Source: MISSISSIPPI STATE UNIV submitted to
CENTER OF BIOMEDICAL RESEARCH EXCELLENCE
Sponsoring Institution
Cooperating Schools of Veterinary Medicine
Project Status
TERMINATED
Funding Source
STATE
Reporting Frequency
Annual
Accession No.
0200899
Grant No.
(N/A)
Project No.
MISV-399020
Proposal No.
(N/A)
Multistate No.
(N/A)
Program Code
(N/A)
Project Start Date
Oct 1, 2002
Project End Date
Sep 30, 2009
Grant Year
(N/A)
Project Director
CHAMBERS, J. E.
Recipient Organization
MISSISSIPPI STATE UNIV
(N/A)
MISSISSIPPI STATE,MS 39762
Performing Department
COLLEGE OF VETERINARY MEDICINE
Non Technical Summary
COBRE will be a multi-disciplinary research effort.
Animal Health Component
(N/A)
Research Effort Categories
Basic
(N/A)
Applied
100%
Developmental
(N/A)
Classification

Knowledge Area (KA)Subject of Investigation (SOI)Field of Science (FOS)Percent
3143999115080%
7233999115020%
Knowledge Area
314 - Toxic Chemicals, Poisonous Plants, Naturally Occurring Toxins, and Other Hazards Affecting Animals; 723 - Hazards to Human Health and Safety;

Subject Of Investigation
3999 - Animal research, general;

Field Of Science
1150 - Toxicology;
Goals / Objectives
The Center for Environmental Health Sciences within the College of Veterinary Medicine of Mississippi State University is developing a Center of Biomedical Research Excellence (COBRE) with the overall scientific theme of environmental health, and a specific emphasis on the toxicological effects of pesticides. COBRE would be a multi-disciplinary research effort with two overarching goals: 1) to develop individual junior faculty expertise and credibility so that each is recognized as a successful, fully enfranchised member of the community of environmental health scientists with independent, competitive funding support from peer-reviewed mechanisms; and 2) to develop a team of scientists who can compete for programmatic research support, such as a Program Project Grant for investigation of environmental health problems elicited by agricultural chemicals.
Project Methods
An Administrative Core would coordinate overall activities of the COBRE and be responsible for mentoring the junior scientists in their career development to increase their competitiveness and for data management activities (date entry and statistical guidance). Four biomedical mechanistic research projects will be based on hypothesis-driven studies of the potential effects of pesticides on the mammalian nervous or endocrine systems at various stages of development (from early development through aging). The mechanisms of toxicity of pesticides will be investigated in animal models (both traditional laboratory rodents as well as new animal models). A Research Resources Core would provide infrastructure to these biomedical projects through animal resources (Animal Sub-Core) and shared instrumental (Imaging Sub-Core and Analytical Chemistry Sub-Core). In addition, an epidemiology and exposure assessment project would bring real world perspectives to the biochemical and physiological mechanisms under study.

Progress 10/01/02 to 09/30/09

Outputs
OUTPUTS: Eells Project The optimization of techniques for gene knockdown of the transcription factor Nurr1 provides new fundamental knowledge for further experiments and is essential for understanding how gene expression interacts with environmental toxicants. Ross Project Pesticides are detoxified in the body by several classes of xenobiotic-metabolizing enzymes, e.g. cytochrome P450s, glutathione transferases, and carboxylesterases. While regulation of cytochrome P450s has been extensively studied, much less is known about the family of detoxifying enzymes called carboxylesterases (CEs). The current studies were initiated to determine if pyrethroid compounds (e.g., permethrin) can modulate the expression of carboxylesterase enzymes in cultured hepatocytes. Carr Project The object of this project was to investigate the effects of repeated developmental exposure to organophosphorus (OP) insecticides on behavioral function, signaling molecules, and neurochomeical parameters. Data was presented at the Society of Toxicology national meeting. Filipov Project The cause of Parkinson's disease (PD), a debilitating neurodegenerative disease of the basal ganglia, still remains elusive. 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. PARTICIPANTS: Janice E. Chambers, Jeffrey B. Eells, Matt Ross, Russell Carr, Nick Filipov TARGET AUDIENCES: Scientific Community PROJECT MODIFICATIONS: No Project Modifications information reported.

Impacts
Eells Project Parkinson's disease, a disorder caused primarily by the loss of dopamine neurons, has been linked with genetic predisposition and pesticide exposure based on mutation analysis and epidemiological data, respectively. How specific genes may cause enhanced susceptibility to pesticide and neurotoxin exposure resulting in Parkinson's disease is not clear. Establishing optimal sequences and concentrations that efficiently knockdown gene expression in vitro can be further extended in vivo (i.e. brain infusions) to begin to understand how environmental toxicants interact with changes in gene expression to alter the survival and function of dopamine neurons in the brain. Ross Project The objectives of this study were to evaluate the potential of deltamethrin and permethrin to induce CYP isoforms in cultured human hepatocytes and to also determine whether these pyrethroids positively regulate the human carboxylesterase 1 (hCE1) gene. Our results have shown that the common pyrethroids deltamethrin and permethrin positively influence the induction of several cytochrome P450 enzymes, and this effect is mediated in part by the nuclear receptor PXR. Carr Project Data suggest that the deficits in learning may be related to attention to detail. It is possible that the induction of hyperactivity in the cholinergic system by OP exposure during development, as indicated by the decreased receptor numbers, can altered the establishment of the correct architecture in regions important in learning. Filipov Project Some of our findings indicate that younger animals are sensitive to atrazine. A manuscript describing our findings was published in Journal of Neurochemistry. We assessed the neurotoxic potential of atrazine using striatal slices and published our findings in 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

  • 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. Toxicol. Sci.
  • 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.
  • Crow, J.A., A. Borazjani, P.M. Potter and M.K. Ross. 2007. Hydrolysis of pyrethroids by human and rat tissues: Examination of intestinal, liver and serum carboxylesterases. Toxicol. Appl. Pharmacol. 221:1-12. Dail, M.B., S.C. Burgess, E.C. Meek, J. Wagner, J. Baravik, and J.E. Chambers. 2007. Effects of dieldrin and phenobarbital on the spatial distribution of CYP2B1/2 messenger RNA within the liver acinus. Tox. Sci. 99:35-42.
  • 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.
  • Godin, S.J., J.A. Crow, E.J. Scollon, M.F. Hughes, M.J. Devito and M.K. Ross. 2007. Identification of rat and human cytochrome P450s and a rat serum esterase which metabolize deltamethrin and esfenvalerate. Drug Metab. Dispos. 35:1664-1671.
  • Hossain, D. C.U. Pittman, Jr. and S.R. Gwaltney. 2007. Structures and stabilities of copper encapsulated within silicon nanoclusters: Cu@Sin (N=9-15). Chem. Phys. Lett. 451-93-97.
  • Ross, M.K. and A. Borazjani. 2007. Unit 14.6: Enzymatic activity of human carboxylesterases. Curr. Protocol. Toxicol. 4.24.1-4.24.14.
  • Ross, M.K. and J.A. Crow. 2007. Role of carboxylesterases in xenobiotic and endobiotic metabolism. J. Biochem. Mol. Toxicol. 21:187-196.
  • Sistrunk, S.C., N.M. Filipov and M.K. Ross. 2007. Direct effects of manganese compounds on dopamine and its metabolite Dopac: An in vitro study. Environ. Toxicol. Pharmacol. 23:286-296.
  • Das, P.C., T.M. Streit, Y. Cao, R.L. Rose, N. Cherrington, M.K. Ross, A.D. Wallace and E. Hodgson. 2008. Pyrethroids: cytotoxicity and induction of CYP isoforms in human hepatocytes. Drug Metabolism and Drug Interactions. In press.
  • Mohanraj, R. and H. Wu. 2008. Simulation of dynamics of a nematic liquid crystal for a biosensor application. Sensor Letters. In press.
  • Pinchuk, L.M., S.-R. Lee and N.M. Filipov. 2008. In vitro atrazine exposure affects the phenotypic and functional maturation of dendritic cells. Toxicol. Applied Pharmacol. In press.
  • Pruett, S., R. Fan and S. Oppenheimer. 2008. Greater than additive suppression of TLR3-induced IL-6 responses by administration of dieldrin and atrazine. J. of Immunotoxicology. In press.
  • Streit, T.M., A. Borazjani, S. Lentz, P.M. Potter, S. Gwaltney and M.K. Ross. 2008. Investigator of side-door residues of a carboxylesterase: Role in enzyme catalysis. Chem. Res. Toxicol. In press.


Progress 01/01/06 to 12/31/06

Outputs
The following projects were pursued as part of the COBRE funding: effects of pesticide exposure on the development of the rat nervous system (Carr), effects of pesticides in neurodegeneration in the mouse (Filipov), effects of estrogenic pesticides on cultured human breast cancer cell populations (Willard), and the environmental levels of pesticides in water and soil and their relationship to cancer incidences in three Mississippi counties (Wills). Two other pilot projects were initiated. A renew application was submitted but was unsuccessful. We will resubmitting in June 2007.

Impacts
The results of these scientific studies will provide information on neurodevelopment, neurodegeneration, breast cancer, and cancer incidence.

Publications

  • No publications reported this period