupational manganese exposure as measured by MRS. The ISMRM 17th Scientific Meeting & Exhibition, Honolulu, Hawai'i, USA 18-24 April 2009.
- Dydak U, Jiang Y, Long L, Chen J, Li W, Murdoch J, Meier D, Aschner M, and Zheng W (2009). Assessment of manganese exposure by 3D high-resolution T1-weighted MRI. Toxicol Sci supplement 108(1):362 (Baltimore)
- Dydak U, Yoder K. How to Measure Neurotransmitters with MRS and PET: Focus on GABA, Glutamate, and Dopamine (Educational Exhibit). Radiological Society of North America Annual Meeting, Chicago, IL, USA, Nov 29-Dec 4 2009.
- Monnot AD, Ho S, and Zheng W* (2010). Regulation of copper (Cu) homeostasis at the brain barriers: Effects of Fe-overload and Fe-deficiency. Toxicol Sci suppl. 114(1): 983. (Salt Lake City).
- Fu X, Zhang Y, Jiang W, Behl M, Monnet AD, and Zheng W (2010). Increased P-glycoprotein expression at the blood-cerebrospinal fluid barrier following acute lead exposure. Toxicol Sci suppl. 114(1): 984.
- Yoshimoto Ninamango EQ, Zhao C, Yung K-T, Zheng W, Ackley E, Dager S, VanMeter J, Dydak U, Heberlein K, Tsai S-Y, Lin F-H, Wald L, Van Der Kouwe1 A, Bustilo J, Posse S. 3D High Spatial Resolution Short TE Proton-Echo-Planar-Spectroscopic-Imaging (PEPSI) at 3T in Clinically Feasible Measurement Times. ISMRM 18th Scientific Meeting & Exhibition, Stockholm, Sweden, May 1-7, 2010.
- Zheng W, Monnot AD, Choi B, and Zhang Y (2010). Regulation of copper homeostasis in brain and cerebrospinal fluid: Effect of Manganese exposure. Toxicol Sci suppl. 114(1): 1365.
- Behl M, Zhang Y, Shi Y, Cheng J, and Zheng W (2010). Activation of protein kinase C in lead-induced accumulation of β-amyloid in the choroid plexus: Relationship to subcellular relocation of low density lipoprotein receptor protein-1 (LRP1). Toxicol Sci suppl. 114(1): 1842.
- Zhang Y, Fan Q, Behl M, Jiang W, Fu S, Hong L, Monnet AD, and Zheng W (2010). Age-dependent transport of copper (Cu) at the blood-cerebrospinal fluid barrier. Toxicol Sci suppl. 114(1): 2163.
- Li GJ, Jing HM, Wei KH, Yang E, Gao WH, Zhao CY, Ma L, Liu JZ, Zhang T, and Zheng W (2010). Ultrastructural and toxicoproteomic studies of structure and function of the blood-CSF barrier in manganese-exposed rat model. Toxicol Sci suppl. 114(1): 2173.
- Dydak U, Jiang Y, Long Z, Long L, Chen J, Harezlak J, Zhu H, Aschner M, Murdoch J, and Zheng W (2010). GABA increases in basal ganglia in manganese exposed smelters. Toxicol Sci suppl. 114(1): 1000.
- Fu X, Zhang YS, Robinson G, Zakharova TP, Jiang W, Pushkar YN, and Zheng W (2011). In vivo manganese exposure disrupts brain copper homeostasis by reducing copper clearance at brain barriers. Xi’an International Neurotoxicology Conference. June 5-10.
- Long ZY, Xu J, Li XR, Long LL, Jiang YM, Zheng W, and Dydak U (2011). Neuroimaging parameters correlate with exposure time and motor test scores in occupationally manganese- exposed workers. Xi’an International Neurotoxicology Conference. June 5-10.
- Liang TJ, Mo XA, Jiang YM, Wang J, Qin WP, Guo SC, Wei XM and Zheng W (2011). Manganism and sodium para-aminosalicylic acid treatment I. New evidence of clinical therapeutic effectiveness of PAS in treatment of chronic manganism patients. Xi’an International Neurotoxicology Conference. June 5-10.
- Ou CY, Huang ML, Luo HL, Deng XF, Wang F, Wang C, Huang XW, Zheng W, and Jiang YM (2011). Manganism and sodium para-aminosalicylic acid treatment. II. Effect of PAS-Na on concentrations of amino acid neurotransmitters in basal ganglia of manganese-exposed rats. Xi’an International Neurotoxicology Conference. June 5-10.
- Dydak U, Xu J, Epur A, Li X, Streitmatter S, Long L-J, Zheng W, and Jiang Y-M (2011). Brain regions showing manganese accumulation in the human versus the rat brain. The International Society for Magnetic Resonance in Medicine May 7-13, 2011, Montreal, Canada
- Zheng G, and Zheng W (2011). Ctr1, but less likely DMT1, plays a critical role in manganese (Mn)-induced copper (Cu) accumulation in the blood-CSF barrier. Toxicologist 2122.
- Li GJ, Wei KH, Jing HM, Yang F, Zhao CY, Ma L, Zhang J, Zhang XY, Liu JZ, Liu LP, and Zheng W (2011). Peptidome and proteome in murine choroid plexus-cerebrospinal fluid system: Effect of chronic manganese (Mn) exposure. Toxicologist 2136.
- Fu X, Zhang YS, Jiang W, Monnot AD, and Zheng W (2011). Reduced copper (Cu) clearance by the blood-CSF barrier following in vivo manganese exposure and the role of Cu transporter ATP7A. Toxicologist 2137.
- Zheng W, Gu HY, Wei X, Monnot AD, and Du Y (2011). Increased beta-amyloid deposition in transgenic APP mice following chronic lead (Pb) exposure. Washington DC. Toxicologist 2138.
- Xu J, Li X, Streitmatter S, Long L, Zheng W, Jiang Y, and Dydak U (2011). Neuroimaging of manganese toxicity, effect of exposure time on accumulation in human brain. Toxicologist 2139.
- Long Z, Jiang YM, Li XR, Xu J, Long LL, Zheng W, Dydak U (2011). Neuroimaging of manganese toxicity: GABA and metabolic changes in the human brain. Toxicologist 2140.
- Zhang J, Peterson SM, Zheng W, and Freeman JL (2011). Lead (Pb) exposure on neurodevelopmental toxicity: A morphologic study in embryonic zebrafish brains. Toxicologist 2144.
- Epur A, Xu J, Zheng W and Dydak U (2011). Neuroimaging of manganese toxicity: Therapeutic effect of para-amino salicylic acid in a rat model. Toxicologist 2592.
Last updated: July 2011