Progress 07/01/02 to 06/30/08
Outputs
OUTPUTS: The cause of Parkinsons disease (PD), a debilitation neurodegenerative disease of the basal ganglia, still remains elusive. However, factors such as occupation, lifestyle, increased age, and exposure to several environmental contaminants have been linked to PD. Of the environmental contaminants linked to PD whose exposure induces various aspects of PD symptomatology in animal models, several are currently used in pesticides. The main objectives of this research were: to access whether both very young and aged animals are more susceptible to pesticide neurotoxicity than their adult counterparts and short-term exposure to different pesticides during adolescence will potentiate the age-related neurodegeneration. PARTICIPANTS: Nick M. Filipov, PhD TARGET AUDIENCES: Scientific Community PROJECT MODIFICATIONS: Nothing significant to report during this reporting period.
Impacts
Some of our findings indicate that younger animals are sensitive to atrazine. Young animals exposed to atrazine lost dopamine producing neurons in two areas of the brain, this loss appears to be irreversible. A manuscript describing our findings was published in the Journal of Neurochemistry. In addition, we assessed the neurotoxic potential of atrazine using striatal slices. A manuscript was published in Toxicology. We also investigated the mechanism of atrazine's neurotoxicity using isolated synaptic vesicles and synaptosomes. In these studies, we compared effects of exposure to atrazine with the effects of its major mammalian metabolities. A manuscript was submitted to Toxicology. We also performed a series of experiments pertaining to the neurotoxic effects of manganese. These findings were published in Environmental Toxicology and Pharmacology and in Toxicology.
Publications
- No publications reported this period
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Progress 01/01/07 to 12/31/07
Outputs
OUTPUTS: The cause of Parkinson's disease (PD), a debilitating neurodegenerative disease of the basal ganglia, still remains elusive. However, factors such as occupation, lifestyle, increased age, and exposure to several environmental contaminants have been linked to PD. Of the environmental contaminants linked to PD whose exposure induces various aspects of PD symptomatology in animal models, several are currently used pesticides, such as the fungicide maneb and the herbicides paraquat and, as we have demonstrated recently, atrazine. The main objectives pf this research were to assess whether [i] both very young and aged animals are more susceptible to pesticide neurotoxicity (with a particular reference to basal ganglia neurodegeneration) than their adult counterparts and [ii] short-term exposure to different pesticides during adolescence will potentiate the age-related neurodegeneration. An additional objective was to determine whether pesticide exposure also results in toxicity to other organ systems, e.g., the immune system. PARTICIPANTS: Nick M. Filipov, PhD TARGET AUDIENCES: Scientific community PROJECT MODIFICATIONS: No Project Modifications information reported.
Impacts
Some of our findings indicate that younger animals are sensitive to atrazine. Young animals exposed to atrazine lost dopamine producing neurons in two areas of the brain, substantia nigra and ventral tegmental area; this loss appears to be irreversible. A manuscript describing our findings was published in Journal of Neurochemistry. In addition, we assessed the neurotoxic potential of atrazine using striatal slices. A manuscript describing our findings was published in Toxicology. We also investigated the mechanism of atrazine's neurotoxicity using isolated synaptic vesicles and synaptosomes. In these studies we compared effects of exposure to atrazine with the effects of its major mammalian metabolites. A manuscript describing our findings was submitted to Toxicology. During that year we also performed series of experiments pertaining to the neurotoxic effects of manganese, with particular reference to dopamine oxidation and the role of inflammation. These findings were recently published in Environmental Toxicology and Pharmacology and in Toxicology in vitro, respectively.
Publications
- Sistrunk, S.C., M.K. Ross, and N.M. Filipov. 2007. Direct effects of manganese compounds on dopamine and its metabolite Dopac: An in vitro study. Environ. Toxicol. Pharmacol. 23: 286-296. Epub: Nov 17, 2006.
- Filipov, N.M, M.A. Stewart, R.L. Carr, and S.C. Sistrunk. 2007. Dopaminergic toxicity of the herbicide atrazine in rat striatal slices. Toxicology. 232: 68-78. Epub: Dec 15, 2006.
- Pinchuk, L.M., S.-R. Lee, and N.M. Filipov. 2007. In vitro atrazine exposure affects the phenotypic and functional maturation of dendritic cells. Toxicol. Applied Pharmacol. 223: 206-217. Epub: June 21, 2007.
- Betancourt, A.M., N.M. Filipov, and R.L. Carr. 2007. Alteration of neurotrophins in the hippocampus and cerebral cortex of young rats exposed to chlorpyrifos and methyl parathion. Toxicological Sciences. 100(2): 445-455. Epub: Sep 24, 2007.
- Crittenden, P.L., and N.M. Filipov. 2008. Manganese-induced potentiation of in vitro proinflammatory cytokine production by activated microglial cells is associated with persistent activation of p38 MAPK. Toxicology in Vitro. 22: 18-27. Epub: July 21, 2007.
- Coban, A., and N.M. Filipov. 2007. Dopaminergic toxicity associated with oral exposure to the herbicide atrazine in juvenile male C57BL/6 mice. J. Neurochem. 100: 1177-1187. Epub: Jan 8, 2007.
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Progress 01/01/06 to 12/31/06
Outputs
The objective of this project is to assess the dopaminergic neurotoxicity of several agricultural pesticides in adolescent, adult, and aged animals by using in vivo and in vitro approaches and examining the degree of neuronal loss and microglial cell activation. It has been suggested that exposure to several different agricultural pesticides may contribute to Parkinson's Disease. In 2006, we continued our in vivo studies with mice aged 1, 3, and 18 months, which were treated with different doses of atrazine, the fungicide maneb, and other pesticides for various lengths of time. The level of dopaminergic toxicity as well as regional microglial cell activation was being assessed at different time points after termination of the respective pesticide exposure. Few of these studies are still ongoing. Sone of our findings indicate that younger animals are sensitive to atrazine. Young animals exposed to atrazine lose dopamine producing neurons in two areas of the brain,
substantia nigra and ventral tegmental area; this loss appears to be irreversible. These findings are described in a manuscript that was recently published in the Journal of Neurochemistry. In addition, in 2006, we assessed the neurotoxic potential of atrazine using striatal slices. A manuscript describing our findings was published in Toxicology. During that year we also performed series of experiments pertaining to the neurotoxic effects of manganese, with particular reference to dopamine oxidation. These findings were recently published in Environmental Toxicology and Pharmacology. The method that we developed for analysis of atrazine and its major metabolites in various biological matrices, which was reported in Press in 2005, was published in 2006.
Impacts
These studies are furthering our understanding regarding the impact of pesticide exposure during various stages of life on basal ganglia function with a special emphasis on Parkinson's Disease-like neuropathology.
Publications
- Orr, A.I., B.J. Rude, D.L. Christiansen, V. Akay, N. M. Filipov, N. S. Hill, B. P. Fitzgerald, and P. L. Ryan. 2006. Glucomannan as a dietary ergot alkaloid adsorbent for mares. Journal of Animal and Veterinary Advances. 5(12): 1242-1250.
- Coban, A., and N.M. Filipov. 2007. Dopaminergic toxicity associated with oral exposure to the herbicide atrazine in juvenile male C57BL/6 mice. Journal of Neurochemistry. 100: 1177-1187.
- Sistrunk, S.C., M.K. Ross, and N.M. Filipov. 2006. Direct effects of manganese compounds on dopamine and its metabolite Dopac: An in vitro study. Environmental Toxicology and Pharmacology. In Press.
- Filipov, N.M, M.A. Stewart, R.L. Carr, and S.C. Sistrunk. 2006. Dopaminergic toxicity of the herbicide atrazine in rat striatal slices. Toxicology. In Press.
- Norwood, A.B., A. Coban, S.C. Sistrunk, and N.M. Filipov. (2006) Chronic exposure to atrazine modulates the dopaminergic toxicity of MPTP. Toxicol. Sci. 90 (Suppl.): 1487.
- Crittenden, P.L., and N.M. Filipov. (2006) Time course of p38-alpha phosphorylation in N9 microglial cells following exposure to manganese in vitro. Toxicol. Sci. 90 (Suppl.): 1758.
- Filipov, N.M., A.B. Norwood, A. Coban, and S.C. Sistrunk. (2006) Effects on striatal neurochemistry of chronic atrazine exposure interphased with short-term exposure to maneb. Toxicol. Sci. 90 (Suppl.): 1486.
- Coban, A., A.B. Norwood, S.C. Sistrunk, and N.M. Filipov. (2006) Effects of exposure to the herbicide atrazine on basal ganglia function: in vitro and in vivo studies. Abstracts, National Institutional Development Award Symposium of Biomedical Research Excellence, July 20-22, 2006, Washington, D.C. C223.
- Wiest, A.-M., and N.M. Filipov. (2006) Glial response to stereotaxic brain manipulation: an in vivo bioluminescence imaging study. Merck-Merial Veterinary Scholars Program Symposium, August 3-6, 2006. Louisiana State University School of Veterinary Medicine, Baton Rouge, LA.
- Filipov, N.M., A.B. Norwood, and S.C. Sistrunk. (2006) Enhanced proinflammatory cytokine production by striatal slices exposed to manganese and LPS in vitro. Abstracts, XXIII Neurotoxicology Conference. September 17-21, 2006, Little Rock, AR.
- Crittenden, P.L., and N.M. Filipov. (2006) Increased activity of p38 mitogen activated protein kinase in manganese/lipopolysaccharide-exposed N9 microglia correlates with enhanced proinflammatory cytokine production in vitro. Abstracts, South Central Chapter of the Society of Toxicology Annual Meeting, October 12-13, 2006, Monroe, LA.
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Progress 01/01/05 to 12/31/05
Outputs
The objective of this project is to assess the dopaminergic neurotoxicity of several agricultural pesticides in adolescent, adult, and aged animals by using in vivo and in vitro approaches and examining the degree of neuronal loss and microglial cell activation. It has been suggested that exposure to several different agricultural pesticides may contribute to Parkinsons Disease. In 2005, we continued our in vivo studies with mice aged 1, 3, and 18 months, which were treated with different doses of atrazine, the fungicide maneb, and other pesticides for various lengths of time. The level of dopaminergic toxicity as well as regional microglial cell activation was being assessed at different time points after termination of the respective pesticide exposure. These studies are still ongoing. Preliminary findings indicate that younger animals are more sensitive to atrazine than their older counterparts. Young animals exposed to atrazine lose dopamine producing neurons in
two areas of the brain, substantia nigra and ventral tegmental area; this loss appears to be irreversible. These findings are described in a manuscript that was recently submitted to the Journal of Neurochemistry. In addition, in 2005, we assessed the immunotoxic potential of the pesticide atrazine in juvenile mice and a manuscript describing our findings was published in Toxicological Sciences. During that year we also developed a method for analysis of atrazine and its major metabolites in various biological matrices. A manuscript describing our method was accepted for publication in Analytical Biochemistry and it is now in press.
Impacts
These studies are furthering our understanding regarding the impact of pesticide exposure during various stages of life on basal ganglia function with a special emphasis on Parkinsons Disease-like neuropathology.
Publications
- Filipov, N. M., L. M. Pinchuk, B. L. Boyd, and P. L. Crittenden. 2005. Immunotoxic effects of short-term atrazine exposure in young male C57BL/6 mice. Toxicol. Sci. 86(2): 324-332. Epub: May 11, 2005.
- Ross M. K., and N. M. Filipov. 2006. Determination of atrazine and its metabolites in mouse urine and plasma by LC-MS analysis. Analytical Biochemistry. In Press.
- Filipov, N. M., R. F. Seegal, and D. A. Lawrence. 2005. Manganese potentiates in vitro production of proinflammatory cytokines and nitric oxide by microglia through a nuclear factor kappa B-dependent mechanism. Toxicol. Sci. 84: 139-148. Epub: Dec. 15, 2004.
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Progress 01/01/04 to 12/31/04
Outputs
The objective of this project is to assess the dopaminergic neurotoxicity of several agricultural pesticides in adolescent, adult, and aged animals by using in vivo and in vitro approaches and examining the degree of neuronal loss and microglial cell activation. It has been suggested that exposure to several different agricultural pesticides may contribute to Parkinsons Disease. In 2003, we showed that naive striatal tissue exposed ex vivo to the herbicide atrazine exhibited selective dopaminergic toxicity. A manuscript describing these findings is in later stages of preparation. In 2004, further in vivo studies with mice aged 1, 3, and 18 months, were initiated where mice were treated with different doses of atrazine, the fungicide maneb, and other pesticides for various lengths of time. The level of dopaminergic toxicity as well as regional microglial cell activation was being assessed at different time points after termination of the respective pesticide exposure.
These studies are still ongoing. Preliminary findings indicate that younger animals are more sensitive to atrazine than their older counterparts. Young animals exposed to atrazine loose dopamine producing neurons in two areas of the brain, substantia nigra and ventral tegmental area; this loss appears to be irreversible.
Impacts
These studies are furthering our understanding regarding the impact of pesticide exposure during various stages of life on basal ganglia function with a special emphasis on Parkinsons Disease-like neuropathology.
Publications
- Youngblood, R. C., N. M. Filipov, B. J. Rude, D. L. Christiansen, R. M. Hopper, P. D. Gerard, N. S. Hill, B. P. Fitzgerald, and P. L. Ryan. 2004. Effects of short-term early gestational exposure to endophyte-infected tall fescue diets on plasma 3,4-dihydrophenyl acetic acid and fetal development in mares. J. Anim. Sci. 82: 2919-2929.
- Filipov, N. M., D. A. Lawrence, and R. F. Seegal. 2005. Influence of polychlorinated biphenyls and turning preference on striatal dopamine metabolism. J. Toxicol. Environ. Health, 68 (3): 167-183.
- Filipov, N. M., R. F. Seegal, and D. A. Lawrence. 2005. Manganese potentiates in vitro production of proinflammatory cytokines and nitric oxide by microglia through a nuclear factor kappa beta-dependent mechanism. Toxicol. Sci. 84: 139-148.
- Filipov, N. M., and M. Tsunoda. 2004. Safety evaluation of new artificial dura mater (GM972) and its tin compounds constituents using ex vivo striatal slices. Abstracts, Society for Neuroscience, Volume 30: 345.13.
- Crittenden, P. L., and N.M. Filipov. 2004. Manganese/LPS induced proinflammatory cytokine production is p-38 kinase dependent. Abstracts, Annual Meeting of the South Central Chapter of the Society of Toxicology, October 15, 2004, Mississippi State University College of Veterinary Medicine, Mississippi State, MS.
- Coban, A., A. B. Norwood, S. C. Sistrunk, and N. M. Filipov. 2004. Effects of 14-day exposure to atrazine on striatal neurochemistry and nigral/ventral tegmental dopamine neurons in juvenile male C57BL/6 mice. Abstracts, Annual Meeting of the South Central Chapter of the Society of Toxicology, October 15, 2004, Mississippi State University College of Veterinary Medicine, Mississippi State, MS.
- Sistrunk, S. C. and N. M. Filipov. 2004. Direct effects of manganese phosphate (MnPO4) on dopamine and its metabolite 3,4-dihydroxyphenylacetic acid (DOPAC). Abstracts, Annual Meeting of the South Central Chapter of the Society of Toxicology, October 15, 2004, Mississippi State University College of Veterinary Medicine, Mississippi State, MS.
- Christiansen, D. L., R. M. Hopper, N. M. Filipov, N. S. Hill, B. P. Fitgerald, and P. L. Ryan. 2004. A novel approach to alleviate ergot alkaloid toxicosis of mares in early gestation. Abstracts, 2004 Annual Meeting of the Society for Theriogenology, August 4-8, 2004, Lexington, KY.
- Filipov, N. M., A. Coban, S. C. Sistrunk, and A. B. Norwood. 2004. Age-dependent effects of exposure to the pesticide atrazine on striatal dopamine metabolism in male C57BL/6 mice. Toxicol. Applied Pharmacol. 197 (3): 319.
- Coban, A., S. C. Sistrunk, A. B. Norwood, and N. M. Filipov. 2004. Influence of 14-day exposure to atrazine on striatal neurochemistry in juvenile male C57BL/6 mice Toxicol. Sci. 78 (Suppl.): 1349.
- Orr, A. I., D. L. Christiansen, B. J. Rude, N. M. Filipov, and P. L. Ryan. 2004. Effects of feeding a modified yeast cell wall extract upon the occurrence of fescue toxicosis in mares. Abstracts, Southern Section, American Society of Animal Science, February 14-18, 2004, Tulsa, OK.
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Progress 01/01/03 to 12/31/03
Outputs
The objective of this project is to assess the dopaminergic neurotoxicity of several agricultural pesticides in adolescent, adult, and aged animals by using in vivo and in vitro approaches and examining the degree of neuronal loss and microglial cell activation. It has been suggested that exposure to several different agricultural pesticides may contribute to Parkinsons Disease. Last year we showed that naive striatal tissue exposed ex vivo to the herbicide atrazine exhibited selective dopaminergic toxicity. Considering that atrazine is the most widely used pesticide in the US, its role in basal ganglia neurodegeneration was and is currently investigated further in vivo. In ongoing studies mice, aged 1, 3, and 18 months, are/will be treated with different doses of atrazine, the fungicide maneb, and other pesticides for various lengths of time. The level of dopaminergic toxicity as well as regional microglial cell activation was/will be assessed at different time
points after termination of the respective pesticide exposure. So far, it appears that younger animals are more sensitive to atrazine than their older counterparts.
Impacts
These studies are furthering our understanding regarding the impact of pesticide exposure during various stages of life on basal ganglia function with a special emphasis on Parkinsons Disease-like neuropathology.
Publications
- Whitehead, J. A., S. C. Sistrunk and N, M, Filipov. Species, strain, and sex influence on the dopaminergic toxicity of the herbicide atrazine ex vivo. Abstracts, SOT Annual Meeting, March 21-25, 2004, Baltimore, MD.
- Crittenden, P. L. and N. M. Filipov. Enhanced proinflammatory cytokine production by activated microglial and macrophage cell lines exposed to manganese in vitro. Abstracts, SOT Annual Meeting, March 21-25, 2004, Baltimore, MD.
- Crittenden, P. L., L.M. Pinchuk, B.L. Boyd, T.M. Lee, A. Coban, and N.M. Filipov. Immunotoxicity of the herbicide atrazine in juvenile male C57BL/6 mice. Abstracts, Annual Meeting of the South Central Chapter of the Society of Toxicology, October 10, 2003, LSU Health Sciences Center, Shreveport, LA.
- Coban, A., S. C. Sistrunk, A. B. Norwood, T. Hurt, and N. M. Filipov. Altered striatal neurochemistry following 14-day exposure to atrazine in juvenile male C57BL/6 mice. Abstracts, Annual Meeting of the South Central Chapter of the Society of Toxicology, October 10, 2003, LSU Health Sciences Center, Shreveport, LA.
- Sistrunk, S. C. and N. M. Filipov. Manganese phosphate affects dopamine metabolism in rat striatal slices partly by a direct interaction with the dopamine metabolite DOPAC. Abstracts, Annual Meeting of the South Central Chapter of the Society of Toxicology, October 10, 2003, LSU Health Sciences Center, Shreveport, LA.
- Coban, A., S. C. Sistrunk, A. B. Norwood, and N. M. Filipov. Influence of 14-day exposure to atrazine on striatal neurochemistry in juvenile male C57BL/6 mice. Abstracts, SOT Annual Meeting, March 21-25, 2004, Baltimore, MD.
- Filipov, N. M., M. Tsunoda, and S. C. Sistrunk. Modulation of dopamine metabolism by several metabolites of the herbicide atrazine in rat striatal slices. Abstracts, SOT Annual Meeting, March 21-25, 2004, Baltimore, MD.
- Pinchuk, L. M, P. L. Crittenden, B. L. Boyd, A. Coban, and N. M. Filipov. Immunotoxicity of short-term exposure to the pesticide atrazine in young male C57BL/6 mice. Abstracts, FASEB Annual Meeting, April 17-21, 2004, Washington, DC.
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Progress 01/01/02 to 12/31/02
Outputs
The objective of this project is to assess the dopaminergic neurotoxicity of several agricultural pesticides in adolescent, adult, and aged animals by using in vivo and in vitro approaches and examining the degree of neuronal loss and microglial cell activation. It has been suggested that exposure to several different agricultural pesticides may contribute to Parkinson's disease. In studies that are almost completed at this point, naive striatal tissue exposed ex vivo to the herbicide atrazine exhibited selective dopaminergic toxicity. Striatal dopamine levels were dose-dependently decreased and, at this point, this decrease appears to be due to increased dopamine turnover. Considering that atrazine is the most widely used pesticide in the US, its role in basal ganglia neurodegeneration is currently further investigated. In ongoing studies mice, aged 1, 3, and 18 months, are/will be treated with different doses of atrazine, the fungicide Maneb, and other pesticides
for various lengths of time. The level of dopaminergic toxicity as well as regional microglial cell activation will be assessed at different time points after termination of the respective pesticide exposure.
Impacts
These studies are furthering our understanding regarding the impact of pesticide exposure during various stages of life on basal ganglia function with a special emphasis on Parkinson's Disease-like neuropathology.
Publications
- Filipov, N. M, M. A. Stewart, R. L. Carr, and S. C. Sistrunk 2003. Dopaminergic toxicity of the herbicide atrazine in ex vivo striatal slices. Toxicol. Sci. 72 (Suppl.): 1302.
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