PON1 status of farmworker mothers and children as a predictor of organophosphate sensitivity.

Department of Genome Sciences, Division of Medical Genetics, University of Washington, Seattle, Washington 98195-7720, USA.
Pharmacogenetics and Genomics (Impact Factor: 3.45). 04/2006; 16(3):183-90. DOI: 10.1097/01.fpc.0000189796.21770.d3
Source: PubMed

ABSTRACT The objective was to determine PON1 status as a predictor for organophosphorus insecticide sensitivity in a cohort of Latina mothers and newborns from the Salinas Valley, California, an area with high levels of organophosphorus insecticide use. PON1 status was established for 130 pregnant Latina women and their newborns using a high-throughput two substrate activity/analysis method which plots rates of diazoxon (DZO) hydrolysis against rates of paraoxon (PO) hydrolysis. Arylesterase activity (AREase) was determined using phenylacetate as a substrate, allowing comparison of PON1 levels across PON1192 genotypes in mothers and children. Phenylacetate hydrolysis is not affected by the Q192R polymorphism. Among newborns, levels of PON1 (AREase) varied by 26-fold (4.3-110.7 U/ml) and among mothers by 14-fold (19.8-281.4 U/ml). On average, children's PON1 levels were four-fold lower than the mothers' PON1 levels (P<0.001). Average PON1 levels in newborns were comparable with reported hPON1 levels in transgenic mice expressing human PON1Q192 or PON1R192, allowing for prediction of relative sensitivity to chlorpyrifos oxon (CPO) and DZO. The predicted range of variability in sensitivity of mothers and children in the same Latino cohort was 65-fold for DZO and 131 to 164-fold for CPO. Overall, these findings indicate that many of the newborns and some of the mothers in this cohort would be more susceptible to the adverse effects of specific organophosphorus pesticide exposure due to their PON1 status. Of particular concern are exposures of pregnant mothers and newborns with low PON1 status.

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    ABSTRACT: There is evidence that genetic factors influence the probability of comorbidity of tobacco use disorder (TUD) with mood disorders. This study was carried out to examine whether both TUD and mood disorders are associated with genetic biomarkers particularly paraoxonase 1 (PON1) status, polymorphisms of glutathione S-transferases (GSTs), such as GSTM1 and GSTT1, and the STIn 2 polymorphism of the serotonin transporter. PON1 status (Q192R polymorphism and PON1 plasmatic activity), GSTM1, GSTT1, and STin.2 genotypes and alleles were assayed in 4 mutually exclusive study groups, i.e., comorbid mood disorder and TUD (n=95); TUD without mood disorders (n=90); mood disorders but no TUD (n=62); and controls (never-smokers without mood disorders; n=113). Logistic regression analyses showed that comorbid mood disorders and TUD were associated with significantly lower PON1 activity, the STin2.10/10 genotype (protective) or the Stin2.12 allele (risk factor) and the GSTM1 and GSTT1 null genotypes (protective). These results show that comorbid mood disorders and TUD are associated with specific polymorphisms related to oxidative stress and serotonin pathways. Copyright © 2014. Published by Elsevier Ireland Ltd.
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    ABSTRACT: Introduction Organophosphate (OP) pesticides remain widely used in agriculture. Previously, we reported that PON1 genotype was directly associated with neurodevelopment at age two, and that PON1 genotype may increase susceptibility to OP exposure. Objectives We examined the relationships of maternal and child PON1 genotype and enzyme activity levels and neurodevelopment at school age and examined their interaction with maternal dialkyl phosphate (DAP) metabolite levels to investigate differential susceptibility to OP-related neurotoxicity. Methods Participants were from the CHAMACOS longitudinal birth cohort of Latino families in an agricultural region of California. We measured DAP metabolites of OP pesticides in maternal and child urine samples, and analyzed PON1192 and PON1−108 genotypes and enzyme activity [arylesterase (ARYase), paraoxonase (POase)] in maternal and child blood. We examined their association with children׳s performance on the Conners׳ Kiddie Continuous Performance Test (K-CPT) at 5 years (n=296) and the Wechsler Intelligence Scale for Children (WISC-IV) at 7 years (n=327). Results Maternal and child PON1 genotype was not related to performance on K-CPT or WISC, although WISC scores tended to be lowest in children and children of mothers who carried the PON−108TT genotype. Pregnancy ARYase levels were positively associated with all WISC subscales (e.g., 4.0 point increase in Full Scale IQ per standard deviation increase in ARYase, 95% CI=1.6, 6.4), while pregnancy POase levels were positively associated with WISC Processing Speed only. Maternal PON1−108 weakly modified the relationship of maternal DAPS and K-CPT scores (pinteraction=0.21) and WISC verbal IQ (pinteraction=0.71). The association between DAPs and Full-Scale IQ was strongest for children of mothers with lowest-tertile ARYase levels (pinteraction=0.27). This relationship held for both diethyl and dimethyl DAPs and for all subscales of the WISC. Conclusions We extend our previous findings that PON1 genotype and enzyme levels may be directly related to performance on certain domains of neurodevelopment in school-age children. Lower maternal PON1 enzyme levels during pregnancy may also increase susceptibility of children to neurotoxicity from OP pesticide exposure.
    Environmental Research 10/2014; 134:149–157. · 3.95 Impact Factor
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    Environmental Research 05/2014; 132C:342-349. · 3.95 Impact Factor


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