PON1 Genotype Research Articles

Gestational organophosphate pesticide exposure and childhood cardiovascular outcomes

IntroductionThe general population is chronically exposed to organophosphate pesticides through various routes including ingestion, hand-to-mouth contact, inhalation, and dermal contact. Exposure to organophosphate pesticides during pregnancy impairs fetal development, but the potential long-term effects of gestational organophosphate pesticide exposure are less well understood. MethodsWe investigated associations between gestational organophosphate pesticide exposure and cardiovascular outcomes in 643 children in the Generation R Study, a prospective pregnancy cohort based in Rotterdam, The Netherlands. Urinary organophosphate pesticide metabolites (dimethyl [∑DMAP], diethyl [∑DEAP], and total dialkyl phosphate [∑DAP] metabolites) were quantified in three urine samples collected from pregnant participants, and their children were followed until age 10 years at which time cardiac magnetic resonance imaging, ultrasonography, blood pressure, and serum biomarkers assessed cardiovascular health. Linear regression models estimated associations (β and 95 % confidence interval [CI]) between a one-interquartile range (IQR) increase in averaged gestational exposure biomarker concentrations and z-scored pediatric cardiovascular outcomes. We investigated effect modification of associations by PON1 genotype. ResultsCarotid intima-media thickness z-score was lower (β: -0.14 [95 % CI: −0.25, −0.02]) and HDL cholesterol z-score was higher (β: 0.14 [95 % CI: 0.02, 0.25]) for increases in ∑DEAP concentrations. Carotid intima-media distensibility z-score was lower (β: -0.08 [95 % CI: −0.19, 0.03]) for increases in ∑DMAP concentrations, and systolic blood pressure z-score was higher (β: 0.10 [95 % CI: −0.01, 0.21]) for increases in ∑DMAP and ∑DAP. Among those with PON1-161CC and PON1-L55MTT genotypes, higher organophosphate pesticide concentrations conferred an excess risk of adverse vascular and glycemic outcomes, respectively. ConclusionsWe observed heterogenous associations between gestational organophosphate pesticide exposure and pediatric cardiovascular health: an anti-atherogenic profile was observed for increases in ∑DEAP concentrations, and impairments in multiple aspects of cardiovascular health was observed for increases in ∑DMAP concentrations. PON1-161 and PON1-L55M single nucleotide polymorphisms modified associations for vascular and glycemic outcomes, respectively.

Role of paraoxonase 1 activity and PON1 gene polymorphisms in sickle cell disease

Sickle cell disease (SCD) patients often exhibit a dyslipidemic sub-phenotype. Paraoxonase 1 (PON 1) is a serum glycoprotein associated with the high-density lipoproteins cholesterol (HDL-C), and variability in PON1 activity depends on the PON1 genotypes. We investigated the influence of PON1c.192Q > R and PON1c.55L > M polymorphisms on PON1 activity and laboratory parameters and the association between PON1 activity and clinical manifestations in SCD patients. We recruited 350 individuals, including 154 SCD patients and 196 healthy volunteers, which comprised the control group. Laboratory parameters and molecular analyses were investigated from the participants' blood samples. We have found increased PON1 activity in SCD individuals compared to the control group. In addition, carriers of the variant genotype of each polymorphism presented lower PON1 activity. SCD individuals carrying the variant genotype of PON1c.55L > M polymorphism had lower platelet and reticulocyte counts, C-reactive protein, and aspartate aminotransferase levels; in addition to higher creatinine levels. SCD individuals carrying the variant genotype of PON1c.192Q > R polymorphism had lower triglyceride, VLDL-c, and indirect bilirubin levels. Furthermore, we observed an association between PON1 activity history of stroke and splenectomy. The present study confirmed the association between PON1c.192Q > R and PON1c.55L > M polymorphisms and PON1 activity, in addition to demonstrate their effects on markers of dislipidemia, hemolysis and inflammation, in SCD individuals. Moreover, data suggest PON1 activity as a potential biomarker related to stroke and splenectomy.

Joint effects of paraoxonase 1 rs662 polymorphism and vitamins C/E intake on coronary artery disease severity (Gensini and SYNTAX scores) and lipid profile in patients undergoing coronary angiography.

Considering the emergence of the concept of personalized nutrition in recent years and its importance in the treatment of diseases, the purpose of this study was to investigate the interaction of paraoxonase (PON)1 rs662 polymorphism and vitamin C/E intake on coronary artery disease (CAD) severity and lipid profile in patients undergoing diagnostic angiography. This cross-sectional study was carried out on 428 patients undergoing angiography. The PON-1 genotypes were detected by the polymerase chain reaction-restriction fragment length polymorphism technique. Dietary intake was obtained using a valid questionnaire. After adjustment for potential confounders, R allele carriers (RR + RQ) have lower HDL-C levels than non-carriers (QQ) (P ≤ 0.05). On the other hand, higher consumption of vitamin C was associated with a reduced risk of high total cholesterol (OR: 0.42, 95% CI 0.23-0.75, P = 0.003) and low-density lipoprotein cholesterol (OR: 0.49, 95% CI 0.25-0.96, P = 0.038) and an increased risk of low high-density lipoprotein cholesterol (OR: 1.88, 95% CI 1.03-3.42, P = 0.037). Furthermore, a significant interaction was observed between vitamin C intake and genotypes of rs66 polymorphism on LDL-C (P = 0.050). In detail, the R-allele carriers with lower vitamin C intake had higher LDL-C levels than QQ genotype carriers. No significant interaction was found between vitamin E intake and rs662 polymorphism genotypes on the Gensini and SYNTAX scores and lipid profile (P > 0.05). The novel finding of the present study was the existence of a significant interaction between rs662 polymorphism and vitamin C intake on LDL-C. More specifically, R allele carriers with lower vitamin C intake were susceptible to higher LDL-C.

The association of the paraoxonase 1 Q192R polymorphism with coronary artery disease (CAD) and cardiometabolic risk factors in Iranian patients suspected of CAD.

The present study aimed to investigate the association of the paraoxonase 1 (PON1) Q192R polymorphism with coronary artery disease (CAD) and cardiometabolic risk factors in Iranian patients suspected of CAD. This cross-sectional study was conducted on 428 patients undergoing angiography. The data related to demographic information and physical activity were collected by valid and reliable questionnaires. The PON-1 genotypes were detected by the polymerase chain reaction-restriction fragment length polymorphism (RFLP-PCR) technique. The Gensini and SYNTAX score, anthropometric measurements, and biochemical and clinical parameters were measured by standard protocols. Findings indicated that the odds of obesity was significantly higher in people with the RR genotype compared to the QQ genotype carriers (OR: 2.95 CI: 1.25-6.93, P = 0.014) and also odds of low high-density lipoprotein cholesterol (HDL-C) was marginally higher (OR: 2.31 CI: 0.97-5.49, P = 0.056). There was no significant association between other CAD risk factors with PON1 Q192R polymorphism (P > 0.05). Further analysis showed a significant interaction between sex and 192QR (P = 0.019) and 192 RR (P = 0.007) genotypes on body mass index (BMI). More specifically, the risk of obesity in men carrying the RR genotype was 3.38 times (OR: 3.38 CI: 1.08-10.58, P = 0.036). Also, a significant joint effect of the RR genotype and sex on HDL-C was seen (P = 0.003). The stratification based on sex showed that the risk of low HDL-C is significantly higher in women carrying the RR genotype (OR: 6.18 CI: 1.21-31.46, P = 0.028). A marginal sex-genotype interaction was also found in the risk of elevated alanine aminotransferase (ALT) (P = 0.057). In summary, the findings showed that the risk of obesity and low HDL-C was higher in people carrying the RR genotype. On the other hand, a Q192R polymorphism-sex interaction was observed on the risk of obesity, elevated ALT, and low HDL-C.

Gene-Toxicant Interactions in Gulf War Illness: Differential Effects of the PON1 Genotype.

About 25–35% of United States veterans who fought in the 1990–1991 Gulf War report several moderate or severe chronic systemic symptoms, defined as Gulf War illness (GWI). Thirty years later, there is little consensus on the causes or biological underpinnings of GWI. The Gulf War Era Cohort and Biorepository (GWECB) was designed to investigate genetic and environmental associations with GWI and consists of 1343 veterans. We investigate candidate gene–toxicant interactions that may be associated with GWI based on prior associations found in human and animal model studies, focusing on SNPs in or near ACHE, BCHE, and PON1 genes to replicate results from prior studies. SOD1 was also considered as a candidate gene. CDC Severe GWI, the primary outcome, was observed in 26% of the 810 deployed veterans included in this study. The interaction between the candidate SNP rs662 and pyridostigmine bromide (PB) pills was found to be associated with CDC Severe GWI. Interactions between PB pill exposure and rs3917545, rs3917550, and rs2299255, all in high linkage disequilibrium in PON1, were also associated with respiratory symptoms. These SNPs could point toward biological pathways through which GWI may develop, which could lead to biomarkers to detect GWI or to better treatment options for veterans with GWI.

Association Between PON1 (L55M and Q192R) Genetic Polymorphism and Recurrent Pregnancy Loss in North Indian Women Exposed to Pesticides.

The aim of the present study was to examine the relation between the PON1 polymorphisms and recurrent pregnancy loss (RPL). In a cross-sectional study, blood samples were collected from 100 females. DNA was extracted and PON1 genotypes were determined by polymerase chain reaction (PCR) amplification. Regarding PON1 L55M, the mutated allele (M) frequency was found in 70.5% in RPL and in 53.5% in controls; the M allele was significantly associated with an increased risk of RPL (adjusted odds ratio [ORadj] = 2.07; 95% confidence interval [CI]; p < 0.001). However, regarding PON1 Q192R, the R mutated allele frequency was found in 28.5% in RPL and in 33% in controls. The R allele did not show any risk for RPL (ORadj 0.81; 95%CI; p = 0.329). The present study suggests that there is an effect of genetic polymorphism on RPL and provides additional evidence that combines with the growing information about the ways in which certain PON1 genotypes can affect the development of the fetus in the uterus.

The association between PON1 gene polymorphisms (Q192R and L55M) and nephrotic syndrome in Iraqi children

Background: The role of paraoxonase 1 enzyme (PON1) and its single nucleotide polymorphisms (SNPs) in children with nephrotic syndrome (NS) has been reported previously in different ethnic and racial groups with divergent results. The human PON1 gene contains two coding region polymorphisms leading to two different PON1 isoforms. Objectives: The aim of the present study was to find out the association between the PON1 (Q192R and L55M) polymorphisms and their relation with serum PON1 activity as well as lipid profile tests (total cholesterol, TC; triglycerides, TG; high-density lipoprotein cholesterol, HDL-c; and low-density lipoprotein cholesterol, LDL-c) in children with NS. Methods: This study included a total of 80 participants (40 with NS in the age group of 2-14 years and 40 age and sex-matched healthy controls). The PON1 enzyme activity and lipid profile tests were measured in serum samples of all included participants. The PON1 genotype was determined by PCR-restriction enzyme fragment length polymorphism (PCR-RFLP) for both PON1 alleles (192 and 55) SNPs. Results: Our findings showed that the mean levels of lipid profile tests (TC, TG, LDL-c) were significantly increased in patients when compared with healthy controls (p&lt;0.05), while the HDL-c concentration was significantly decreased in patients than that of controls. Also, the patients had significantly lower concentrations of PON1 when compared with the controls regardless of the genotype Q192R and L55M polymorphisms. Moreover, the homozygous RR genotype for PON1 SNP 192 and MM homozygous genotype for PON1 SNP 55 were significantly frequent in patients when compared with the controls. Conclusions: Our results support that the presence of the homozygous RR genotype for PON1 SNP 192 and MM homozygous genotype for PON1 SNP 55 were significantly higher in patients compared with the controls.

Paraoxonase-1 (PON1) Status Analysis Using Non-Organophosphate Substrates.

Human paraoxonase-1 (PON1) is a high-density lipoprotein-associated enzyme with antioxidant, anti-inflammatory, and antiapoptotic roles. The ability of PON1 to hydrolyze specific organophosphate (OP) compounds and prevent accumulation of oxidized lipids in lipoproteins has prompted a large number of studies investigating PON1's role in modulating toxicity and disease. Most of these studies, however, have only focused on PON1 single nucleotide polymorphism analyses and have ignored PON1 activity levels, arguably the most important parameter in determining protection against exposure and disease. We developed a two-substrate activity assay termed "PON1 status" that reveals both the functional PON1192 genotype and plasma PON1 activity levels. While our previous studies with PON1 status demonstrated that both PON1192 functional genotype and enzymatic activity levels obtained exclusively by determining PON1 status are required for a proper evaluation of PON1's role in modulating OP exposures and risk of disease, the original PON1 status assay requires the use of highly toxic OP metabolites. As many laboratories are not prepared to handle such toxic compounds and the associated waste generated, determination of PON1 status has been limited to rather few studies. Here, we describe a PON1 status protocol that uses non-OP substrates with a resolution equivalent to that of the original PON1 status approach. We have also included useful suggestions to ensure the assays can easily be carried out in any laboratory. The protocols described here will enable a proper examination of the risk of exposure or susceptibility to disease in PON1 epidemiological studies without the need to handle highly toxic substrates. © 2021 Wiley Periodicals LLC. Basic Protocol: Determining PON1 status using non-organophosphate substrates Support Protocol 1: Experimental pathlength determination Support Protocol 2: PON1 DNA genotyping for the Q192R (rs662) polymorphism.

Epigenetic study of global gene methylation in PON1, XRCC1 and GSTs different genotypes in rural and urban pesticide exposed workers.

Background Epigenetic represents a study of occurred heritable gene expression changes without changing in the DNA sequence. It includes DNA methylation and miRNA expression that attract increasing attention as potential links between the genetic and environmental determinants of health and disease. Pesticide exposure is associated with adverse health effects and DNA methylation due to oxidative stress induced following its exposure. This study aimed to define the association of genetic polymorphisms of XRCC1, PON1, GSTP1 and GST genes with global genes DNA methylation in urban and rural occupationally pesticides exposed workers. Methods This study included 100 pesticides exposed workers; 50 rural sprayers (RE) and 50 urban researchers (UE). Controls included equal numbers. DNA methylation of global genes was evaluated by pyrosequencing assay. XRCC1, PON1 and GSTP1 genotyping were assessed by PCR-RFLP, and GST M1 and T1 were performed by PCR. Results The results of this study revealed that most genotypes in XRCC1, PON1, GSTP1 and GST genes were associated with LINE-1 hypomethylation among UE group. However, heterozygote genotypes (Gln-Arg and Ile-Val) in XRCC1 and GSTP1 genes, respectively, were associated with LINE-1 hypermethylation among UE compared with other corresponding genotypes. Only GSTT1 polymorphism recorded a significant change in percent methylation of Alu elements among urban and rural groups. Conclusion Urbanization could play an additional risk for epigenetic changes associated with pesticide exposure, and that could be attributed to the quality of life including their dietary habits, working and living in closed areas, and their exposure to extra pollutions emitted from urbanization sources.

Effect of gene-environment interaction (arsenic exposure - PON1 Q192R polymorphism) on cardiovascular disease biomarkers in Mexican population

Cardiovascular diseases (CVDs) are the primary cause of death worldwide. However, little is known about how the interaction between risk factors affects CVDs. Therefore, the aim of this study was to evaluate the effect of the gene-environment interaction (arsenic exposure x PON1 Q192R polymorphism) on serum levels of CVDs biomarkers in Mexican women. Urinary arsenic levels (UAs) ranged from 5.50–145 μg/g creatinine. The allele frequency was 0.38 and 0.62 for the Q and R alleles, respectively. Moreover, significant associations (p<0.05) were detected between UAs and CVDs biomarkers (ADMA, FABP4, and miR-155). Comparable data were found when CVDs biomarkers were evaluated through PON1 genotype, significant (p<0.05) higher serum concentrations of CVDs biomarkers were identified in R allele carriers compared to levels found in Q allele carriers. Besides, a gene-environment interaction was documented. The results of this study we believe should be of significant interest to regulatory authorities worldwide.

The Role of PON1 Variants in Disease Susceptibility in a Turkish Population

Paraoxonase 1 (PON1) enzyme plays a major role in antioxidant defense and protects the cells against reactive species. The most common PON1 Q192R and L55M polymorphisms are responsible for a wide variation of PON1 activity, which showed an up to 13-fold interindividual variation among the same genotype. PON1 genotypes were evaluated with the development of pancreatitis, colorectal cancer, and hypothyroidism in a hospital-based, case-control study. Individuals with rs662 G allele had a two-fold risk of developing hypothyroidism. A weak association was found between rs854560 T allele and pancreatitis. The results were preliminary. Further studies with a larger number and detailed biochemical parameters are needed.

Prenatal maternal organophosphorus pesticide exposures, paraoxonase 1, and childhood adiposity in the Mount Sinai Children’s Environmental Health Study

BackgroundAnimal studies suggest that organophosphorus pesticides (OPs) may be environmental obesogens. While prenatal OP exposures have been associated with altered infant glucose metabolism, associations with pediatric adiposity remain unknown. MethodsWe summed concentrations of three dimethylphosphate (∑DMP) and three diethylphosphate (∑DEP) metabolites of OPs measured in third trimester spot urine samples collected from pregnant women enrolled in New York City, 1998–2002. We measured percent fat mass using bio-electrical impedance analysis and calculated age- and sex-standardized body mass index (BMI) z-scores from anthropometric measurements collected at approximately 4, 6, and 7–9 years of age (166 children, 333 observations). We assessed covariate-adjusted associations of OPs with repeated adiposity measures using linear mixed models and evaluated effect measure modification (EMM) by sex and paroxonase (PON) 1 –108C/T and Q192R polymorphisms measured in maternal peripheral blood samples. ResultsThe geometric mean urinary concentration of ∑DMP metabolites (29.9 nmol/L, IQR: 105.2 nmol/L) was higher than ∑DEP metabolites (8.8 nmol/L, IQR: 31.2 nmol/L). Adjusted associations were null, with differences in fat mass per 10-fold increase in prenatal ∑DMP and ∑DEP concentrations of 0.7% (95% CI: −0.6, 2.0) and 0.8% (95% CI: −0.4, 2.0), respectively. Maternal PON1-108C/T polymorphisms modified relationships of prenatal ∑DMP with percent fat mass (EMM p-value = 0.18) and ∑DEP with BMI z-scores (EMM p-value = 0.12). For example, ∑DMP was modestly associated with increased percent fat mass among children of mothers with the at-risk CT or TT genotype (β = 1.2%, 95% CI: −0.6, 3.0) but not among those whose mothers had the CC genotype (β = −0.4%, 95% CI: −2.4, 1.5). Associations were not modified by sex or maternal PON1 Q192R polymorphisms. ConclusionsWe observed little evidence of a relationship between prenatal OP exposures and child adiposity, although there was some suggestion of increased risk among offspring of mothers who were slow OP metabolizers. Larger studies are warranted to further evaluate possible associations of prenatal OP exposures with child adiposity and differences by maternal PON1 genotype, which regulates OP metabolism and may increase susceptibility to exposure.

Carotid plaques in adult rheumatoid arthritis patients; association with paroxonase 1 enzymatic activity and Q192R paroxonase 1 gene polymorphism.

Paroxonase 1 (PON 1) enzymatic activity and Q192R PON polymorphism has been implicated with greater cardiovascular risk in general population. Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized with increased inflammatory markers leading to increased cardiovascular morbidity. The aim of the work was to study association between PON1 enzymatic activity & gene polymorphism with carotid plaques in RA patients. This case-control study was carried out at Zagazig University Hospitals on 99 subjects divided randomly into two groups; 48 RA patients and 51 controls. RA patients fulfilled the revised 2010 EULAR/ACR classification criteria of RA. All patients were subjected to history taking, clinical evaluation, laboratory investigations & plain X-rays. Carotid intima-media thickness (CIMT) and PON1 enzyme assay & genotyping were done for both groups. PON1 enzyme levels were significantly higher in patients than controls. Also, there was a significant negative correlation of PON1 enzyme activity with increased CIMT & plaques. The cut-off value of PON1 enzyme level that had the highest CVD prediction was 4.2 U/ml. Although PON1 genotyping was insignificantly different between patients and controls, patients with QQ genotype had the lowest PON1 activity then patients with QR genotype then RR genotype. In RA patients, decreased serum PON1 enzymatic activity and QQ genotyping of Q192R PON polymorphism was associated with increased CIMT & plaques. Serum PON1 could be a good marker for atherosclerosis prediction in RA patients at cutoff 4.2 U/ml.

Allelic frequency of PON1 Q192R, CYP2C19*2 and CYP2C19*17 among Jordanian patients taking clopidogrel

Purpose: To investigate the influence of allelic frequencies of PON1 Q192R, CYP2C19*2 and CYP2C19*17 genetic polymorphisms on the response to clopidogrel among Jordanian patients. Methods: Polymorphisms in CYP2C19 were assessed among 148 patients using PCR-RFLP assay. Results: The CYP2C19*2, CYP2C19*17, and PON1 Q192R allele frequencies were 9.8, 28.72 and 28.7 %, respectively. On the genotyping side, the frequencies of CYP2C19*1/1* and CYP2C19*1/2* were 80.4 and 19.6 %, respectively, but none of the patients had CYP2C19*2/2* genotype. The genotype frequencies CYP2C19*17 were 47.97, 46.62 and 5.41 % for wild-type C-C, heterozygote C-T, and the mutant T-T, respectively. PON1 genotype was 42.7 % for QQ, and 57.8 % for QR. None of the patients had RR genotype. Conclusion: Relative to other populations, the observed allelic frequencies are consistent with the values reported for Caucasian and Middle Eastern populations. Keywords: CYP2C9 polymorphisms, Clopidogrel, Genotype, Allele frequency, PON1 genes

Effects of nanoparticles exposure and PON1 genotype on heart rate variability

ObjectivesThis study was to assess the association between different NPs exposure and PON1 genotype on Heart Rate Variability (HRV) parameters among workers. MethodsThis study included 235 non-CVD subjects handled to nanomaterials (NM) and 185 non-exposed controls without CVD from 14 NM plants. All participants completed short-term HRV measurements, and were collected blood specimens to measure PON1 activities and the genotype of the PON1 Q192R polymorphism. ResultsIn a multivariate regression model, this study observed a positive relationship between nano-Ag exposure and HRV time-domain (RMSSD) and frequency-domain (HF). After adjusting for confounders, the results showed positive associations between RR homozygosity, PON1 paraoxonase/arylesterase activities with HRV, and was particularly noteworthy in RMSSD and HF. ConclusionsThis study shows a significant increment of RMSSD and HF among workers who handled Nano-Ag materials. These results imply that Nano-Ag and PON1 Q192R genotype can trigger ANS reflexes and alter cardiac frequency and function.

Impact of hepatitis B virus (HBV) infection on platelet response to clopidogrel in patients undergoing coronary stent implantation

BackgroundHepatitis B virus (HBV) infection has been reported to down-regulate the expression of CYP2C19 gene, which may decrease the bioactivation of clopidogrel into active metabolites. We aimed to evaluate the impact of HBV infection on platelet response to clopidogrel in patients undergoing coronary stent implantation. MethodsA total of 1805 patients who had received coronary stent implantation and taken aspirin 100 mg in combination with clopidogrel 75 mg daily ≥5 days were consecutively recruited. The serologic identifications for HBV, platelet aggregations in response to arachidonic acid (PLAA) and adenosine diphosphate (PLADP), as well as ABCB1, CYP2C19, CYP3A5, PON1 and P2RY12 genotypes were determined. Clopidogrel low response (CLR) was defined as PLADP > 40%. ResultsAmong the recruited subjects, 102 patients showed hepatitis B surface antigen (HBsAg) positive and 1703 patients negative. PLADP was significantly higher in HBsAg positive group than that in HBsAg negative group [38 (24–48) % vs. 29 (20–39) %, p < 0.001] while the difference of PLAA was not statistically significant (p = 0.329). The incidence of CLR was significantly higher in HBsAg positive group compared with that in HBsAg negative group (43.1% vs. 23.4%, p < 0.001). After adjusted for CYP2C19 genotype and known risk factors, HBsAg positive patients exhibited a significantly higher risk of CLR (adjusted odds ratio: 2.81, 95% confidence interval: 1.73 to 4.58, p < 0.001). ConclusionsHBV infection is an independent risk factor of CLR, in addition to CYP2C19 gene mutations. (Pharmacogenetic and Pharmacokinetic Study of Clopidogrel; NCT01968499).

Urinary organophosphate insecticide metabolite concentrations during pregnancy and children's interpersonal, communication, repetitive, and stereotypic behaviors at 8 years of age: The home study

BackgroundPrenatal exposure to organophosphate insecticides may be associated with autism spectrum disorders and related behaviors. This association may be modified by single nucleotide polymorphisms in the paraoxonase (PON1) enzyme. ObjectiveWe examined the relationship of prenatal organophosphate insecticide biomarkers with reciprocal social, repetitive, and stereotypic behaviors in 8-year old children, and modification of this relationship by child PON1 polymorphisms. MethodsAmong 224 pregnant women, we quantified concentrations of six nonspecific dialkyl phosphate (DAP) metabolites of organophosphate insecticides in two urine samples collected at ~16 and ~26 weeks gestation. When children were eight years old, we administered the Social Responsiveness Scale (SRS), a continuous measure of various dimensions of interpersonal behavior, communication, and repetitive/stereotypic behaviors. We estimated the association between a 10-fold increase in the sum of six DAP concentrations (ΣDAP) and SRS scores. We examined whether child PON1192 and PON1–108 genotypes modified this association. ResultsAfter covariate adjustment, ΣDAP concentrations were not associated with SRS scores[β=–1.2; 95% confidence interval (CI): –4.0, 1.6]. Among children with the PON1–108TT genotype, ΣDAP concentrations were associated with 2.5-point higher (95% CI: −4.9, 9.8) SRS scores; however, the association was not different from the 1.8-point decrease (95% CI: −5.8, 2.2) among children with PON1–108CT/CC genotypes (ΣDAP × PON1–108 p-value =0.54). The association between ΣDAP concentrations and SRS scores was not modified by PON1192 (ΣDAP × PON1192 p-value =0.89). ConclusionsIn this cohort, prenatal urinary DAP concentrations were not associated with children's social behaviors; these associations were not modified by child PON1 genotype.

Prenatal pesticide exposure and PON1 genotype associated with adolescent body fat distribution evaluated by dual X-ray absorptiometry (DXA).

Many modern pesticides have endocrine disrupting abilities and early-life exposure may affect growth and disease risk later in life. Previously, we reported associations between prenatal pesticide exposure and higher childhood body fat content measured by anthropometry. The associations were affected by child PON1 Q192R genotype. We aimed to study whether prenatal pesticide exposure was still associated with body fat content and distribution in the children at puberty and the potential impact of both maternal and child PON1 Q192R genotype. In this prospective cohort study of 247 children born by occupationally exposed or unexposed women (greenhouse workers and controls) two follow-up examinations (age 10-15 and 11-16years) including simple anthropometry, skinfold measurements, pubertal staging and blood sampling were performed. Total and regional fat% was determined by dual X-ray absorptiometry (DXA) at age 10-15. Prenatal pesticide exposure was associated with increased total, android, and gynoid fat percentage (DXA) at age 10-15years after adjustment for sex, socioeconomic status, and puberty (all β=0.5 standard deviation score (SDS) p<0.05). Stratified by sex, the associations were significant in girls (total fat: β=0.7 SDS, android-gynoid ratio: β=0.1, both p<0.05), but not in boys. Carrying the R-allele (child or mother, separately, or both) augmented the differences between exposed and unexposed children (total fat: β=1.0 SDS, β=0.8 SDS, p<0.05, respectively, and β=1.2 SDS, p<0.01). No exposure-related differences were found if either the child or mother had the QQ wild-type. At age 11-16, exposed children tended to have a higher total fat% estimated by skinfolds than unexposed children (p=0.06). No significant associations between prenatal exposure and body mass index or waist circumference were found. Prenatal pesticide exposure was associated with higher adolescent body fat content, including android fat deposition, independent of puberty. Girls appeared more susceptible than boys. Furthermore, the association depended on maternal and child PON1 Q192R genotype.

Paraoxonase-1 and Simvastatin Treatment in Patients with Stable Coronary Artery Disease.

Background. Paraoxonase-1 (PON1) is the crucial antioxidant marker of high-density lipoproteins. The present study is aimed at assessing the effect of simvastatin treatment on PON1 activity and its relationship to Q192R and M55L polymorphisms in subjects with stable coronary artery disease (CAD). Methods. The patient group was composed of 53 individuals with stable CAD, and the control group included 53 sex-matched police officers without CAD. CAD patients were treated with simvastatin 40mg/day for 12 months. Respectively, flow mediated dilatation (FMD), serum hs-CRP and TNF-α levels, urinary 8-iso-PGF2α concentrations, and PON1 activity were evaluated in definitive intervals. Results. There was no effect of simvastatin treatment on urinary 8-iso-PGF2α. Simvastatin treatment significantly increased FMD value, decreased CRP and TNF-α concentration. After adjusting for PON1 genotypes, significantly higher PON1 activity was noted in the 192R allele carriers, in both groups. Regardless of genotype, PON1 activity remained stable after simvastatin treatment. Conclusions. The present study confirms a positive effect of simvastatin therapy on endothelial function and inflammatory markers in secondary prevention. Simvastatin treatment shows no effects on PON1 activity and 8-isoprostanes level. The effect of simvastatin therapy on PON1 activity is not modulated by Q192R and M55L polymorphisms.

Prenatal Exposure to Organophosphorous Pesticides and Fetal Growth: Pooled Results from Four Longitudinal Birth Cohort Studies.

Background:Organophosphorous (OP) pesticides are associated with reduced fetal growth in animals, but human studies are inconsistent.Objectives:We pooled data from four cohorts to examine associations of prenatal OP exposure with birth weight (n = 1,169), length (n = 1,152), and head circumference (n = 1,143).Methods:Data were from the CHAMACOS, HOME, Columbia, and Mount Sinai birth cohorts. Concentrations of three diethyl phosphate (ΣDEP) and three dimethyl phosphate (ΣDMP) metabolites of OP pesticides [summed to six dialkyl phosphates (ΣDAPs)] were measured in maternal urine. Linear regression and mixed-effects models were used to examine associations with birth outcomes.Results:We found no significant associations of ΣDEP, ΣDMP, or ΣDAPs with birth weight, length, or head circumference overall. However, among non-Hispanic black women, increasing urinary ΣDAP and ΣDMP concentrations were associated with decreased birth length (β = –0.4 cm; 95% CI: –0.9, 0.0 and β = –0.4 cm; 95% CI: –0.8, 0.0, respectively, for each 10-fold increase in metabolite concentration). Among infants with the PON1192RR genotype, ΣDAP and ΣDMP were negatively associated with length (β = –0.4 cm; 95% CI: –0.9, 0.0 and β = –0.5 cm; 95% CI: –0.9, –0.1).Conclusions:This study confirms previously reported associations of prenatal OP exposure among black women with decreased infant size at birth, but finds no evidence of smaller birth weight, length, or head circumference among whites or Hispanics. Contrary to our hypothesis, we found stronger inverse associations of DAPs and birth outcome in infants with the less susceptible PON1192RR genotype. The large pooled data set facilitated exploration of interactions by race/ethnicity and PON1 genotype, but was limited by differences in study populations.Citation:Harley KG, Engel SM, Vedar MG, Eskenazi B, Whyatt RM, Lanphear BP, Bradman A, Rauh VA, Yolton K, Hornung RW, Wetmur JG, Chen J, Holland NT, Barr DB, Perera FP, Wolff MS. 2016. Prenatal exposure to organophosphorous pesticides and fetal growth: pooled results from four longitudinal birth cohort studies. Environ Health Perspect 124:1084–1092; http://dx.doi.org/10.1289/ehp.1409362