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ABSTRACT: Published data on the association between the methylenetetrahydrofolate reductase (MTHFR) gene A1298C (rs1801131) polymorphism and male infertility risk are inconclusive. To derive a more precise estimation of the relationship, a meta-analysis was performed. In this meta-analysis, a total of seven case-control studies including 1633 cases and 1735 controls were selected to evaluate the possible association. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of association in the additive model, dominant model, recessive model, and allele-frequency genetic model. In the overall analysis, the frequency of the C1298 allele (C vs. A) was significantly associated with susceptibility to male infertility (OR = 1.12, 95% CI = 1.00-1.26). A subgroup analysis of the subjects showed that MTHFR 1298C was associated with significant increased risk of azoospermia in homozygote comparison (CC vs. AA) and recessive mode (CC vs. AA/AC) (OR = 1.66 for CC vs. AA genotype; OR = 1.67 for CC vs. AA/AC genotype). However, no statistically significant increased risk of oligoasthenoteratozoospermia was found in any of the genetic models. In conclusion, this meta-analysis supports that the MTHFR A1298C polymorphism is capable of causing male infertility susceptibility, especially azoospermia.
Annals of Human Genetics 01/2012; 76(1):25-32. · 2.57 Impact Factor
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ABSTRACT: Methoxylated brominated diphenyl ethers (MeO-BDEs) in aquatic environments have been found to be primarily of natural origin in the marine environment and not from biotransformation of synthetic PBDEs. Two of the eight MeO-PBDEs (2'-MeO-BDE-68 and 6-MeO-BDE-47) that were detected in anchovy from the Yangtze River Delta, were natural products from marine organisms. So 2'-MeO-BDE-68 and 6-MeO-BDE-47 were chosen to study the potential to modulate androgen, estrogen, or thyroid hormone receptor- (AR, ER, ThR) mediated responses by use of reporter gene assays. 2'-MeO-BDE-68 was antiandrogenic at 50 μM, estrogenic at 10 μM and antiestrogenic at 10 and 50 μM (IC50=4.88 μM). 2'-MeO-BDE-68 enhanced luciferase expression by 5 nM T3 at 50 μM. 6-MeO-BDE-47 exhibited potent antiandrogenicity at 1 μM and greater (IC50=41.8 μM) and possessed estrogenic activity at 10 μM and antiestrogenic activity at 10 and 50 μM (IC50=6.02 μM).
Marine pollution bulletin 09/2011; 62(11):2356-61. · 2.63 Impact Factor
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ABSTRACT: Polybrominated diphenyl ethers (PBDEs) constitute an important group of flame retardants. 2,2',4,4',6-Pentabromodiphenylether (BDE100) is a prominent PBDE congener in some human populations. The potential of BDE100 to modulate responses mediated by the estrogen (ER), thyroid hormone (ThR) or androgen receptors (AR) were investigated by use of transactivation reporter gene assays. The African green monkey kidney CV-1 cell transiently transfected with the constructed reporter gene plasmid ERE-TATA-Luc and pUAS-tk-Luc with luciferase (Luc) under control of the estrogen response (ERE), or thyroid hormone response (ThRE) elements were used to evaluate (anti)estrogen and thyroid effects of BDE100. The (anti)androgenic potency of BDE100 was also evaluated by use of MDA-kb2 cells, which were stably transfected with MMTV-luciferase. The assays displayed appropriate responses to known natural estrogen 17β-estradiol (E2), ThR ligand triiodothyronine (T3), and the AR agonist 5α-dihydrotestosterone (DHT). 10 or 50 μM BDE100 significantly up-regulated expression of Luc under control of the ER. Antiestrogenic potency was observed for BDE100 (IC50 = 6.21 μM). Co-exposure to 50 μM BDE100 significantly enhanced expression of Luc caused by 5 nM T3. BDE100 was antiandrogenic at 10 and 50 μM with an IC50 of 28.60 μM BDE100. These results suggest that BDE100 can modulate the endocrine system in multiple ways by interfering with several hormonal signaling pathways simultaneously.
Journal of Environmental Monitoring 03/2011; 13(4):850-4. · 1.99 Impact Factor
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Ouxi Shen,
Wei Wu,
Guizhen Du,
Renping Liu,
Lugang Yu,
Hong Sun,
Xiumei Han,
Yi Jiang,
Wei Shi,
Wei Hu,
Ling Song,
Yankai Xia,
Shoulin Wang,
Xinru Wang
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ABSTRACT: Di-n-butyl phthalate (DBP), a chemical widely used in many consumer products, is estrogenic and capable of producing seriously reproductive and developmental effects in laboratory animals. However, recent in vitro studies have shown that DBP and mono-n-butyl phthalate (MBP), the major metabolite of DBP, possessed thyroid hormone receptor (TR) antagonist activity. It is therefore important to consider DBP and MBP that may interfere with thyroid hormone system.
Nieuwkoop and Faber stage 51 Xenopus laevis were exposed to DBP and MBP (2, 10 or 15 mg/L) separately for 21 days. The two test chemicals decelerated spontaneous metamorphosis in X. laevis at concentrations of 10 and 15 mg/L. Moreover, MBP seemed to possess stronger activity. The effects of DBP and MBP on inducing changes of expression of selected thyroid hormone response genes: thyroid hormone receptor-beta (TRβ), retinoid X receptor gamma (RXRγ), alpha and beta subunits of thyroid-stimulating hormone (TSHα and TSHβ) were detected by qPCR at all concentrations of the compounds. Using mammalian two-hybrid assay in vitro, we found that DBP and MBP enhanced the interactions between co-repressor SMRT (silencing mediator for retinoid and thyroid hormone receptors) and TR in a dose-dependent manner, and MBP displayed more markedly. In addition, MBP at low concentrations (2 and 10 mg/L) caused aberrant methylation of TRβ in head tissue.
The current findings highlight potential disruption of thyroid signalling by DBP and MBP and provide data for human risk assessment.
PLoS ONE 01/2011; 6(4):e19159. · 4.09 Impact Factor
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ABSTRACT: The potential of 2,2',4,4'-tetrabromodiphenyl ether (BDE47) and its related hydroxylated analogs (2'-HO-BDE28, 6-HO-BDE47, 4'-HO-BDE17, and 4'-HO-BDE49) to modulate estrogen/thyroid/androgen receptor-(ER, TR, AR), mediated responses were investigated by use of reporter gene assays. Exposure to 1 or 10 μM, 4'-HO-BDE17 significantly up-regulated expression of Luc, whereas other four chemicals did not induce Luc expression under control of the ER. Anti-estrogenic potency was observed for 4'-HO-BDE17 (IC50=1.14 μM)>6-HO-BDE47 (IC50=2.65 μM)>2'-HO-BDE28 (IC50=9.49 μM)>BDE47 (IC50=21.11 μM). No anti-estrogenic effect of 4'-HO-BDE49 was observed. Both 4'-HO-BDE17, 4'-HO-BDE49 resulted in greater responses of Luc expression induced by T3. BDE47, 2'-HO-BDE28, 6-HO-BDE47 did not show any effect on the expression of Luc induced by 5 nM T3. 6-HO-BDE47 (IC50=0.34 μM)>4'-HO-BDE17 (IC50=1.41 μM)>BDE47 (IC50=3.83 μM)>2'-HO-BDE28 (IC50=29.22 μM) exhibited anti-androgenic potency, while 4'-HO-BDE49 did not show androgenic transcriptional activity.
Marine pollution bulletin 01/2011; 63(5-12):287-96. · 2.63 Impact Factor
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ABSTRACT: Pyrethroid insecticides, the most commonly used insecticides worldwide, are suspected endocrine-disrupting chemicals. But their interactions with hormone receptors are still unclear. The present study intended to evaluate and compare the hormone receptor (estrogen receptor [ER], androgen receptor [AR], and thyroid hormone receptor [TR]) activities of nine pyrethroids (cycloprothrin, cyfluthrin, cyhalothrin, cypermethrin, deltamethrin, etofenprox, fenvalerate, permethrin, and tetramethrin) and their metabolites (3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropne carboxylic acid [DCCA] and 3-phenoxybenzoic acid [3-PBA]) using receptor-mediated luciferase reporter gene assays. Of the 11 compounds tested, four showed very weak ER agonistic activities and six displayed antiestrogenic effects, among which cyhalothrin and DCCA possessed the most potent estrogenic and antiestrogenic activity respectively. Antagonistic effects to AR were found in 7 compounds, with cyfluthrin and deltamethrin exhibiting stronger AR antagonistic capacity. In the TR assay, all of tested chemicals except DCCA showed antagonistic effects. In this study, we provided evidence that a variety of pyrethroids and their metabolites might disrupt the function of multiple nuclear hormone receptors and thus have the potentials to affect the endocrine and the reproductive systems in humans.
Toxicological Sciences 07/2010; 116(1):58-66. · 4.65 Impact Factor
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ABSTRACT: Abnormal DNA methylation of the male germ line is proposed as a possible mechanism causing compromised spermatogenesis in some men diagnosed with idiopathic infertility. Previous studies suggested that aberrant DNA methylation of several genes is associated with disruptions in spermatogenesis. However, little information is available on DNA methylation patterns of testis-specific genes in idiopathic male infertility.
To investigate the association between DAZ gene methylation patterns and spermatogenic failure, we performed an analysis of methylation patterns in 174 idiopathic infertile patients and 58 fertile controls using bisulfite-modified sequencing.
We found that the methylation patterns of CpG island (CGI) in the DAZ gene promoter region were different between somatic cells and spermatic cells in the control group. DAZ gene methylation patterns among groups with different spermatogenic status were the same in somatic cells, completely methylated, and in spermatic cells. The results were concordant, except for the group with azoospermia (AZ) which were completely unmethylated.
Our data indicate that the methylation patterns of the DAZ gene are not associated with spermatogenic failure. This suggests that epigenetic modification of DAZ is unlikely to be involved in the etiology of spermatogenic failure.
Clinical Chemistry and Laboratory Medicine 03/2010; 48(3):355-60. · 2.15 Impact Factor
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ABSTRACT: The purpose of this study was to determine the relationship between hypomethylation of HOXA10 gene's promoter and high expression in malignant ovarian tissues, and to confirm the level of hypomethylation in ovarian cell lines.
We performed the methylation status of 29 samples from ovarian carcinomas and 16 from normal tissues by methylation-specific polymerase chain reaction (MSP). Then, we evaluated the expression of mRNA and protein of HOXA10 in all samples to work out the relationship between the methylation status of HOXA10 and its expression in transcriptional and translational levels. We then confirmed our present study using SKOV3 and HEY ovarian cancer cell lines treated with the demethylating agent 5-aza-2'-deoxycytidine (5-aza-dC) to detect whether the expression of HoxA10 in the two cell lines was altered.
Increased expression of HOXA10 was detected in almost all ovarian carcinomas (p < 0.05). Promoter hypomethylation was found in (17 of 29) 58.62% ovarian cancers and (4 of 16) 25% normal ovaries (p < 0.05). The HOXA10 expression is higher when the status of HOXA10 gene promoter is hypomethylated than in methylated tissues (p < 0.05). After 5-aza-dC treatment, the expression level of HOXA10 mRNA transcript was increased in the two cell lines.
Our results indicate that promoter hypomethylation is an important mechanism for high expression of HOXA10 in human ovarian cancer and may be a potential prognostic factor in ovarian cancer.
Journal of Cancer Research and Clinical Oncology 02/2010; 136(8):1221-7. · 2.56 Impact Factor
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ABSTRACT: Abnormal germline DNA methylation in males has been proposed as a possible mechanism compromising spermatogenesis of some men currently diagnosed with idiopathic infertility. Previous studies have been focused on imprinted genes with DNA methylation in poor quality human sperms. However, recent but limited data have revealed that sperm methylation abnormalities may involve large numbers of genes or shown that genes that are not imprinted are also affected.
Using the methylation-specific polymerase chain reaction and bisulfite sequencing method, we examined methylation patterns of the promoter of methylenetetrahydrofolate reductase (MTHFR) gene (NG_013351: 1538-1719) in sperm DNA obtained from 94 idiopathic infertile men and 54 normal fertile controls. Subjects with idiopathic infertility were further divided into groups of normozoospermia and oligozoospermia. Overall, 45% (41/94) of idiopathic infertile males had MTHFR hypermethylation (both hemimethylation and full methylation), compared with 15% of fertile controls (P<0.05). Subjects with higher methylation level of MTHFR were more likely to have idiopathic male infertility (P-value for trend = 0.0007). Comparing the two groups of idiopathic infertile subjects with different sperm concentrations, a higher methylation pattern was found in the group with oligozoospermia.
Hypermethylation of the promoter of MTHFR gene in sperms is associated with idiopathic male infertility. The functional relevance of hypermathylation of MTHFR to male fertility warrants further investigation.
PLoS ONE 01/2010; 5(11):e13884. · 4.09 Impact Factor
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ABSTRACT: Phthalates are widely used in the plastic industry and food packaging, imparting softness and flexibility to normally rigid plastic medical devices and children's toys. Even though phthalates display low general toxicity, there is increasing concern on the effects of endocrine system induced by some of phthalate compounds. The hormone activity of dibutyl phthalate (DBP), mono-n-butyl phthalate (MBP) and di-2-ethylhexyl phthalate (DEHP) were assessed using the luciferase reporter gene assays. The results showed that DBP, MBP and DEHP, not only exhibited potent antiandrogenic activity, with IC(50) value of 1.05x10(-6), 1.22x10(-7)M and exceeding 1x10(-4)M respectively, but also showed the androgenic activity with EC(50) value of 6.17x10(-6), 1.13x10(-5)M and exceeding 1x10(-4)M. We also found that all the three related chemicals possessed thyroid receptor (TR) antagonist activity with IC(50) of 1.31x10(-5), 2.77x10(-6)M and exceeding 1x10(-4)M respectively, and none showed TR agonist activity. These results indicate that TR might be the targets of industrial chemicals. In the ER mediate reporter gene assay, three chemicals showed no agonistic activity except for DBP, which appeared weakly estrogenic at the concentration of 1.0x10(-4)M. Together, the findings demonstrate that the three phthalates could simultaneously disrupt the function of two or more hormonal receptors. Therefore, these phthalates should be considered in risk assessments for human health.
Toxicology Letters 08/2009; 191(1):9-14. · 3.23 Impact Factor
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ABSTRACT: The endocrine-disrupting equivalents in effluents from three chemical industry wastewater treatment systems in the vicinity of Yangtze River were determined by several transactivation reporter gene assays. Transient transfections of African green monkey kidney cell line (CV-1) were used to determine the estrogenic, anti-androgenic and anti-thyroid equivalents in the effluents. Organic extracts of the effluents contained compounds that were potent anti-androgens and the activities measured as an equivalent concentration of flutamide were 45.53, 34.65 and 91.61 nM, respectively. The extracts also contained detectable concentrations of thyroid antagonists. Estrogenic activities, measured with the reporter gene assay, were near or below the method detection limit (0.58 pM as E2). Concentrations of some of the major constituents such as di(2-ethylhexyl)phthalate, dibutyl phthalate, 2,6-dinitrotoluene and nitrobenzene were quantified. The data suggest that the reporter gene assay is useful to predication of endocrine disrupting effects in polluted aquatic body.
Ecotoxicology 07/2009; 18(6):685-92. · 2.36 Impact Factor
