Paraoxonases: Biomarkers of Susceptibility to Environmentally-Induced Diseases
The overall aim of this project is to investigate various aspects of the functions and roles of two paraoxonases (PON1 and PON2) in determining susceptibility to environmentally-induced neurotoxicity and neurodegenerative diseases, with the goal of increasing confidence in their use as reliable markers of susceptibility for use in molecular epidemiology studies.
One aspect of the project focuses on the role of PON1 in modulating the toxicity and neurotoxicity of OPs derived from exposure to mixtures of these compounds. Carboxylesterases, which are crucial for detoxifying malathion/malaozon and pyrethroids, are inhibited by the oxons of chlorpyrifos and diazinon. Genetic variability of PON1 affects the detoxication of these oxons and thereby the sensitivity to malathion/malaoxon and pyrethroid exposures. A second aspect of the research examines the roles of PON1 and PON2 in Parkinson’s disease. More recent studies have examined the relationship of PON1 status to ALS. In related research, we have shown that low PON1 levels are a risk factor for carotid artery disease. The examination of other substrates of PONs 1, 2 and 3 have shown that all three of these proteins inactivate the quorum sensing factors of Pseudomonads.
READ Hofmann JN, Keifer MC, De Roos AJ, Fenske RA, Furlong CE, van Belle G, Checkoway H. Occupational determinants of serum cholinesterase inhibition among organophosphate-exposed agricultural pesticide handlers in Washington state. Occup Environ Med 2010 Jun;67:375-386.
READ Hofmann JN, Furlong CE, Farin FM, et al. Serum cholinesterase inhibition in relation to paraoxonase (PON1) status among organophosphate-exposed agricultural pesticide handlers. EHP 2009 Sep;117(9):1402-8.
READ Wills A-M, Landers JE, Richter RJ, Caraganis AJ, Cudkowicz ME, Furlong CE, Brown RH Jr. 2008. Paraoxonase 1 (PON1) organophosphate hydrolysis is not reduced in ALS. Neurology 70 (12): 929-34.
READ Furlong C, Holland N, Richter R, Bradman A, Ho A, and B Eskenazi. 2006. PON1 status of farmworker mothers and children as a predictor of organophosphate sensitivity. Pharmacogenetics and Genomics. 16:183-190.
READ SBRP 20th Annual Meeting Presentation: Adventures In Research Translation
Multiple Uses for Recombinant Paraoxonase 1 (PON1) Purified from an E.coli System. Stephanie Suzuki, Richard Stevens, Toby Cole, Sarah Park, Rebecca Richter, and Clement Furlong. 2011 Superfund Annual Meeting, Lexington, KY.
Characterization of organophosphorous exposures in agricultural workers. J Marsillach, EJ Hsieh, RJ Richter, MJ MacCoss, D Tomazela, MH Paulsen, LG Costa, CD Simpson, CE Furlong. 2011 Superfund Annual Meeting, Lexington, KY.