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University of Washington

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
View this project in the NIH Research Portfolio Online Reporting Tools (RePORT)

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Project Summary (2017-2022)

Human environmental exposures to heavy metals such as manganese (Mn) or cadmium (Cd) are common and represent adverse risks to health. Mn and Cd generate neurotoxicity by inducing oxidative stress and neuroinflammation. The paraoxonases (PON1, 2 and 3) are potent antioxidant enzymes that have been associated with a variety of oxidative stress-related diseases. Recent data suggest that PON1 is inactivated by oxidative stress, resulting in decreased antioxidant capacity of the individual and aggravation of disease states. Expression of PON2 in the brain protects cells from oxidative stress and neuroinflammation generated by neurotoxic compounds. Interestingly, PON2 expression is higher in females than in males, and is upregulated by estrogens. This project consists of aims to understand the roles of PON1 and PON2 in modulating oxidative stress-induced neurotoxicity.

The research team is characterizing factors that modify the activities of PON1, including in vitro exposure to oxidized lipid metabolites, and in vivo exposure to Mn and Cd. They are further examining the role of recombinant mouse PON2 in protecting PON1 activity and the modulation of PON2 levels by estrogens and dopamine in cortical neurons. The team is also working to develop a protocol for determining PON2 status by examining the levels of PON2 protein, activity, and mRNA in mouse and human macrophages and monocytes. PON2 levels in males, and in pre- and post-menopausal women are also being analyzed. The research team is also examining the role of PON2 in modulating susceptibility to manganese - and cadmium-induced oxidative stress.

Altogether, the experiments are providing novel information on the roles of PON1 and PON2 in modulating oxidative stress and protecting individuals from cardiovascular and neurological diseases.

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