Organophosphorus esters (OP's) used in agriculture (e.g. parathion, DEF), industry (TOCP) and the military (sarin, VX) have several major toxic effects: most of them impede neuromuscular transmission by blocking the enzyme acetylcholinesterase (AChE); some (parathion) are known to cause muscle damage; others (DEF, TOCP, sarin) cause severe nerve damage (organophosphate induced delayed neuropathy, OPIDN). Inhibition of an enzyme activity known as neurotoxic esterase (NTE) is believed by some to initiate OPIDN. This project uses muscle and nerve cell cultures, chickens, quail and sometimes rats to investigate macromolecules such as AChE and NTE that are specific targets of OP's, and to examine the causes of and possible therapies for the damage caused by these agents. Hypotheses under investigation include the ideas that proteins that are phosphorylated by OP's interrupt somatic gene action, and that glucocorticoid receptors are involved in OPIDN and in regulation of the macromolecules at the motor end plate (MEP), the region where nerves and muscle join. Experiments underway seek to: identify and isolate a serum factor that prevents formation of the collagen-tailed AChE form associated with the MEP; establish whether or not inactive AChE precursors play a role in the rapid recovery of AChE after OP poisoning; isolate and purify the 9S protein that is associated with NTE activity; find out if receptor molecules for glucocorticoid hormones are altered in OP treated animals and cell cultures; critically test the findings that glucocorticoids alleviate the damage caused by surgical denervation and OP treatments, and seek early warning signs in blood of nerve and muscle damage due to OP's. The findings will establish how AChE forms are assembled and regulated during development, how cells recover from OP poisoning, and how nerves develop OPIDN. In addition, the experiments will assist in developing clinical tests for damage due to OP's and in improving the standards for evaluating the toxicities of these toxic agents.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES000202-21
Application #
3249418
Study Section
Toxicology Study Section (TOX)
Project Start
1977-12-01
Project End
1993-11-30
Budget Start
1988-12-01
Budget End
1993-11-30
Support Year
21
Fiscal Year
1989
Total Cost
Indirect Cost
Name
University of California Davis
Department
Type
Earth Sciences/Resources
DUNS #
094878337
City
Davis
State
CA
Country
United States
Zip Code
95618