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Infertility is known to occur frequently worldwide, and the incidence is continuing to rise in China. It is known that semenogelin (SEMG) protein secreted by human seminal vesicles plays an important role in male reproductive system function. However, an association between alterations in SEMG gene functions and idiopathic male infertility occurrence in Chinese-Han population has not been examined. The aim of this study was thus to investigate the inherent relationship between SEMG gene alterations and idiopathic male infertility using a method of variant genotyping selection and semen quality analysis. A population of 484 males with clinically diagnosed idiopathic male infertility and 246 fertile controls were selected after signing consent forms. Results demonstrated a significantly increased frequency of idiopathic infertility with abnormal semen parameters such as semen volume, sperm concentration, sperm number per ejaculate, and sperm motility in variants carrying the rs2301366 TA genotype. Combined association analysis from target single-nucleotide polymorphisms (SNPs) was selected from the genotype database of unrelated Chinese-Han in Beijing individuals from the Hap Map. SNP array analysis in blood samples in each group was carried out by TaqMan Universal PCR Master Mix and TaqMan SNP Genotyping Assays. In addition, the interaction between SEMG SNPs and binding protein epididymal protease inhibitor (EPPIN) SNPs was determined. Our findings demonstrated that the presence of SEMG SNPs and EPPIN SNPs increased the frequency of idiopathic male infertility in Chinese-Han population. It is proposed that measurement of SEMG SNPs and EPPIN SNPs in carriers may thus be utilized to identify idiopathic male infertility. [ABSTRACT FROM AUTHOR]

Certain genetic background (mainly Y chromosome haplogroups, Y-hg) may modify the susceptibility of certain environmental exposure to some diseases. Compared with respective main effects of genetic background or environmental exposure, interactions between them reflect more realistic combined effects on the susceptibility to a disease. To identify the interactions on spermatogenic impairment, we performed Y chromosome haplotyping and measurement of 9 urinary phenols concentrations in 774 infertile males and 520 healthy controls in a Han Chinese population, and likelihood ratio tests were used to examine the interactions between Y-hgs and phenols. Originally, we observed that Y-hg C and Y-hg F * might modify the susceptibility to male infertility with urinary 4-n-octylphenol (4-n-OP) level ( P inter = 0.005 and 0.019, respectively). Subsequently, based on our results, two panels were tested to identify the possible protective sub-branches of Y-hg F * to 4-n-OP exposure, and Y-hg O3 * was uncovered to interact with 4-n-OP ( P inter = 0.019). In conclusion, while 4-n-OP shows an adverse effect on spermatogenesis, Y-hg O3 * makes individuals more adaptive to such an effect for maintaining basic reproductive capacity. [ABSTRACT FROM AUTHOR]

We used a gas chromatography-mass spectrometry (GC-MS) based metabolomics approach to obtain the metabolic profiling of unexplained male infertility (UMI), and identified seminal plasma biomarkers associated with UMI by a two-stage population study. A robust OPLS-DA model based on these identified metabolites was able to distinguish 82% of the UMI patients from health controls with a specificity of 92%. In this model, 44 metabolites were found differentially expressed in UMI subjects compared with health controls. By pathway enrichment analysis, we identified several major changed metabolic pathways related to UMI. Our findings provide new perspective for the diagnosis of UMI. [ABSTRACT FROM AUTHOR]

Recent experimental animal studies suggested that the circadian locomotor output cycles kaput protein gene (CLOCK) has been reported to play a critical role in sperm function and male fertility. The aim of this study was to determine whether variants of the CLOCK gene are involved in idiopathic male infertility. The study included 478 idiopathic infertile men and 194 fertile controls who completed physical examinations. Each subject donated 5 ml of peripheral blood and a sample of semen in the ejaculate. An aliquot of each blood sample was used to separate the serum for the measurement of testosterone as well as follicular stimulating hormone (FSH) using the standard radioimmunoassay. The rest of the blood samples was used to extract the DNA for the assay of three tagging single-nucleotide polymorphisms of CLOCK gene, viz., rs1801260, rs3817444 and rs3749474, using the real-time fluorescence quantitative PCR. The ejaculate of each subject was used for semen analysis by computer-assisted semen analysis system. The results indicated: (a) the variant rs1801260 associated with normal semen parameters was linked to a significant increase in the risk of idiopathic infertility, (b) the variant rs3817444 associated with both normal and abnormal semen parameters also indicated an increased risk of idiopathic infertility, and (c) the variants rs3749474 associated with both normal and abnormal semen parameters, on the other hand, conferred no significant risk for male infertility. Furthermore, elevated serum testosterone and FSH levels were correlated with the three variants of CLOCK gene in idiopathic infertility. The findings demonstrate that the human subjects with variants of the CLOCK gene are associated with idiopathic male infertility and therefore may be applied as a risk factor of male infertility. [ABSTRACT FROM PUBLISHER]

STUDY QUESTION Do genetic variants in known canonical pathways that have been widely suggested to affect spermatogenesis confer susceptibility to non-obstructive azoospermia (NOA)? SUMMARY ANSWER Rs1406714 in CHD2, rs2126986 in GNAO1 and rs7226979 in BCL2 were associated with NOA in Han Chinese men at a significant level after multiple testing corrections. WHAT IS KNOWN ALREADY Previous genome-wide association studies (GWASs) have identified three loci for NOA, whereas less attention has been given to those markers that did not exceed the genome-wide significance threshold. STUDY DESIGN, SIZE, DURATION We conducted a two-stage association study containing 1653 NOA cases and 2329 controls to investigate the susceptibility markers for NOA. PARTICIPANTS/MATERIALS, SETTING, METHODS Imputation and pathway-based approaches can be applied to identify additional causal makers with small effects on NOA. We performed a candidate pathway-based association study using imputed-genotyping data for 24 238 single nucleotide polymorphisms estimated from NOA GWAS. Remarkably, 40 markers were associated with NOA in both imputation analysis and NOA GWAS (Stage 1) after linkage disequilibrium analysis and selected for validation (Stage 2) in another population. MAIN RESULTS AND THE ROLE OF CHANCE Based on the literature, genes from 11 biological pathways known or hypothesized to be important in spermatogenesis were selected. Combined analysis using directly genotyped data for Stages 1 and 2 revealed that rs1406714 in CHD2 was associated with decreased risk of NOA [odds ratio (OR) = 0.78, 95% confidence interval (CI) = 0.68–0.89, Pmeta = 1.7E−04], whereas rs2126986 in GNAO1 and rs7226979 in BCL2 were both risk makers for NOA (rs2126986: OR = 1.28, 95% CI = 1.15–1.41, Pmeta = 2.3E−06; rs7226979: OR = 1.21, 95% CI = 1.11–1.33, Pmeta = 4.5E−05). LIMITATIONS, REASONS FOR CAUTION Our analysis of genes in the pathways studied was not exhaustive. WIDER IMPLICATIONS OF THE FINDINGS Our study opens new avenues for the identification of other novel causal markers that are related to NOA. It will also provide a new paradigm for understanding the etiology of male infertility and contribute to the development of targeted therapies. STUDY FUNDING/COMPETING INTEREST(S) This study was supported in part by National Basic Research Program of China (973 Program, 2011CB944304); National Science Fund for Outstanding Young Scholars (81322039); National Natural Science Foundation (31371524); Distinguished Young Scholars of Jiangsu Province (BK20130041); The Program for Postgraduates Research Innovation in University of Jiangsu Province (CXZZ12-0600). Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD). There were no competing interests. [ABSTRACT FROM AUTHOR]

STUDY QUESTION What is the profile of miRNAs in seminal plasma of patients with non-obstructive azoospermia (NOA)? SUMMARY ANSWER miR-141, miR-429 and miR-7-1-3p are significantly increased in seminal plasma of patients with NOA compared with fertile controls. WHAT IS KNOWN ALREADY There is currently an urgent need to develop a noninvasive diagnostic test for NOA. Altered microRNA (miRNA) profiles have been proposed as potential biomarkers for the diagnosis of disease states. STUDY DESIGN, SIZE, DURATION A total of 200 subjects (n = 100 for NOA, n = 100 for fertile control) were recruited to participate in this study. Recruitment took place from May 2008 to June 2010. PARTICIPANTS/MATERIALS, SETTING, METHODS We employed a strategy consisting of initial screening by TaqMan Low Density Array then further validation with a TaqMan quantitative RT–PCR assay. Validation of the profiling results was conducted in two independent phases. In addition, the expression of the three validated seminal plasma miRNAs (sp-miRNAs) was examined in testicular tissues of patients with NOA and of fertile controls. Methylation status and functional analyses were also performed for the identified sp-miRNAs. MAIN RESULTS AND THE ROLE OF CHANCE miR-141, miR-429 and miR-7-1-3p were significantly increased in seminal plasma of patients with NOA compared with fertile controls. As sensitive and specific biomarkers, the profiling of these three identified sp-miRNAs provides a novel noninvasive, semen-based test for NOA diagnosis. The methylation status of these sp-miRNAs was inversely associated with their expression patterns. Additionally, we found that Cbl and Tgfβ2 were down-regulated by miR-141, while Rb1 and Pik3r3 were down-regulated by miR-7-1-3p. LIMITATIONS, REASONS FOR CAUTION miRNA expression profile was investigated in seminal plasma samples from only a small number of NOA patients. In future investigations, a larger sample size should be adopted and the functional role of the three sp-miRNAs should be further characterized in animal models. WIDER IMPLICATIONS OF THE FINDINGS Given that sp-miRNAs show reproducible and stable expression levels, they are potentially novel noninvasive biomarkers for the diagnosis of NOA. We propose that the three sp-miRNAs described above may participate in a methylation-miRNA-gene network related to NOA development. This work provides a foundation for interpretation of miRNA changes associated with pathogenesis of NOA and extends the current understanding of human NOA pathogenesis. STUDY FUNDING/COMPETING INTEREST(S) This work was supported by the following grants: Key Project of National Natural Science Foundation of China (No. 30930079), National Basic Research Program of China (973 Program) (No. 2009CB941703, 2011CB944304), National Natural Science Foundation of China (No. 81072328 and 30901232); Science and Technology Development Fund Key Project of Nanjing Medical University (No. 2012NJMU002) and Priority Academic Program Development of Jiangsu Higher Education Institutions. The funding organizations played no role in the design and conduct of the study, in collection, management, analysis and interpretation of the data, or in the presentation, review or approval of the manuscript. There are no conflicts of interest to be declared. [ABSTRACT FROM AUTHOR]

Octylphenol (OP) and Trichlorophenol (TCP) act as endocrine disruptors and have effects on male reproductive function. We studied the interactions between 4-tert-Octylphenol (4-t-OP), 4-n- Octylphenol (4-n-OP), 2,3,4-Trichlorophenol (2,3,4-TCP), 2,4,5-Trichlorophenol (2,4,5-TCP) urinary exposure levels and polymorphisms in selected xenobiotic metabolism enzyme genes among 589 idiopathic male infertile patients and 396 controls in a Han-Chinese population. Ultra high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was used to measure alkylphenols and chlorophenols in urine. Polymorphisms were genotyped using the SNPstream platform and the Taqman method. Among four phenols that were detected, we found that only exposure to 4-t-OP increased the risk of male infertility (Ptrend = 1.70×10−7). The strongest interaction was between 4-t-OP and rs4918758 in CYP2C9 (Pinter = 6.05×10−7). It presented a significant monotonic increase in risk estimates for male infertility with increasing 4-t-OP exposure levels among men with TC/CC genotype (low level compared with non-exposed, odds ratio (OR) = 2.26, 95% confidence intervals (CI) = 1.06, 4.83; high level compared with non-exposed, OR = 9.22, 95% CI = 2.78, 30.59), but no associations observed among men with TT genotype. We also found interactions between 4-t-OP and rs4986894 in CYP2C19, and between rs1048943 in CYP1A1, on male infertile risk (Pinter = 8.09×10−7, Pinter = 3.73×10−4, respectively).We observed notable interactions between 4-t-OP exposure and metabolism enzyme gene polymorphisms on idiopathic infertility in Han-Chinese men. [ABSTRACT FROM AUTHOR]

Non-obstructive azoospermia (NOA) is one of the most severe forms of male infertility. Its pathophysiology is largely unknown, and few genetic influences have been defined. To identify common variants contributing to NOA in Han Chinese men, we performed a three-stage genome-wide association study of 2,927 individuals with NOA and 5,734 controls. The combined analyses identified significant (P < 5.0 × 10?8) associations between NOA risk and common variants near PRMT6 (rs12097821 at 1p13.3: odds ratio (OR) = 1.25, P = 5.7 × 10?10), PEX10 (rs2477686 at 1p36.32: OR = 1.39, P = 5.7 × 10?12) and SOX5 (rs10842262 at 12p12.1: OR = 1.23, P = 2.3 × 10?9). These findings implicate genetic variants at 1p13.3, 1p36.32 and 12p12.1 in the etiology of NOA in Han Chinese men. [ABSTRACT FROM AUTHOR]

Summary 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. [ABSTRACT FROM AUTHOR]

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that mediates the toxicity of a variety of environmental chemicals, such as polycyclic aromatic hydrocarbons (PAHs) and dioxins. We hypothesized that polymorphisms of AHR may result in significant differences in sensitivity to toxic effects of PAHs or dioxins and contribute to susceptibility to male infertility. To address this possibility, we conducted a study including 580 idiopathic infertile subjects and 580 fertile controls to assess associations between the male infertility risk and six tagging single nucleotide polymorphisms of AHR gene. Additionally, correlations between AHR polymorphisms and sperm concentration, levels of DNA fragmentation, and benzo(a)pyrene diolepoxide (BPDE)-DNA adducts in sperm were determined in 420 patients. Genotypes were determined using the ABI OpenArray platform. Sperm DNA fragmentation was evaluated by terminal deoxyribonucleotidyl transferase (TdT)-mediated dUDP nick-end labelling (TUNEL) assay, and sperm BPDE-DNA adducts were measured by immunofluorescent assay using flow cytometry. We found that the G variant of rs2158041 was associated with significantly increased risk of male infertility (adjusted odds ratio 1.53, 95% confidence interval 1.21–1.93; p = 6.0 × 10−6; GA/AA vs. GG genotypes). Furthermore, patients with rs2158041 AA genotype showed a reduced sperm concentration. In addition, a gradual increase of sperm DNA fragmentation and sperm BPDE-DNA adducts was found among the three rs2158041 subgroups (GG → GA → AA), though the differences were not statistically significant. These results suggested that the AHR polymorphism might be associated with individual risk of male infertility in the Chinese population study. [ABSTRACT FROM AUTHOR]

Background: The Piwi subfamily of genes is involved in spermatogenesis for the maintenance and meiosis of germline stem cells. Mice bearing targeted mutations in Piwi genes (Miwi, Mili and Miwi2) are sterile with distinct defects in spermatogenesis. We hypothesized that Piwi gene polymorphisms could be a risk factor for spermatogenic failure.Methods: For this study, 490 patients with idiopathic azoospermia or oligozoospermia and 468 fertile controls were recruited from an infertility clinic. Nine single nucleotide polymorphisms (SNPs) of four Piwi genes (PIWIL1/HIWI, PIWIL2/HILI, PIWIL3/HIWI3 and PIWIL4/HIWI2) were genotyped using the SNPstream® 12-plex platform and the Taqman method.Results: An SNP in the 3'untranslated region of HIWI2 and a non-synonymous SNP in HIWI3 were significantly associated with an altered risk of oligozoospermia. The variant-containing genotypes of HIWI2 rs508485 exhibited a significantly increased risk, with an odds ratios (OR) of 1.49 [95% confidence interval (CI), 1.02-2.18], and individuals with HIWI3 non-synonymous rs11703684 variant genotypes exhibited a significantly reduced oligozoospermia risk (OR = 0.70; 95% CI, 0.49-1.00). The haplotype analysis showed that a common haplotype of HIWI2 was associated with a significant reduction in the risk of oligozoospermia (OR = 0.73, 95% CI, 0.56-0.97). In addition, to assess the cumulative effects, we performed a combined unfavourable genotype analysis. A significant trend towards increased risk of oligozoospermia with an increasing number of unfavourable genotypes was observed (P for trend < 0.001).Conclusions: We present the first epidemiologic evidence supporting the involvement of genetic polymorphisms in Piwi genes in spermatogenic failure. [ABSTRACT FROM AUTHOR]

Background: It has been identified that human epididymal protease inhibitor (EPPIN) plays a critical role in sperm function and male fertility. The aim of this study was to determine whether variants of the EPPIN gene are risk factors for idiopathic male infertility.Methods: All subjects, including 473 idiopathic infertile men and 198 fertile controls, underwent complete historical and physical examinations. Each subject donated 5 ml of peripheral blood for genomic DNA extraction and serum testosterone evaluation and an ejaculate for semen analysis. The semen analysis was performed by computer-assisted semen analysis system. The serum testosterone level was evaluated by radioimmunoassay. Four tagging single-nucleotide polymorphisms were analyzed by polymerase chain reaction-restriction fragment length polymorphism.Results: We have demonstrated a significant decreased risk of idiopathic infertility with abnormal semen parameters in association with the variant rs2231829, and an increased risk of idiopathic infertility with abnormal semen parameters in association with the variant rs11594. However, among men with normal semen parameters, there were no differences in risk for these genotypes. Furthermore, no significant differences were found for the other variants, rs6124715 and rs2227290, on the risk of male infertility with normal or abnormal semen parameters. Similar serum testosterone levels among different EPPIN genotypes were observed for each group.Conclusions: These results suggest that different variants in the EPPIN gene may have different relationships with idiopathic male infertility and men carrying these variants have a decreased or increased risk of abnormal semen parameters associated with male infertility. [ABSTRACT FROM AUTHOR]

Exposure to toxic environmental chemicals during pregnancy is a ubiquitous threat to health with potentially transgenerational consequences. However, the underlying mechanism of how transgenerational effects occur as part of environmental chemical exposure are not well understood. We investigated the potential molecular changes associated with dibutyl phthalate exposure that induced transgenerational effects, using a rat model. Through the analysis of the Gene Expression Omnibus database, we found some similar studies of environmental exposure induced transgenerational effects. Then, we analyzed one of the studies and our results to identify the adenomatous polyposis coli (APC) gene. This gene participated the most of the pathways and was upregulated in both studies. We used the miRWALK data set to predict the microRNAs which targeted the APC gene. We confirmed the miR‐30 family were significantly downregulated in F3 testis tissues and targeted the APC gene. In conclusion, the miR‐30 family/APC interaction is a potential mechanism for the transgenerational effects induced by the environmental chemical. [ABSTRACT FROM AUTHOR]

Background: Limited studies have suggested that male reproductive function might be associated with exposure to polycyclic aromatic hydrocarbons (PAHs).Methods: Five hundred and thirteen idiopathic infertile male subjects and 273 fertile males as controls were recruited in this study, through eligibility screening procedures. Individual exposures to PAHs were measured as spot urinary concentrations of four PAH metabolites, including 1-hydroxynaphthalene (1-N), 2-hydroxynaphthalene (2-N), 1-hydroxypyrene (1-OHP) and 2-hydroxyfluorene (2-OHF), which were adjusted by urinary creatinine (CR). Subjects with idiopathic infertility were further divided into 'normal' and 'abnormal' semen quality groups based on their semen volume, sperm concentration, sperm number per ejaculum and sperm motility.Results: The median CR-adjusted urinary concentrations of 1-N, 2-N, 1-OHP, 2-OHF and Sum PAH metabolites (sum of all four metabolites) of control group were lower than those found in case groups. Subjects with higher urinary concentrations of 1-OHP, 2-OHF and Sum PAH metabolites (assessed as tertiles) were more likely to have idiopathic male infertility (P-value for trend = 0.034, 0.022 and 0.022, respectively). Comparing the two groups of idiopathic infertile subjects with different semen quality, a higher idiopathic infertility risk was found in the group with abnormal semen quality.Conclusions: Increased urinary concentrations of 1-OHP, 2-OHF and Sum PAH metabolites were associated with increased male idiopathic infertility risks, while the idiopathic infertile subjects with abnormal semen might be at higher risk. [ABSTRACT FROM AUTHOR]

Infertility affects about 17% couples, and males contribute to half of the cases. Compared with independent effects of genetic and environmental factors, interactions between them help in the understanding of the susceptibility to male infertility. Thus, we genotyped 25 polymorphisms, measured 16 urinary chemical concentrations and explored interactions between gene-gene and gene-environment in 1039 Han Chinese using metabolomic analysis. We first observed that GSTT1 might interact with GSTM1 ( P inter = 6.33 × 10 − 8 ). Furthermore, an interaction between GSTM1 and 4- n -octylphenol (4- n -OP) was identified ( P inter = 7.00 × 10 − 3 ), as well as a 2-order interaction among GSTT1 , GSTM1 and 4- n -OP ( P inter = 0.04). Subjects with GSTT1 -present and GSTM1 -null genotypes were susceptible to male infertility when exposed to 4- n -OP (OR = 14.05, 95% CI = 4.78–60.20, P = 2.34 × 10 − 5 ). Most metabolites identified were involved in the tricarboxylic acid cycle. In conclusion, it is a novel study of the interaction on male infertility from the aspect of metabolomics. [ABSTRACT FROM AUTHOR]

Abstract: Phytoestrogens (PEs) are naturally occurring chemical constituents of certain plants. The internal PE exposures, mainly from diet, vary among different populations and in different regions due to various eating habits. To investigate the potential relationship between urinary PE levels and idiopathic male infertility and semen quality in Chinese adult males, 608 idiopathic infertile men and 469 fertile controls were recruited by eligibility screening procedures. Individual exposure to PEs was measured using UPLC–MS/MS as spot urinary concentrations of 6 PEs (daidzein, DAI; equol, EQU; genistein, GEN; naringenin, NAR; coumestrol, COU; and secoisolariciresinol, SEC), which were adjusted with urinary creatinine (CR). Semen quality was assessed by sperm concentration, number per ejaculum and motility. We found that exposures to DAI, GEN and SEC were significantly associated with idiopathic male infertility (P-value for trend=0.036; 0.002; and 0.0001, respectively), while these exposures had stronger association with infertile subjects with at least one abnormal semen parameter than those with all normal semen parameters. Exposures to DAI, GEN and SEC were also related to idiopathic male infertility with abnormal sperm concentration, number per ejaculum and motility (P-value for trend<0.05), while these exposures had stronger association with the infertile men with abnormal sperm number per ejaculum. These findings provide the evidence that PE exposures are related to male reproductive function and raise a public health concern because that exposure to PEs is ubiquitous in China. [Copyright &y& Elsevier]

Abstract: β-Microseminoprotein (MSMB) is one of the most abundant proteins in human seminal plasma. It has been identified that MSMB increased significantly in oligoasthenoteratozoospermic patients compared with fertile controls. We hypothesized that the functional polymorphism (rs10993994) of MSMB gene could be a risk factor for spermatogenic failure. For this study, 338 patients with idiopathic oligozoospermia or azoospermia and 382 fertile controls were recruited from an infertility clinic. Semen analysis was performed by computer-assisted semen analysis system. The functional polymorphism of MSMB gene was genotyped using TaqMan method. Sixty three seminal plasma samples were used to test the expression of MSMB by enzyme-linked immunosorbent assay (ELISA). The TT genotype and T allele were associated with an increased risk of idiopathic infertility with azoospermia (TT genotype: OR, 1.75; 95% CI, 1.03–2.95; T allele: OR, 1.34; 95% CI, 1.03–1.75). However, no differences were found in risk for the TT genotype or T allele among men with oligozoospermia. In addition, idiopathic infertile males have significantly higher MSMB expression levels than fertile controls. We present the first epidemiologic evidence supporting the involvement of common genetic polymorphism in MSMB gene in spermatogenic failure. These results suggest that men carrying the variant have an increased risk of spermatogenic failure associated with male infertility. Further studies are needed to confirm the roles of the polymorphism in idiopathic azoospermia and investigate the biological mechanism of elevated MSMB expression in infertile males. [Copyright &y& Elsevier]

Abstract: Widespread human exposure to phenols has been documented recently, and some phenols which are potential endocrine disruptors have demonstrated adverse effects on male reproduction in animal and in vitro studies. However, implications about exposure to phenols and male infertility are scarce in humans. Case–control study of 877 idiopathic infertile men and 713 fertile controls was conducted. Urinary levels of bisphenol A, benzophenone-3, pentachlorophenol, triclosan, 4-tert-octylphenol (4-t-OP), 4-n-octylphenol (4-n-OP) and 4-n-nonylphenol (4-n-NP) and semen parameters were measured. After multivariate adjustment, we found 4-t-OP, 4-n-OP and 4-n-NP exposure was associated with idiopathic male infertility (p-value for trend: <0.0001, 0.014 and 0.001, respectively). Aside from these associations, 4-t-OP and 4-n-NP exposure was also associated with idiopathic male infertility with abnormal semen parameters. Moreover, we observed significant associations between sum alkylphenols (APs) exposure and idiopathic male infertility. There were no relationships between exposure to other phenols and idiopathic male infertility in the present study. Our study provides the first evidence that exposure to APs (4-t-OP, 4-n-OP and 4-n-NP) is associated with idiopathic male infertility. [Copyright &y& Elsevier]

Abstract: Objectives: Epoxide hydrolases are involved in detoxifying and excreting the environmental chemicals, which are associated with decreased semen quality and male infertility. We hypothesized that polymorphisms in epoxide hydrolases may be associated with risk of oligozoospermia and asthenospermia. Design and methods: In this study, 468 fertile controls and 672 idiopathic male infertile patients were recruited. SNPstream and TaqMan assay were used to genotype four single nucleotide polymorphisms in EPHX1 and EPHX2. The semen analysis was performed by computer-assisted semen analysis system. Results: Our results demonstrated that rs1042064 of EPHX2 was significantly associated with decreased risk of oligozoospermia (OR=0.65, 95% CI: 0.44–0.98) and asthenospermia (OR=0.66, 95% CI: 0.46–0.94). Conclusions: Our results provided evidence that genetic variants in epoxide hydrolases may modify the risk of oligozoospermia and asthenospermia in Han-Chinese population. [Copyright &y& Elsevier]

Abstract: Studies of the relationship between male infertility and polymorphisms in the regions of FSHR G-29A (rs1394205), 919A>G (Thr307Ala, rs6165) and 2039A>G (Asn680Ser, rs6166) have reported inconsistent results. To assess the association between them, a meta-analysis was conducted. PubMed and CBMdisc literature search were conducted to identify all eligible studies investigating such a relationship. The pooled ORs were performed for co-dominant model, dominant model and recessive model in FSHR G-29A, Thr307Ala and Asn680Ser respectively to assess the strength of association. A total of 1644 male infertility cases and 1748 controls were collected from seven case–control studies. In the overall analysis, no significant association between the three polymorphisms and risk of male infertility was observed. Stratified analysis showed that there were no significantly increased risks of azoospermia and oligoasthenoteratozoospermia (OAT) in any of the genetic models. This meta-analysis supports that FSHR G-29A, Thr307Ala and Asn680Ser polymorphisms may not be capable of causing male infertility susceptibility. [Copyright &y& Elsevier]

Abstract: To test the hypothesis that polymorphisms in antioxidant genes are more susceptible to sperm DNA damage and male infertility, we examined 11 single-nucleotide polymorphisms from six antioxidant genes (GPX1, CAT, PON1, NQO1, SOD2/MnSOD, and SOD3) in 580 infertility cases and 580 controls from a Chinese population-based case–control study (NJMU Infertility Study). Genotypes were determined using the OpenArray platform. Sperm DNA fragmentation was detected using the Tdt-mediated dUTP nick-end labeling assay, and the level of 8-hydroxydeoxyguanosine (8-OHdG) in sperm DNA was measured using immunofluorescence. The adjusted odds ratio and 95% confidence interval (CI) were estimated using unconditional logistic regression. The results indicated that the PON1 Arg192Glu (rs662) and SOD2 Val16Ala (rs4880) variant genotypes were associated with a significantly higher risk of male infertility. In addition, subjects carrying variant genotypes of both loci had a twofold (95% CI, 1.42–2.90) increase in the risk of male infertility, indicating a significant gene–gene interaction between these two loci (P for multiplicative interaction=0.045). Moreover, linear regression analysis showed that individuals carrying the PON1 Arg192Glu (rs662) or SOD2 Val16Ala (rs4880) variants have significantly higher levels of sperm DNA fragmentation and 8-OHdG. These data suggest that genetic variations in antioxidant genes may contribute to oxidative sperm DNA damage and male infertility. [Copyright &y& Elsevier]

Abstract: Background: It is acknowledged that Cytochrome P450 1B1 (CYP1B1) plays a crucial role in metabolism and is involved in lots of diseases. We carried out this study to evaluate the association between CYP1B1 single nucleotide polymorphisms (SNPs) and male infertility in the Han-Chinese population with abnormal semen parameters. Methods: We genotyped five CYP1B1 polymorphisms by using TaqMan allelic discrimination assay and Genome Lab SNP-stream. A total of 591 idiopathic infertile men and 419 fertile controls were comprised in the research. Semen quality analysis was performed using computer assisted sperm analysis. According to semen parameters, we divided cases into 3 subgroups in the stratified analysis. Results: In our study, we only found genetic variant rs1056836 is correlated with idiopathic male infertility (P =0.012). Additionally, in strategy analysis, rs1056836 may decrease the risk of abnormal sperm motility (OR=0.11, 95% CI=0.01, 0.86). While other four variants showed no significant association with male infertility. Conclusions: Our results suggested that polymorphism of CYP1B1 modified the risk of male infertility, and men harboring this polymorphism had lower risk of abnormal sperm parameters. These findings should be validated by more epidemiological and functional studies. [Copyright &y& Elsevier]

Abstract: Background: Follicle stimulating hormone receptor (FSHR), which mediates the effects of FSH, is essential for normal spermatogenesis and male reproduction. This study aimed to investigate the effects of the FSHR polymorphisms on idiopathic male infertility and serum FSH levels in Han-Chinese population. Methods: A case–control study was conducted with 364 idiopathic infertile patients (97 nonobstructive azoospermic, 79 oligozoospermic and 188 normozoospermic) and 281 fertile controls. Three polymorphisms at nucleotide position −29 and codons 307 and 680 of the FSHR gene were genotyped by Taqman allelic discrimination and RFLP. FSH levels were measured by RIA. Results: The allele and genotype frequencies of these three polymorphisms were not significantly different between each group of the cases and controls. Serum FSH concentrations did not differ between subjects with different genotypes within each group. Together the three SNPs mainly formed four discrete haplotypes. The distribution of the haplotype was not different between each group of infertile men and fertile controls and did not influence serum FSH levels in each group. Conclusions: Our findings suggest that the FSHR polymorphisms at the studied sites do not associate with idiopathic male infertility and have no influence on FSH levels both in normal and infertile males in the Han-Chinese population. [Copyright &y& Elsevier]

Objectives: To investigate the possible association between the spermatogenic chromosomal aberrations and idiopathic male infertility with normal semen volume, sperm concentration, sperm number per ejaculum, and sperm motility. Male infertility can be considered as a syndrome that results from many congenital or acquired illness. Currently, there is an increasing awareness of the potential role of chromosomal factors in the idiopathic forms of male infertility. Methods: A total of 202 idiopathic infertile men and 41 normal fertile donors were recruited into this study, through eligibility screening procedures. Proportions and chromatin status of sperm were assessed by flow cytometry after staining the DNA with propidium iodide. Sperm chromosome aneuploidy rates for chromosome 13, 18, 21, X, and Y were evaluated by fluorescence in situ hybridization using five-color probes. Results: Infertile males showed a significantly lower percentage of mature haploid sperm cells and higher percentage of haploid round spermatids than the controls. A significantly higher frequency of disomy on spermatozoa was also detected in infertile males compared with the controls. Conclusions: These findings suggest that higher frequencies of haploid round spermatids and spermatogenic disomy rate may contribute to elevated risk of idiopathic male infertility. [ABSTRACT FROM AUTHOR]

Abstract: A limited number of studies have suggested that exposure to PAHs may affect reproductive hormones. Subjects (n =642) in this study were from the affiliated hospitals of Nanjing Medical University. Individual exposures to PAHs were measured as spot urinary concentrations of four PAH metabolites, including 1-naphthol (1-N), 2-naphthol (2-N), 2-hydroxyfluorene (2-OF) and 1-hydroxypyrene (1-OP), which were adjusted by urinary creatinine (CR). Blood samples were collected to measure serum levels of reproductive hormones, including follicle-stimulating hormone (FSH), luteotrophic hormone (LH), estradiol (E2), testosterone (T) and prolactin (PRL). All of the subjects had detectable levels of the four metabolites of PAHs in their urine samples. The median concentrations of 1-N, 2-N, 2-OF and 1-OP were 2.440, 4.176, 2.843 and 1.148µg/g of CR. There were significant P-values between increased CR-adjusted 1-N tertiles and E2 concentration, 2-OF tertiles and LH, FSH level, 1-OP and E2 level. The multivariate linear regression results also showed significant correlation between the levels of serum LH and 1-OP (the adjusting P-value was 0.048), but no correlations were found between other hormones and the level of PAH metabolites. These observed correlations between levels of hydroxy-PAH and some altered hormones indicated slight endocrine effects on adult men with PAH exposure. [Copyright &y& Elsevier]

Objective: To evaluate the effects of polycyclic aromatic hydrocarbon (PAH) exposure and four functional genetic polymorphisms in the nucleotide excision repair pathway, alone or combined, on sperm DNA integrity and male fertility. Design: Retrospective case-only and case-control study. Setting: One university and three centers of clinical reproductive medicine in the Jiangsu Province of China. Patient(s): Six hundred twenty infertile men and 273 controls were recruited for the study. Intervention(s): None. Main Outcome Measure(s): Exposure to PAHs was detected as urinary 1-hydroxypyrene level. Genotypes were determined by polymerase chain reaction–restriction fragment length polymorphism, and sperm DNA damage was detected by terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate nick end labeling assay with use of flow cytometry. Result(s): Increased sperm DNA damage was found to be associated significantly with increased urinary concentrations of 1-hydroxypyrene. We also observed that the xeroderma pigmentosum group A (XPA)-4 G/A polymorphism was associated with sperm DNA damage. Subjects homozygous for XPA-4 AA had significantly more sperm DNA damage compared with subjects for XPA-4 GG. Moreover, on the basis of a case-control study, a significant interaction was found between XPA-4 G/A polymorphism and PAH exposures on the sperm DNA damage risk (odds ratio = 2.86, 95% confidence interval = 1.77–4.61). Conclusion(s): We provide the first evidence for potential gene-environment interactions between nucleotide excision repair polymorphisms and PAH exposure on the sperm DNA damage and male factor infertility in men with no occupational exposure to PAHs. [ABSTRACT FROM AUTHOR]