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Final Progress Reports: University of Washington: Role of Paraoxonases (PONs) in Modulating Cadmium and Manganese Neurotoxicity

Superfund Research Program

Role of Paraoxonases (PONs) in Modulating Cadmium and Manganese Neurotoxicity

Project Leader: Clement E. Furlong
Co-Investigators: Lucio G. Costa, Judit Marsillach Lopez
Grant Number: P42ES004696
Funding Period: 2009-2023
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Final Progress Reports

Year:   2016  2014 

The focus of this project is neurotoxicity, and the role of oxidative stress in human diseases and environmental exposures. During 2016, the researchers pursued experiments relevant to the aims in this project.

In examining the fate and function of recombinant mouse Pon2 (rMoPON2) in Pon2 knockout mice, the researchers initiated the cloning and expression of rMoPON2 in E.coli. The construct design is based on previous work in our laboratory generating active rHuPON2. The construct will produce the native amino terminus.

Examining the modulation of PON2 in the CNS, the researchers observed a developmental regulation of PON2 in mice and non-human primates, resulting in lower levels of PON2 in younger and older animals, suggesting potential windows of susceptibility to oxidative stress and inflammation. They are currently investigating potential signal-transduction mechanisms involved in the modulation of PON2 by estrogens in neurons, astrocytes and microglia.

Examining the role of PON2 in modulating susceptibility to neurotoxicants, the researchers found that subcutaneous exposures to manganese (100 mg/kg) in wild-type and Pon2-/- mice resulted in decreased exploratory behavior and poor motor coordination. Pon2-/- mice showed anxiety-related behaviors and significant inhibition of plasma PON1 activity. The researchers are currently carrying out manganese exposures via drinking water (80 mg/kg) that will reflect a more physiological route of exposure.

These results point to gender differences in PON2 expression and a role of PON2 in protecting PON1 from the inhibitory effects of manganese-induced oxidative stress and will be essential for understanding potential gender differences in susceptibility to neurotoxicity and oxidative stress.

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