Paraoxonase-1 and Early-Life Environmental Exposures.
Acute and chronic exposures to widely used organophosphorus (OP) insecticides are common. Children's detoxification mechanisms are not well developed until several years after birth. The increased cases of neurodevelopmental disorders in children, together with their increased susceptibility to OP neurotoxicity cannot be explained by genetic factors alone but could be related to gene-environment interactions. Paraoxonase-1 (PON1) is an enzyme that can detoxify OPs but its catalytic efficiency for hydrolysis to certain OPs is modulated by the Q192R polymorphism. Studies with animals have provided important information on the role of PON1 in protecting against gestational and postnatal toxicity to OPs. The PON1Q192 allele is less efficient in hydrolyzing certain OPs than the PON1R192 allele. Maternal PON1 status (PON1 activity levels, the most important measurement, and functional Q192R phenotype) modulates the detrimental effects of exposure to the OP chlorpyrifos oxon on fetal brain gene expression and biomarkers of exposure. Epidemiologic studies suggest that children from mothers with lower PON1 status who were in contact with OPs during pregnancy tend to show smaller head circumference at birth and adverse effects in cognitive function during childhood. Infants and children are vulnerable to OP toxicity. The detrimental consequences of OPs on neurodevelopment can lead to future generations with permanent cognitive problems and susceptibility to develop neurodegenerative diseases. Improved methods using mass spectrometry to monitor OP-adducted biomarker proteins are needed and will be extremely helpful in early life biomonitoring, while measurement of PON1 status as a biomarker of susceptibility will help identify mothers and children highly sensitive to OPs. The use of adductomics instead of enzymatic activity assays for biomonitoring OP exposures have proved to provide several advantages, including the use of dried blood spots, which would facilitate monitoring newborn babies and children.
Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA.
Judit
J
Marsillach
Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA; Department of Neuroscience, University of Parma, Parma, Italy.
Lucio G
LG
Costa
Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA; Department of Genome Sciences, University of Washington, Seattle, WA. Electronic address: clem@uw.edu.
Clement E
CE
Furlong
D000818:Animals; D043303:Aryldialkylphosphatase / Q000633:toxicity*; D004781:Environmental Exposure / Q000009:adverse effects*; D004785:Environmental Pollutants / Q000633:toxicity*; D005260:Female; D059647:Gene-Environment Interaction; D006801:Humans; D007306:Insecticides / Q000633:toxicity*; D011110:Polymorphism, Genetic; D011247:Pregnancy
D004785:Environmental Pollutants; D007306:Insecticides; D043303:Aryldialkylphosphatase
early-life exposures; environmental health; neurodevelopment; organophosphates; paraoxonase-1