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HPMR

paraoxonase 1

OKDB#: 4264

	Symbols:	PON1		Species:	human
	Synonyms:	ESA, PON, MVCD5		Locus:	7q21.3 in Homo sapiens

For retrieval of Nucleotide and Amino Acid sequences please go to: OMIM Entrez Gene
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General Comment

Single-Cell Transcriptomic Atlas of Primate Ovarian Aging. Wang S et al. (2020) Molecular mechanisms of ovarian aging and female age-related fertility decline remain unclear. We surveyed the single-cell transcriptomic landscape of ovaries from young and aged non-human primates (NHPs) and identified seven ovarian cell types with distinct gene-expression signatures, including oocyte and six types of ovarian somatic cells. In-depth dissection of gene-expression dynamics of oocytes revealed four subtypes at sequential and stepwise developmental stages. Further analysis of cell-type-specific aging-associated transcriptional changes uncovered the disturbance of antioxidant signaling specific to early-stage oocytes and granulosa cells, indicative of oxidative damage as a crucial factor in ovarian functional decline with age. Additionally, inactivated antioxidative pathways, increased reactive oxygen species, and apoptosis were observed in granulosa cells from aged women. This study provides a comprehensive understanding of the cell-type-specific mechanisms underlying primate ovarian aging at single-cell resolution, revealing new diagnostic biomarkers and potential therapeutic targets for age-related human ovarian disorders.////////////////// Expression of this gene decreases i n aging oocytes. //////////////////

NCBI Summary: This gene encodes a member of the paraoxonase family of enzymes and exhibits lactonase and ester hydrolase activity. Following synthesis in the kidney and liver, the enzyme is secreted into the circulation, where it binds to high density lipoprotein (HDL) particles and hydrolyzes thiolactones and xenobiotics, including paraoxon, a metabolite of the insecticide parathion. Polymorphisms in this gene may be associated with coronary artery disease and diabetic retinopathy. The gene is found in a cluster of three related paraoxonase genes on chromosome 7. [provided by RefSeq, Aug 2017]

General function

Enzyme

Comment

Association between Serum Paraoxonase 1 Activities (PONase/AREase) and L55M Polymorphism in Risk of Female Infertility. Motovali-Bashi M et al. (2015) The risk of developing female infertility has been associated with gene polymorphisms that decrease the activity of enzymes involved in systemic Oxidative Stress (OS). In this study, PON1 L55M polymorphism for association with susceptibility to infertility was investigated among Iranian female population. Samples from 120 Iranian females [20 endometriosis; 30 Polycystic Ovary Syndrome (PCO); 70 controls] were analyzed and PCR-RFLP assay was used to determine the PON1 rs854560 (L55M) frequencies. The paraoxonase (PONase) and arilesterase (AREase) activities of PON1 enzyme were also assessed in order to investigate the association between serum PON1 activities, female infertility, and PON1 L55M polymorphism. The women with a MM genotype (p=0.021; OR=2.55) showed more possibilities of experiencing infertility than those with a LM genotype (p=0.039; OR=1.91). According to LSD test, endometriosis subjects had significantly lower paraoxonase enzyme activity compared to control group (p=0.0024; CI=95%). No significant difference was found in women with PCOS for both PONase and AREase activity in comparison with control group (p=0.469; CI=95%). Furthermore, PON1 activities were the highest in LL genotype followed by LM and then MM genotype (MM<LM<LL) in both patients and controls. PON1 L55M polymorphism may be associated with serum PON1 activity and the risk of developing female infertility.//////////////////

Cellular localization

Secreted, Cytoplasmic

Comment

Polycystic ovary syndrome and endothelial dysfunction: A potential role for soluble lectin-like oxidized low density lipoprotein receptor-1. Oncul M et al. (2020) The aims of this study were to investigate whether serum soluble lectin-like oxidized low-density lipoprotein receptor-1 (sLOX-1), oxidized LDL (oxLDL), paraoxonase-1(PON-1) and hydroperoxide (LOOH) levels are altered in women with polycystic ovary syndrome (PCOS) and also to determine if hyperandrogenism, insulin resistance (IR) and Anti-Müllerian Hormone (AMH) are associated with endothelial dysfunction in PCOS. A total of 46 women with PCOS and 46 non-PCOS healthy controls were recruited. Women with PCOS had significantly higher sLOX-1, oxLDL and LOOH concentrations than non-PCOS women [6.16 (3.92-13.95) vs 1.37 (0.63-4.43) ng/mL, p < 0.001; 6.48 ± 1.03 vs 3.16 ± 1.02 μU/L, p < 0.001; 2.45 (1.45-3.45) vs 1.06 (0.64-1.56) μmol/L, p < 0.001]. The mean PON-1 level of PCOS group was lower than non-PCOS group (69.47 ± 10.75 vs 104.08 ± 21.43 U/mL, p < 0.001). There was no significant difference in terms of the sLOX-1, oxLDL, LOOH and PON-1 levels between normal weight and overweight PCOS women. On univariate logistic regression analysis, Ferriman-Gallwey scale (FGS), HOMA-IR and AMH were an independent predictors of high risk group of endothelial dysfunction markers (HR-EDm). Age and BMI were not associated with HR-EDm. When incorporated into the multivariate model, endotelial dysfunction markers independently correlated with clinical hyperandrogenism (FGS) but not with AMH. In conclusion, our results indicated that an increased concentration of sLOX-1 might be an early predictor of endothelial damage in patients with PCOS. Women with PCOS have elevated sLOX-1, oxLDL, LOOH and decreased PON-1 levels, independent of BMI. Endothelial dysfunction in women with PCOS is associated with hyperandrogenism. Further studies are required to confirm our findings.//////////////////

Ovarian function

Ovulation

Comment

Evaluation of the relationship between serum paraoxonase-1 activity and superovulation response/embryo yield in Holstein cows. Alkan H et al. (2021) In this study, the effect of serum paraoxonase-1 (PON-1) activity on superovulation response and embryo yield was evaluated. The study material comprised 50 Holstein cows aged 3-4 years on postpartum day 90-120 with a body condition score of 3-3.25. A progesterone-based estrus synchronization protocol was initially administered to the selected donors. For this purpose, progesterone source was inserted intravaginally (day 0) and gonadotropin-releasing hormone injection was performed (day 6). Seven days after the insertion of progesterone device, follicle-stimulating hormone injections (total dose of 500 μg in decreasing doses for 4 days) were administered for superovulation. On the morning of the ninth day, prostaglandin (PG) F2α was administered, and the progesterone device was removed from the vagina in the evening on the same day. Two days after PGF2α administration, fixed-time artificial insemination was performed in the morning and in the evening. On the day of artificial insemination, blood samples were taken from the donors to determine the serum PON-1 activity. Uterine flushing was performed seven days after insemination. The results revealed that the serum PON-1 activity (mean ± SD, 562.71 ± 140.23 U/l) of the cows that responded to superovulation (donors with total corpus luteum count of ≥3 in both ovaries) was higher than those (389.91 ± 80.51 U/l) that did not (P<0.05). On the day of insemination, a positive correlation was determined between serum PON-1 activity and the counts of total corpus luteum (r=0.398), total oocyte/embryo (r=0.468), transferable embryo (r=0.453), and Code I embryos (r=0.315, P<0.05). Unlike the Code I embryos, there was no significant correlation between serum PON-1 activity and the number of Code III embryos. Moreover, no significant difference in the number of Code III embryos between the two PON-1 groups was observed. However, embryo yield and quality were found to have increased with increased PON-1 activity. Therefore, it was concluded that serum PON-1 activity may be associated with superovulation response, embryo yield and quality in donor cows.////////////////// .Paraoxonase activities in human follicular fluid: role in follicular maturation. Meijide S et al. (2017) The paraoxonases (PONs) are antioxidant enzymes associated with beneficial effects against several diseases and some exposures. Little is known, however, about the role of PONs in human reproduction. This work was conducted to investigate whether any association existed between the activities of the PON enzymes (1, 2, and 3) with the follicular size and fertility parameters in assisted reproduction. The study included 100 subfertile women (patients) and 55 proven fertile women (oocyte donors), all undergoing an ovarian stimulation cycle. Follicular fluid from small (diameter <12 mm) and large (diameter ≥18 mm) follicles was collected from each woman. The PONs were quantified in follicular fluid by immunoblotting. PON1 arylesterase and paraoxonase, PON2 methyl paraoxonase and PON3 simvastatinase activities from both donors and patients were significantly higher (P < 0.001) in follicular fluid from large follicles compared with small ones. In large follicles, PON3 activity was significantly higher (P < 0.01) in donors compared with patients. Follicular fluid PON1 arylesterase and paraoxonase activity was positively correlated with the number of retrieved oocytes in donors. This study shows an increase in the activities of PONs with follicle size, thus providing indirect evidence for the role of PONs in follicle maturation.//////////////////.......Characterization of the paraoxonase system in follicular fluid of women subjected to an ovarian stimulation cycle. Meijide S et al. (2015) Reactive oxygen species (ROS) and antioxidants are involved in the regulation of reproductive processes. Previous studies in infertile women undergoing an ovarian stimulation cycle have suggested a possible role for ROS in the occurrence of conception in In Vitro Fertilization. In this context the control of the redox balance of follicular fluid becomes essential for reproduction, so that the presence of enzymes with antioxidant activities, such as the paraoxonase (PON) system, would play a role in maintaining this balance. The objective of this work was a) to characterize the paraoxonase system in follicular fluid of women undergoing a controlled ovarian stimulation cycle, analysing the associated PON1, PON2, and PON3 activities, and b) to study the possible involvement of the PON system in follicular maturation. The enzyme activities were quantified in follicular fluid from large and small follicles from women undergoing an ovarian stimulation cycle in the IVI-Bilbao clinic. PON activities were quantified using spectrophotometric and HPLC techniques. Statistical comparisons were performed using the Student's t-test for paired data. Results indicate that follicular fluid presents paraoxonase activities which are detectable by the methods developed in this study. PON activities were associated with follicular maturation, suggesting that the PON system plays a role in oocyte maturation. This work was supported by research grants from the Ministry of Health and Consumption (FIS/FEDER PI11/02559), the Basque Country Government (Dep. Education, Universities and Research ref. IT687-13, and DCIT ref. S-PE13UN063), and UPV/EHU (CLUMBER UFI11/20 and PES13/58). The work was approved by the Ethics Committee of the UPV/EHU (CEISH/96/2011/RUIZLARREA), and performed according to the UPV/EHU and IVI-Bilbao agreement (Ref. 2012/01).//////////////////

Expression regulated by

Comment

Ovarian localization

Oocyte, Granulosa, Follicular Fluid

Comment

Paraoxonase (PON) 1, 2 and 3 Expression in Granulosa Cells and PON1 Activity in Follicular Fluid of Dairy Cows. Schneider A et al. Normal metabolic activity in ovarian follicles may result in oxidative stress and damage to oocytes. The aim of this study was to evaluate expression of the natural anti-oxidants paraoxonase (PON) 1, 2 and 3 in granulosa cells and PON1 activity in follicular fluid (FF) and plasma of dairy cows. For the first experiment, ovaries were collected from cows at slaughter, after which follicles were dissected and classified as oestrogen active (EAF) or atretic (ATF). Expression of PON1, PON2 and PON3 mRNA was evaluated in granulosa cells, and activity of PON1 was measured in FF. PON1 mRNA was undetectable in granulosa cells, PON2 mRNA expression was not different between follicle types, and PON3 mRNA tended to be higher in EAF (p?=?0.11). The activity of PON1 in FF was higher (p?=?0.01) for EAF (82.6???8.0 kU/L) than ATF (53.9???6.8 kU/L), as were high-density lipoproteins (HDL), low-density lipoproteins (LDL) and total cholesterol concentrations. In the second experiment, we aimed to compare plasma and FF PON1 activity in early lactation Holstein cows (n?=?15) with pre-ovulatory EAF. Activity of PON1 was twofold higher (p?

Follicle stages

Comment

Phenotypes

PCO (polycystic ovarian syndrome)

Mutations

6 mutations

Species: human
Mutation name: None
type: naturally occurring
fertility: subfertile
Comment: The role of chronic inflammation and Leu55Met PON1 polymorphism in the pathogenesis of polycystic ovary syndrome. Lenarcik A et al. Introduction. Polycystic ovary syndrome (PCOS) is an endocrine disorder with a complex pathogenesis in which hormonal disturbances, metabolic disorders and chronic inflammation have been considered. Relationships among the paraoxonase 1 (PON1) gene, hyperandrogenism and insulin resistance in women with PCOS have been reported. Aim. The aim of this study was to evaluate patients with PCOS for the existence of chronic inflammation and to assess the relationship between PON1 polymorphism and hormonal, metabolic and inflammatory parameters in these women. Material and methods. One hundred thirty women with PCOS and 70 healthy women were studied. Anthropometric, hormonal (total testosterone, androstenedione, DHEA-S, LH, FSH), metabolic (fasting glucose and insulin, oral glucose tolerance test, insulin sensitivity and resistance indices, lipids) and inflammatory parameters (hsCRP, fibrinogen, WBC) were assessed and analysis of PON1 Leu55Met polymorphism was carried out in all subjects. Results. WBC, fibrinogen and hsCRP levels did not differ significantly between the PCOS and control groups. The genotype frequencies of the Leu55Met PON1 polymorphism were similar in both groups. There were no relationships between PON1 genotypes and metabolic parameters. Conclusions. As chronic low-grade inflammation was not observed in the women with PCOS, there is no direct link between inflammation and PCOS markers per se. None of the variants of the Leu55Met PON1 polymorphism was associated with more frequent occurrence of PCOS or metabolic disorders, including insulin resistance.

Species: human
Mutation name: None
type: None
fertility: subfertile
Comment: Assessment of paraoxonase 1, xanthine oxidase, glutathione peroxidase activities, nitric oxide and thiol levels in women with polycystic ovary syndrome. Baskol G et al. Objectives. To investigate whether there is any relation between oxidative stress and the antioxidant system in the development of polycystic ovary syndrome (PCOS) by measuring serum nitric oxide (NO) levels and xanthine oxidase (XO) activity (a generator of reactive oxygen species) and antioxidant status by measuring serum thiol levels, glutathione peroxidase (GSHPx) and paraoxonase 1 (PON1) activities. Design. Prospective case-control study. Setting. University hospital in Turkey. Population. Thirty women with polycystic ovary syndrome and 20 age and gender-matched healthy controls were included. Methods. Serum XO, PON1, GSH activity, NO and thiol levels determined by spectrophotometric methods. Main Outcome Measures. Activity of serum XO, PON1 and GSH as well as NO and thiol levels. Results. Serum XO activities were higher in women with PCOS than the controls (p<0.001). PON1 activity was lower in women with PCOS than the controls (p<0.001). No significant difference was found between NO, thiol levels and GSHPx activities of women with PCOS and the controls (p> 0.05). Serum PON1 activities were negatively correlated with serum XO activities and NO levels. Conclusion. Increased oxidant XO activity and decreased lipid antioxidant PON1 activity along with the observed negative correlation between these parameters suggests that women with PCOS are under oxidative stress and that there is XO mediated lipid peroxidation which may be related to increased atherosclerosis seen in later life in such women.

Species: human
Mutation name: None
type: naturally occurring
fertility: fertile
Comment: Association of -108 C>T PON1 polymorphism with polycystic ovary syndrome. Ferk P 2014 et al. Polycystic ovary syndrome (PCOS) is possibly the most common endocrine disorder in premenopausal women. In this study, we aimed to investigate the association of the -108 C>T polymorphism in the PON1 gene, which encodes the antioxidant enzyme paraoxonase-1, with PCOS. A total of 118 women with PCOS and 108 control subjects were included in this case-control study. The PON1 polymorphism was genotyped, biochemical and clinical parameters were determined and the correlations between the parameters were statistically evaluated. The differences in the PON1 allele and genotype distributions between PCOS patients and controls did not reach a statistical significance. The serum fasting glucose (GLU) levels did not differ significantly between the PCOS patients and the controls. However, the serum fasting insulin (INS) concentration, INS/GLU ratio and homeostasis model assessment (HOMA) index, although within the normal range, were significantly higher in the PCOS group. When considering PCOS patients and controls as separate groups or as a single group of patients, none of the analyzed biochemical or clinical parameters were found to be significantly correlated with the PON1 polymorphism. Therefore, the -108 C>T PON1 polymorphism was not found to be significantly associated with the presence of PCOS or with its particular clinical and biochemical characteristics in non-insulin resistant, non-obese patients. /////////////////////////

Species: human
Mutation name:
type: naturally occurring
fertility: subfertile
Comment: PON1 polymorphisms are associated with polycystic ovary syndrome susceptibility, related traits, and PON1 activity in Indian women with the syndrome. Dadachanji R et al. (2015) To investigate the association of paraoxonase 1 (PON1) polymorphisms (L55M and Q192R) with polycystic ovary syndrome (PCOS) susceptibility and its related traits in Indian women. Case-control study. Academic research institute, infertility, and endocrinology clinics. Controls (n = 326), women with PCOS (n = 482). None. Genotypic and allelic frequency distribution, genotype-phenotype association, different PON1 activities (lactonase, arylesterase, and paraoxonase). The genotypic and allelic frequency distributions of the L55M polymorphism were significantly different between lean controls and lean women with PCOS, and this polymorphism reduced the risk of PCOS development in lean but not in obese Indian women. Furthermore, this polymorphism was significantly associated with decreased 2-hour glucose, apolipoprotein B, free and bioavailable T, and free androgen index concurrent with increased sex hormone-binding globulin (SHBG) and FSH levels only in lean women with PCOS. However, Q192R polymorphism showed comparable genotypic frequency distribution between controls and women with PCOS. PON1 lactonase and arylesterase activities were significantly decreased in women with PCOS compared with controls. PON1 polymorphisms were shown to influence its activities. Our study showed that L55M, but not Q192R, polymorphism is significantly associated with reduced PCOS susceptibility only in lean women and also impacts glucose metabolism, lipid parameters, and hyperandrogenemia in them. Our study therefore suggests the possibility of differential genetic pathophysiology of PCOS between lean and obese women.//////////////////

Species: human
Mutation name:
type: naturally occurring
fertility: subfertile
Comment: PON1 promoter polymorphisms contribute to PCOS susceptibility and phenotypic outcomes in Indian women. Dadachanji R et al. (2018) Polycystic ovary syndrome is a common endocrinopathy characterized by anovulatory infertility, hyperandrogenism, insulin resistance and oxidative stress, which predisposes affected women to reproductive and cardiometabolic complications in later life. We have investigated the association of PON1 promoter polymorphisms with PCOS susceptibility, PON1 activity and its related traits in Indian women. The genotypic and allelic frequency distribution of only -907G/C polymorphism in PON1 promoter showed significant difference between non-hyperandrogenic control and PCOS women, and was significantly associated with reduced susceptibility to PCOS, considering the recessive model. PON1 lactonase and arylesterase activities were also significantly decreased in women with PCOS compared to controls. Further, PON1 promoter polymorphisms were linked to altered insulin and testosterone levels in hyperandrogenic and non-hyperandrogenic women with PCOS. This study highlights PON1 as an important candidate gene influencing genetic pathophysiology of PCOS.//////////////////

Species: mouse
Mutation name:
type: null mutation
fertility: fertile
Comment: Mice lacking serum paraoxonase are susceptible to organophosphate toxicity and atherosclerosis. Shih DM et al. (1998) Serum paraoxonase (PON1) is an esterase that is associated with high-density lipoproteins (HDLs) in the plasma; it is involved in the detoxification of organophosphate insecticides such as parathion and chlorpyrifos. PON1 may also confer protection against coronary artery disease by destroying pro-inflammatory oxidized lipids present in oxidized low-density lipoproteins (LDLs). To study the role of PON1 in vivo, we created PON1-knockout mice by gene targeting. Compared with their wild-type littermates, PON1-deficient mice were extremely sensitive to the toxic effects of chlorpyrifos oxon, the activated form of chlorpyrifos, and were more sensitive to chlorpyrifos itself. HDLs isolated from PON1-deficient mice were unable to prevent LDL oxidation in a co-cultured cell model of the artery wall, and both HDLs and LDLs isolated from PON1-knockout mice were more susceptible to oxidation by co-cultured cells than the lipoproteins from wild-type littermates. When fed on a high-fat, high-cholesterol diet, PON1-null mice were more susceptible to atherosclerosis than their wild-type littermates.//////////////////

Genomic Region

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Phenotypes and GWAS

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Links

OMIM (Online Mendelian Inheritance in Man: an excellent source of general gene description and genetic information.)
OMIM \ Animal Model
KEGG Pathways

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March 31, 2010, 11:50 a.m.

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Feb. 14, 2021, 10:42 p.m.

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