Exposure to high concentrations of organophosphate pesticides like chlorpyrifos and diazinon can affect the nervous system, leading to headache, dizziness, weakness and blurred vision. Research has shown that some people are more sensitive to the effects of these compounds than others, while infants and children appear to be the most vulnerable. Research conducted by NIEHS-funded scientists suggests that these differences may be explained by variations in paraoxonase (PON1), an enzyme that provides protection against the toxicity of insecticide compounds. These findings have led to the discovery of new therapeutic treatments for nerve agent exposures.
Researchers at the University of Washington discovered that when they injected a pure form of PON1 into laboratory mice, it protected against the toxic effects of chlorpyrifos and diazinon. Furthermore, mice that were missing the genes necessary for normal production of the PON1 enzyme were much more sensitive to the toxic effects of these compounds.
Subsequent studies on human populations showed that individual differences in sensitivity to pesticide compounds were due to subtle variations in the genes that direct PON1. People with the “Q” form of the PON1 gene produce a PON1 enzyme that is significantly less efficient in detoxifying chlorpyrifos and diazinon, while those with the “R” form of the gene produce an enzyme that is much more resistant to pesticide exposures. The researchers also discovered that infants do not acquire the genetic capacity to produce normal levels of the enzyme until the age of two, a finding that explains the higher sensitivity of young children to the toxic effects of these compounds.
Recent experiments conducted by the University of Washington researchers show that PON1 is also the primary enzyme responsible for inactivating the toxic forms of the nerve agents sarin and soman. The researchers have developed a new method for producing quantities of active human and rabbit PON1 enzyme that can eventually be used as a therapeutic for nerve agent exposure.
Future research will focus on understanding the potential role of the PON1 enzyme in the development of vascular disease. Experiments with animal models show that laboratory mice lacking the enzyme have a higher susceptibility to atherosclerosis, a hardening and narrowing of the body’s arteries. Identification of a similar mechanism in humans may lead to new strategies for the prevention of atherosclerosis and other vascular diseases in susceptible individuals.