Cellular and Molecular Toxicology
Analysis of molecular mechanisms causing immunotoxic effects as a result from exposure to environmental pollutants.
Activation of aryl hydrocarbon receptor (AhR) by environmental pollutants such as Dioxins or PCBs leads to altered expression of key factors critical for the function of Dendritic cells (DCs). The AhR can modify the process of maturation of DCs/Macs, which is important in understanding the development of the different types and subsets of DCs. This project is focusing on the mechanistic understanding of how the activity of AhR may modify the differentiation and function of DCs. Compounds like dioxins/PCBs or other persistent organic pollutants, which activate the AhR will affect the immunogenicity of DCs and the immune response. These mechanisms could possibly represent the reason for the increasing incidence of allergies and autoimmune diseases caused by exposure to environmental pollutants.
Identification of molecular markers (Biomarkers) for risk assessment of the development of chronic diseases (Autoimmune diseases, Cancer) caused by exposure.
Development and application of in vitro models as alternatives to animal experiments.
One major topic is the detection and assessment of the inflammatory and oxidative stress responses caused by chemicals from combustion processes.
Genotoxicity of fuel emission samples.
The Single Cell Gel Electrophoresis assay (also known as Comet Assay) is a sensitive technique for the detection of DNA damage at the level of the individual eukaryotic cell. Human monocytic cells are used to evaluate the potential damage to DNA caused by exposure to fuel emission samples.
Improving Blood Monitoring of Enzymes as Biomarkers of Risk from Anticholinergic Pesticides and Chemical Warfare Agents (Barry Wilson).
Another major problem with using blood cholinesterase measurements as early warnings of exposure to pesticides and chemical warfare weapons is the lack of reliable normal ranges for human values based on modern automated instrumentation. We are working with the Department of Defense laboratory (CHPPM) that monitors more than 25,000 individuals per year for blood cholinesterase, using an accurate but slow pH assay. The major goals of this project are to determine conversion factors between the delta pH and Ellman cholinesterase assays, and to assist with a change to the Ellman assay for DOD. The study is underway, and we hope to soon have normal human ranges for red blood cell AChE and plasma BChE to report. Supported by DAMD17-01-1-0772, 1/1/01 - 12/31/04.
Acetylcholinesterase Values among Defense Laboratory Workers (Stephen McCurdy).
In collaboration with Dr. Raven Reitstetter (U.S. Army), Dr. Barry Wilson (UC Davis) and UC Davis graduate student Daniel Arrieta, we analyzed over 1,400 acetylcholinesterase values among defense laboratory workers potentially exposed to acetylcholinesterase-suppressing agents. Analysis has been completed, and we anticipate utilizing the data to publish a set of normal values. Funding for further work (Barry Wilson, PI) has recently been confirmed.
National Institute of Justice, Networked Terrorism Detection System (Barry Wilson, Carey Pope).
The major goal of the subproject is to test prototype sensors for sarin. This project, led by Dr. Carey Pope (Oklahoma State University), is drawing to a close. Our role was to run some assays with nerve agents to help standardize a cholinesterase-measuring device under development. We performed a few experiments and then were informed that the granting agency was terminating the work. Supported by MIPT 106-113-2999-33 (MIPT-VETMD-03 Subcon), 3/1/01 - 2/29/04.
Effect of Pyridostigmine on the Physiologic and Morphologic Changes Induced by Soman at the Human Neuromuscular Junction (Barry Wilson and Ricardo Maselli).
A project with neurobiologist and neurologist Ricardo Maselli has been funded by the Department of Defense. The major goal of the project is to investigate the protection provided by pyridostigmine against nerve agents. Its objective is to establish conditions in which pretreatment with pyridostigmine bromide will ameliorate the effects of nerve agents such as soman and sarin on isolated human muscle obtained from volunteer donors undergoing surgeries for other matters. A chamber has been constructed, a protocol has been devised, and discussions are underway with the Food and Drug Agency concerning the experimental protocol and the application of the results. Supported by DAMD 17—02-2-0001, 12/10/01 - 1/9/05.