The long-term objective is to understand the mechanisms for acute and delayed toxicity from important organophosphorous (OP) and phosphine insecticides. These compounds are major concerns for human health since they are widely used in agriculture and responsible for more cases of poisoning than any other pesticide class.
The first aim i s to define the mechanisms of OP-induced delayed toxicity (which has afflicted greater than 30,000 people) associated with neuropathy target esterase (NTE) using our newly-developed radioligand [3H]OBDPO and a novel carbamate-biotin affinity agent for target isolation from hen brain in active form of structural and functional characterization. Non-NTE targets phosphorylated by [3H]OBDPO and radioligands based on other OP delayed toxicants will be identified as with NTE itself. Cellular models will determine OP-induced changes in neural growth, essential neurotropic factors and ion transport.
The second aim i s to understand the mechanisms of important OP insecticides because of systemic action in plants and moderate toxicity to mammals. The hypotheses are: acephate toxicity is self-limiting because its metabolite methamidophos inhibits the amidase that activates acephate; methamidophos is bioactivated by S-oxidation (old hypothesis) or N-oxidation (new proposal) requiring studies of chemical models to resolve the site and stability relationships; S-methylation of dimethyl phosphorodithioic acid as a dimethoate metabolite contributes to its toxicological profile including delayed effects.
The third aim i s to establish the mechanisms for toxicity of aluminum phosphide which is increasingly replacing methyl bromide (the ozone depleter) as the major fumigant for stored products. The overall hypothesis is that 1) phosphine, a gas liberated on environmental hydrolysis of aluminum phosphide, undergoes spontaneous or biological oxidation to phosphine oxide, and 2) this phosphinylating agent produces acute toxic effects at a yet undefined target and genotoxic effects on derivatizing DNA leading to conversion of the deoxyguanosine moiety to 8-hydroxydeoxyguanosine. This research is necessary to ensure the safe use of phosphorus-containing insecticides.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Research Project (R01)
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Special Emphasis Panel (ZRG4-ALTX-2 (01))
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Lawler, Cindy P
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University of California Berkeley
Public Health & Prev Medicine
Schools of Earth Sciences/Natur
United States
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Casida, John E; Durkin, Kathleen A (2013) Anticholinesterase insecticide retrospective. Chem Biol Interact 203:221-5
Nomura, Daniel K; Hudak, Carolyn S S; Ward, Anna M et al. (2008) Monoacylglycerol lipase regulates 2-arachidonoylglycerol action and arachidonic acid levels. Bioorg Med Chem Lett 18:5875-8
Nomura, Daniel K; Fujioka, Kazutoshi; Issa, Roger S et al. (2008) Dual roles of brain serine hydrolase KIAA1363 in ether lipid metabolism and organophosphate detoxification. Toxicol Appl Pharmacol 228:42-8
Casida, John E; Nomura, Daniel K; Vose, Sarah C et al. (2008) Organophosphate-sensitive lipases modulate brain lysophospholipids, ether lipids and endocannabinoids. Chem Biol Interact 175:355-64
Vose, Sarah C; Fujioka, Kazutoshi; Gulevich, Alex G et al. (2008) Cellular function of neuropathy target esterase in lysophosphatidylcholine action. Toxicol Appl Pharmacol 232:376-83
Ruby, Maxwell A; Nomura, Daniel K; Hudak, Carolyn S S et al. (2008) Overactive endocannabinoid signaling impairs apolipoprotein E-mediated clearance of triglyceride-rich lipoproteins. Proc Natl Acad Sci U S A 105:14561-6
Nomura, Daniel K; Blankman, Jacqueline L; Simon, Gabriel M et al. (2008) Activation of the endocannabinoid system by organophosphorus nerve agents. Nat Chem Biol 4:373-8
Fujioka, Kazutoshi; Casida, John E (2007) Glutathione S-transferase conjugation of organophosphorus pesticides yields S-phospho-, S-aryl-, and S-alkylglutathione derivatives. Chem Res Toxicol 20:1211-7
Vose, Sarah C; Holland, Nina T; Eskenazi, Brenda et al. (2007) Lysophosphatidylcholine hydrolases of human erythrocytes, lymphocytes, and brain: sensitive targets of conserved specificity for organophosphorus delayed neurotoxicants. Toxicol Appl Pharmacol 224:98-104
Nomura, Daniel K; Durkin, Kathleen A; Chiang, Kyle P et al. (2006) Serine hydrolase KIAA1363: toxicological and structural features with emphasis on organophosphate interactions. Chem Res Toxicol 19:1142-50

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