PON1Q192R genetic polymorphism modifies organophosphorous pesticide effects on semen quality and DNA integrity in agricultural workers from southern Mexico

Pesticide exposure, including organophosphorous (OP) insecticides, has been associated with poor semen quality, and paraoxonase (PON1), an enzyme involved in OP deactivation, may have a role on their susceptibility, due to PON1 polymorphisms. Our objective was to evaluate the role of PON1Q192R polymorphism on the susceptibility to OP toxicity on semen quality and DNA integrity in agricultural workers. A cross-sectional study was conducted in farmers with Mayan ascendancy from southeastern Mexico chronically exposed to pesticides; mostly OP. Fifty four agricultural workers (18-55 years old) were included, who provided semen and blood samples. Semen quality was evaluated according to WHO, sperm DNA damage by in situ-nick translation (NT-positive cells), PON1Q192R polymorphism by real-time PCR and serum PON1 activity by using phenylacetate and paraoxon. Two OP exposure indexes were created: at the month of sampling and during 3 months before sampling, representing the exposure to spermatids-spermatozoa and to cells at one spermatogenic cycle, respectively. PON1 192R and 192Q allele frequencies were 0.54 and 0.46, respectively. Significant associations were found between OP exposure at the month of sampling and NT-positive cells and sperm viability in homozygote 192RR subjects, and dose-effect relationships were observed between OP exposure during 3 months before sampling and sperm quality parameters and NT-positive cells in homozygote 192RR farmers. This suggests that cells at all stages of spermatogenesis are target of OP, and that there exists an interaction between OP exposure and PON1Q192R polymorphism on these effects; farmers featuring the 192RR genotype were more susceptible to develop reproductive toxic effects by OP exposure.     

Association of oxidative stress and PON1 with LDL and HDL particle size in middle-aged subjects

BACKGROUND: Alterations in plasma lipoprotein subclass distributions affect atherosclerosis risk. Smaller, denser low-density lipoprotein (LDL) particles (sdLDL) are more susceptible to oxidation. In contrast, most of the protective effects of high-density lipoproteins (HDL) are attributable to larger particles. This study investigates the connection between LDL and HDL particle heterogeneity and oxidative stress, antioxidative defence (AOD) and paraoxonase (PON1) status in a healthy middle-aged Serbian population. MATERIALS AND METHODS: LDL and HDL particle sizes and subclass distributions were measured by gradient gel electrophoresis in 104 men and 103 women, aged 53 +/- 9.4 years. PON1 activities and PON1(Q192R) phenotypes were determined with paraoxon and diazoxon as substrates. The oxidative stress/AOD status was estimated by measuring malondialdehyde (MDA) and superoxide-anion (O2*(-)) levels and superoxide-dismutase (SOD) activity. RESULTS: Subjects with sdLDL had significantly higher MDA (P < 0.001) and O2*(-)(P < 0.05) levels and greater diazoxonase (DZOase) activity (P < 0.05) compared to subjects with larger LDL particles. A high MDA concentration was a significant predictor of the sdLDL phenotype (P < 0.005). Increased levels of and MDA were associated with smaller HDL(3) subclass abundance. Reduced HDL particle size was associated with lower DZOase activity (P < 0.01). CONCLUSIONS: Even in the absence of symptoms of atherosclerosis, sdLDL particles are associated with increased oxidative stress, which may stimulate a compensatory rise in PON1 DZOase activity. Elevated oxidative stress may significantly affect HDL subclass distribution, resulting in the accumulation of smaller, denser HDL particles with diminished antioxidative capacity.     

Interactions and associations of paraoxonase gene cluster polymorphisms with myocardial infarction in a Pakistani population

Polymorphisms of paraoxonase gene (PON) cluster have been investigated in numerous studies for their association with myocardial infarction (MI) but the results have been conflicting. Epistasis and gene-environment interactions at this locus could possibly modulate susceptibility toward MI and account for the discrepancies. We carried out a case-control study (211 MI patients and 370 control subjects) to test association of PON cluster polymorphisms with MI, their interactions with each other and with smoking. Genotyping was performed by PCR-restriction fragment length polymorphism based assays. The Q192R, C-108T, and A148G polymorphisms were associated with MI. Two haplotypes consisting of C-108T, C311S, and A148G, having allele frequencies of 0.17 and 0.14 in the control population, predisposed to MI (global haplotype statistic chi2 = 34.74, df = 15, p = 0.0027). Multifactor dimensionality reduction analysis showed a significant three-locus model (p = 0.02) involving these three polymorphisms, suggesting a potential gene-gene interaction between PON1 and PON2. These polymorphisms also interacted with smoking, in a three-locus and a four-locus model (p = 0.01 and p = 0.05, respectively). Additionally, the R192 allele may advance the age-at-onset of MI. The PON cluster appears to be a susceptibility locus for MI in Pakistani population, and the susceptibility is modulated through gene-gene and gene-environment interactions.     

Lipoprotein(a), apolipoprotein A-I and B serum levels in young families from Tallinn,Estonia. Relationships with other cardiovascular risk factors and nationality

Serum lipid, lipoprotein(a) (Lp(a)), apolipoprotein (apo) A-I and B concentrations were studied in young families of Tallinn: 157 husbands, 81 wives and 149 newborns participated in the study; 48% of subjects were Estonians, 39% Russians and 13% other nationalities. As previous studies among middle-aged men and school children of Estonia revealed clear national differences in serum lipoprotein profiles, our special interest was to study lipoprotein parameters in relation to ethnic origin. Body mass index (BMI), blood pressure (BP) and smoking habits were determined. In newborns, maturity by physical and neurological criteria and Apgar score after birth were assessed. At the age of 18-30 years, Estonian men had significantly higher serum total cholesterol, LDL cholesterol, triglyceride and Lp(a) levels than did Russian men. Estonian newborns had higher serum triglyceride concentration than Russian ones. Among women no national differences were recorded in the measured parameters. Lp(a) levels were not statistically correlated with age, BMI, BP or current smoking. Negative associations were revealed between Lp(a) and serum level of apo A-I (in men) or triglycerides (in newborns). Lp(a) concentrations correlated positively with LDL cholesterol (in women) and apo B (in newborns). Lp(a) levels of newborns were not associated with birthweight or health status, but correlated strongly with the sum of parental and fathers' Lp(a) concentrations, demonstrating that a genetic factor(s) is involved in the values of plasma Lp(a) levels.     

Genotype and phenotype frequencies of paraoxonase 1 in fertile and infertile men

Abstract

Paraoxonase1 (PON1) is a glycoprotein associated with high density lipoprotein and has antioxidant activity. The impact of PON1 in various stages of spermatogenesis has also been suggested. This study was aimed to investigate frequencies of phenotypes and Q192R genotypes of PON1 in fertile and infertile males. Q192R variants of PON1 were determined in 150 fertile and 150 infertile men using the polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP) technique. Plasma arylesterase and paraoxonase activities were detected by spectrophotometry and malondialdehyde (MDA) level was measured using thiobarbituric acid. Our results showed no significant difference in the distribution of PON1 genotypes and alleles between fertile and infertile groups. However morphology and motility of sperm were associated with various genotypes of PON1. The number of fertile males with the BB phenotype (high activity) was significantly higher than that of infertile males, whereas the number of individuals with the AB phenotype (moderate activity) was statistically higher in infertile men compared with the fertile group. Additionally, MDA and arylesterase activity levels were significantly higher in infertile subjects compared with fertile men. We speculate that the low activity of PON1 can be a risk factor for male infertility probably due to a decrease in antioxidant activity of PON1 and increase in lipid peroxidation.     

Protective effect of yellow tea extract on N-nitrosodiethylamine-induced liver carcinogenesis

Context Yellow tea containing the same catechins as other types of tea but in different proportions has been suggested to possess potent anticancer activities.

Objective This study investigates the chemopreventive effect of yellow tea aqueous extract against N-nitrosodiethylamine (NDEA)-induced liver carcinogenesis in rats by employing histological and biochemical methods.

Materials and methods Wistar rats were divided randomly into four groups: control (I), yellow tea (II), NDEA (III), and yellow tea?+?NDEA (IV). Groups II and IV were exposed via a diet to yellow tea extract in a concentration of 10?g/kg feed; groups III and IV received 0.01% NDEA in drinking water. The experiment lasted for 13 weeks.

Results Daily intake of yellow tea in an average dose of 800?mg/kg b.w. alleviated the carcinogenic effect of NDEA as evidenced by reversed histopathological changes towards normal hepatocellular architecture and decreased lipid peroxidation, protein carbonyl formation, and DNA degradation by 64%, 37% and 15%, respectively, as compared with values obtained in NDEA alone-treated rats. Treatment with yellow tea extract caused protection of superoxide dismutase (SOD) and catalase (CAT); their activity was recovered by 47% and 12%, respectively, as compared with the NDEA-treated rats. Moreover, the extract normalized the NDEA-induced activity of paraoxonase 1 (PON1) and glutathione peroxidase (GPx), while a further increase in the level of reduced glutathione (GSH) was noticed.

Conclusions On the basis of these findings, it can be concluded that treatment with yellow tea partially protected the livers of rats from NDEA-induced hepatocarcinogenesis and that its antioxidant activity contributed to this effect.     

Effects of long-term antidepressant treatment on oxidative status in major depressive disorder: a 24-week follow-up study

Purpose

Major depressive disorder (MDD) is a devastating disease that afflicts large populations and has also been accepted to be an independent risk factor for cardiovascular disease (CVD). Oxidative stress seems to play an essential role in the relationship of MDD and CVD. We aimed to determine the level of oxidative stress in patients with MDD and to investigate the effects of long-term antidepressant (AD) treatment on the oxidative-antioxidative system parameters and CVD risk factors.

Method

Fifty patients who fully met the fourth Diagnostic and Statistical Manual of Mental Disorders criteria for MDD and 44 healthy control subjects were included in the study. Control visits of the patients were repeated 6 weeks, 12 weeks and 24 weeks after beginning of the AD treatment. Lipid profiles, oxidation and oxidizability of apolipoprotein B-containing lipoproteins (expressed as apo B-b-MDA and apo B-Δ-MDA, respectively), levels of plasma malondialdehyde (p-MDA), total antioxidative capacity (TAOC), antioxidant molecules and antioxidant enzyme activities including paraoxonase/arylesterase, red blood cell superoxide dismutase (RBC-SOD) and glutathione peroxidase were determined during 24-week of follow-up period.

Results

According to the results of the study, p-MDA, apo B-b-MDA and RBC-SOD activity were increased and arylesterase activity was decreased in MDD patients. Body mass index (BMI), vitamin A and total cholesterol levels in MDD patients increased after 24-weeks of AD treatment. RBC-SOD activity, TAOC, p-MDA and apo B-b-MDA levels were decreased; paraoxonase/arylesterase activities and apo B-Δ-MDA were increased at the end of 24th week.

Conclusion

Oxidative stress, demonstrated in MDD patients, was partly improved during 24 weeks of AD treatment. Increase in paraoxonase/arylesterase activities and decrease in p-MDA and apo B-b-MDA levels after 24 weeks seem to be beneficial for reduction of CVD risk in MDD patients. However increased BMI and apo B-Δ-MDA levels are negative cardiovascular effects of long-term AD treatment.     

染料木素对大鼠食饵性高脂血症PON1及CRP的影响

目的探讨染料木素(genistein,Gen)对大鼠食饵性高脂血症对氧磷酶(paraoxonase,PON1)活性及C-反应蛋白(C-reactive protein,CRP)的影响。方法健康SD大鼠40只,♀♂各半,随机分为以下5组:①普食组;②高脂血症模型组;③低剂量Gen(0.5 mg.kg-1.d-1)组;④高剂量Gen(5 mg.kg-1.d-1)组;⑤辛伐他汀(5 mg.kg-1.d-1)阳性药物对照组;除普食组给以普通饲料喂养外,其他组均饲以高脂饲料喂养加敌百虫(10 mg.kg-1.d-1)腹腔注射,建立食饵性高脂血症模型。各组大鼠连续喂养及同时用药8周,每2周测1次体重,根据体重调整用药量;定期取血检测胆碱酯酶(acetylcholine esterase,AChE)、血脂、丙二醛(ma-lonaldehyde,MDA)、PON1和CRP的含量,用苏木精/伊红(hematoxylin/eosin,HE)染色检测大鼠肝脏及主动脉弓病理形态变化。结果与模型组相比,高剂量Gen组与辛伐他汀组大鼠总胆固醇(total cholesterol,TC)、低密度脂蛋白胆固醇(low density lipoprotein cholesterol,LDL-C)及动脉粥样硬化指数(atherosclerotic index,AI)明显降低,高密度脂蛋白胆固醇(high density lipoprotein cholesterol/total cholesterol,HDL-C)与TC比值(HDL-C/TC)明显升高,血清MDA含量也明显降低,同时还能明显降低高脂饲料喂养加低剂量敌百虫腹腔注射致高脂血症大鼠血清CRP含量,提高PON1活性,改善大鼠肝与主动脉弓形态变化。结论Gen可以减轻高脂饲料喂养加敌百虫诱发的大鼠高脂血症;其作用机制可能与逆转血脂障碍,抑制过氧化脂质作用抗氧化,降低炎症因子CRP抗炎及通过PON1酶的调节有关。     

Influence of the paraoxonase‐1 Q192R genetic variant on clopidogrel responsiveness and recurrent cardiovascular events: a systematic review and meta‐analysis

Summary. Background: A poor biological response to clopidogrel is associated with an increased risk of major cardiovascular ischemic events (MACE). Paraoxonase 1 (PON1) enzyme activity is modulated by the PON1‐Q192R variant (rs662) and was recently suggested to be strongly involved in clopidogrel bioactivation, but the influence of the PON1‐Q192R variant on the risk of MACE in clopidogrel‐treated patients is controversial. Objectives: To determine whether the PON1‐Q192R variant influences clopidogrel biological responsiveness and the risk of MACE in patients treated with clopidogrel. Methods: Systematic review and meta‐analysis of studies of the association between the PON1‐Q192R polymorphism and the biological response to clopidogrel and/or the risk of MACE during clopidogrel administration. Results: Seventeen studies were included. In the 12 studies of the biological response to clopidogrel (n = 5302 patients), there was no significant difference between 192QQ and 192QR + 192RR subjects, whatever the laboratory method used (global mean standardized difference = 0.10 [?0.06; 0.25], P = 0.22). Eleven studies assessed the risk of MACE, four using a case–control design (n = 2739 patients) and seven a prospective design (n = 5353 patients). Overall, MACE occurred in 19% of patients in case–control studies and in 6% of patients in prospective cohort studies, with no significant difference between 192QQ and 192QR + 192RR patients (OR = 1.28 [0.97; 1.68], P = 0.08). Similar results were obtained when study design was taken into account. Heterogeneity was mainly driven by one publication. Conclusions: This meta‐analysis suggests that the PON1‐Q192R polymorphism has no major impact on the risk of MACE and does not alter the biological response to clopidogrel in clopidogrel‐treated patients.