Downregulation of TAZ elicits a mitochondrial redox imbalance and ferroptosis in lung epithelial cells exposed to diesel exhaust particles.

Mitochondrial dysfunction was reported to be involved in the development of lung diseases including chronic obstructive pulmonary disease (COPD). However, molecular regulation underlying metabolic disorders in the airway epithelia exposed to air pollution remains unclear. In the present study, lung bronchial epithelial BEAS-2B and alveolar epithelial A549 cells were treated with diesel exhaust particles (DEPs), the primary representative of ambient particle matter. This treatment elicited cell death accompanied by induction of lipid reactive oxygen species (ROS) production and ferroptosis. Lipidomics analyses revealed that DEPs increased glycerophospholipid contents. Accordingly, DEPs upregulated expression of the electron transport chain (ETC) complex and induced mitochondrial ROS production. Mechanistically, DEP exposure downregulated the Hippo transducer transcriptional co-activator with PDZ-binding motif (TAZ), which was further identified to be crucial for the ferroptosis-associated antioxidant system, including glutathione peroxidase 4 (GPX4), the glutamate-cysteine ligase catalytic subunit (GCLC), and glutathione-disulfide reductase (GSR). Moreover, immunohistochemistry confirmed downregulation of GPX4 and upregulation of lipid peroxidation in the bronchial epithelium of COPD patients and Sprague-Dawley rats exposed to air pollution. Finally, proteomics analyses confirmed alterations of ETC-related proteins in bronchoalveolar lavage from COPD patients compared to healthy subjects. Together, our study discovered that involvement of mitochondrial redox dysregulation plays a vital role in pulmonary epithelial cell destruction after exposure to air pollution.

Bis(2-ethylhexyl)-2,3,4,5-tetrabromophthalate Affects Lipid Metabolism in Zebrafish Larvae via DNA Methylation Modification.

Bis(2-ethylhexyl)-2,3,4,5-tetrabromophthalate (TBPH) is a ubiquitous environmental contaminant, but its toxicity is not fully understood. Accordingly, we investigated the effects of TBPH and its metabolite, mono-(2-ethyhexyl)tetrabromophthalate (TBMEHP), on lipid metabolism using a zebrafish model. The molecular docking study revealed that TBPH and TBMEHP bind to zebrafish peroxisome proliferator-activated receptor γ (PPARγ), with binding energies similar to rosiglitazone, a PPARγ agonist. Zebrafish embryos 0.75 hpf were exposed to TBPH (0.2-2000 nM) or TBMEHP (0.2-2000 nM) until 72 hpf, and their effects on PPARγ-mediated lipid metabolism were evaluated. Significant regional DNA demethylation of the PPARγ promoter was observed in the larvae at 72 hpf. Demethylation of the PPARγ promoter accompanied by upregulation of tet1 and tet2 transcription caused upregulation of PPARγ transcription and certain downstream genes involved in lipid lipolysis, transport, and metabolism. The triglyceride and total cholesterol concentrations in the larvae were significantly reduced following exposure to TBPH or TBMEHP. Furthermore, significant increases in the whole ATP content and locomotor activity in the 120 hpf larvae were observed. The overall results suggest that both TBPH and TBMEHP affect methylation of the PPARγ promoter, subsequently influencing larvae lipid metabolism via the PPARγ signaling pathway and disrupting energy homeostasis.

Distribution and bioaccumulation of endocrine disrupting chemicals in water, sediment and fishes in a shallow Chinese freshwater lake: Implications for ecological and human health risks.

The occurrence, distribution and bioaccumulation of six endocrine disrupting compounds (EDCs) were investigated in water, sediment and biota samples from Luoma Lake, a shallow Chinese freshwater lake. Total concentrations of ∑phenolic EDCs were much higher than ∑estrogens EDCs in both waters and sediments. There were not obvious differences on the concentrations of target compounds [except nonylphenol (NP)] in upstream, lake and downstream locations, these may be suggested that they were mainly affected by non-point discharges in this area. However, the high concentration of NP in water may be associated with the discharge of rural domestic wastewater without thorough treatment. Furthermore, concentrations of NP were about 2-3 order magnitude higher than those of OP in both water and sediment compartments. Relatively higher bioaccumulation factors (BAF) were obtained for DES and EE2. Ecological risk assessment revealed greater risk of NP in surface water, which may pose a serious threat to aquatic ecosystems. The estrogen equivalent concentration (EEQ) of male were higher than those in female, and occurred in the order of city >rural-urban>countryside.

Occurrence, distribution and risk assessment of suspected endocrine-disrupting chemicals in surface water and suspended particulate matter of Yangtze River (Nanjing section).

The occurrence and distribution of eight selected endocrine-disrupting chemicals were investigated in samples of surface water and suspended particulate matter (SPM) in Nanjing section of Yangtze River over a year (the flow period, the wet period and the dry period). All target compounds were detected at least once in surface water with 4-tert-butylphenol (4-TBP), nonyphenol (NP) and bisphenol A (BPA) as the dominant compounds, with concentrations in the range of 225-1121ng/L, 1.4-858ng/L and 1.7-563ng/L, respectively. Except for December, all selected compounds for the other sampling times were not found in all sampling points. NP (mean concentration 69.8µg/g) and BPA (mean concentration 51.8µg/g) were also the dominant estrogens in SPM. In addition, the highest total compounds concentrations were found in December in both phases, which could be due to the low flow conditions and temperature during this season. Meanwhile, a significant positive correlation was found between the total compounds concentrations in the water phase and those in SPM phase. Risk assessment based on the calculated risk quotients (RQ) showed that low and moderate risk for the aquatic environment from presence of the target compounds at all sampling points with exception of 4-TBP and NP which might pose a high risk to aquatic organisms.

TBBPA induces developmental toxicity, oxidative stress, and apoptosis in embryos and zebrafish larvae (Danio rerio).

Tetrabromobisphenol A (TBBPA) is currently one of the most frequently used brominated flame retardants and can be considered as a high production volume chemical. In this study, zebrafish embryos and larvae served as a biological model to evaluate TBBPA-induced developmental toxicity, oxidative stress, oxidant-associated gene expression, and cell apoptosis. Abnormalities, including hyperemia and pericardial edema, were induced in zebrafish larvae. The results showed that toxicity endpoints such as hatching rate, survival rate, malformation rate, and growth rate had a significant dose-response relationship with TBBPA. Further studies revealed that TBBPA did not alter the enzyme activities of Copper/Zinc Superoxide dismutase (Cu/Zn-SOD), catalase (CAT), and glutathioneperoxidase (GPx) at 0.10 mg/L, but decreased activities following exposure to 0.40, 0.70, and 1.00 mg/L. Despite the significantly decreased gene expression of Cu/Zn-SOD, CAT, and GPx1a in the 1.00 mg/L treatment group, other treatments (0.10, 0.40, 0.70 mg/L) did not alter gene expression. Moreover, Acridine orange staining results showed that apoptotic cells mainly accumulated in the brain, heart, and tail, indicating possible TBBPA-induced brain, cardiac, and blood circulation system impairment in zebrafish embryos and larvae. Histological analysis also showed evidence of obvious heart impairment in TBBPA-treated groups. This study provides new evidence on the developmental toxicity, oxidative stress, and apoptosis of embryos and zebrafish larvae, which is important for the evaluation of environmental toxicity and chemical risk. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1241-1249, 2016.

Seminal superoxide dismutase activity and its relationship with semen quality and SOD gene polymorphism.

PURPOSE: Superoxide dismutase (SOD) is an important component of antioxidative defense systems and plays an important role in protecting spermatozoa from oxidative damage. In this study, we assessed seminal SOD activity, its association with semen parameters, and also genetic and non-genetic factors contributing to the determination of SOD activity in infertile men. METHODS: Semen samples were obtained from 435 male infertility patients. Sperm DNA damage levels were detected with the Tdt-mediated dUTP nick end labelling (TUNEL) assay. Four single nucleotide polymorphisms (SNPs) in SOD2 and SOD3 genes were genotyped using OpenArray platform. RESULTS: We found that seminal SOD activity was positively associated with sperm concentration and overall motility, whereas inversely with sperm DNA fragmentation. In addition, infertile men with SOD2 rs4880 CC variants showed a low level of SOD activity when compared with TT carriers (Mean ± SD: 268.3 ± 102.3 and 342.8 ± 98.2, respectively, P = 0.005). Those who consumed vitamin C/E (≥3 times per week) had a significantly higher SOD activity level than those who did not (mean ± SD: 379.8 ± 93.3 and 332.2 ± 94.9, respectively, P = 0.001). CONCLUSIONS: Seminal SOD activity and other factors influencing SOD activity play a role in determining sperm fertilization potential and male infertility.

[Association of 8-hydroxyguanine glycosidase OGG1 Ser326Cys polymorphism with male infertility].

OBJECTIVE: To explore the association of 8-hydroxyguanine glycosidase OGG1 Ser326Cys polymorphism with semen quality and the risk of male infertility. METHODS: This case-control study included 620 idiopathic infertile patients and 385 normal fertile controls. We determined their genotypes by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and analyzed their semen quality by computer-aided semen analysis (CASA). RESULTS: The individuals with OGG1 326 Cys/Cys showed significantly lower sperm motility and concentration ([52.1 +/- 26.7]% and (3.75 +/- 0.91) x 10(6)/ml, ln transformed value) than the Ser/Ser carriers ([59.0 +/- 21.8] % and (4.12 +/- 0.88) x 10(6)/ml, ln transformed value) (P < 0.05). The risk of male infertility increased 69% in the OGG1 326Cys allele carriers as compared with the Ser carriers (OR = 1.69, 95% CI: 1.24 -2.31). CONCLUSION: OGG1 326 Ser/Cys polymorphism might contribute to the risk of male infertility in the southern Chinese population.

Bulky DNA adducts in human sperm associated with semen parameters and sperm DNA fragmentation in infertile men: a cross-sectional study.

BACKGROUND: DNA adducts are widely used marker of DNA damage induced by environmental pollutants. The present study was designed to explore whether sperm polycyclic aromatic hydrocarbon-DNA adducts were associated with sperm DNA integrity and semen quality. METHODS: A total of 433 Han Chinese men were recruited from an infertility clinic. Immunofluorescence was applied to analyze sperm PAH-DNA adducts. Sperm DNA fragmentation was detected by terminal deoxynucleotidyl transferase (Tdt)-mediated dUTP nick end labelling (TUNEL) assay. RESULTS: After adjustment for potential confounders using linear regression, sperm PAH-DNA adducts were negatively associated with sperm concentration, total sperm count, sperm motility, and curvilinear velocity (VCL). In addition, a positive relationship between sperm PAH-DNA adducts and sperm DNA fragmentation was found. CONCLUSIONS: Our findings suggested an inverse association between sperm PAH-DNA adducts and semen quality, and provided the first epidemiologic evidence of an adverse effect of PAH-DNA adducts on sperm DNA integrity.

[Bulky DNA adducts in human sperm correlate with semen parameters and sperm apoptosis].

OBJECTIVE: To explore the correlation of sperm polycyclic aromatic hydrocarbons (PAH)-DNA adducts with semen quality and sperm apoptosis. METHODS: We collected semen samples from 433 infertile Chinese men, detected sperm PAH-DNA adducts using immunofluorescence staining and flow cytometry, and determined the rate of sperm apoptosis by TUNEL. RESULTS: Multiple linear regression analysis showed that the level of sperm PAH-DNA adducts was correlated negatively with sperm concentration (beta = -0.632), total sperm count (beta = -0.830) and sperm motility (beta = -9.647), but positively with the rate of sperm apoptosis (beta = 0.130). CONCLUSION: Sperm PAH-DNA adducts are evidently correlated with semen quality and sperm apoptosis, and play an important role in the evaluation of male productivity.

Characterization and Risk Assessment of PM2.5-Bound Polycyclic Aromatic Hydrocarbons and their Derivatives Emitted from a Typical Pesticide Factory in China.

Polycyclic aromatic hydrocarbons (PAHs) and their derivatives have received extensive attention due to their negative effects on the environment and on human health. However, few studies have performed comprehensive assessments of PAHs emitted from pesticide factories. This study assessed the concentration, composition, and health risk of 52 PM2.5-bound PAHs during the daytime and nighttime in the vicinity of a typical pesticide factory. The total concentration of 52 PAHs (Σ52PAHs) ranged from 53.04 to 663.55 ng/m3. No significant differences were observed between daytime and nighttime PAH concentrations. The average concentrations of twenty-two parent PAHs, seven alkylated PAHs, ten oxygenated PAHs, and twelve nitrated PAHs were 112.55 ± 89.69, 18.05 ± 13.76, 66.13 ± 54.79, and 3.90 ± 2.24 ng/m3, respectively. A higher proportion of high-molecular-weight (4-5 rings) PAHs than low-molecular-weight (2-3 rings) PAHs was observed. This was likely due to the high-temperature combustion of fuels. Analysis of diagnostic ratios indicated that the PAHs were likely derived from coal combustion and mixed sources. The total carcinogenic equivalent toxicity ranged from 15.93 to 181.27 ng/m3. The incremental lifetime cancer risk from inhalation, ingestion, and dermal contact with the PAHs was 2.33 × 10-3 for men and 2.53 × 10-3 for women, and the loss of life expectancy due to the PAHs was 11,915 min (about 0.023 year) for men and 12,952 min (about 0.025 year) for women. These results suggest that long-term exposure to PM2.5 emissions from a pesticide factory has significant adverse effects on health. The study results support implementing the characterization of PAH emissions from pesticide factories and provides a scientific basis for optimizing the living environment around pesticide factories.

Effects of glyphosate exposure on gut-liver axis: Metabolomic and mechanistic analysis in grass carp (Ctenopharyngodon idellus).

Glyphosate, one of the most widely used herbicide worldwide, is potentially harmful to non-target aquatic organisms. However, the environmental health risks regarding impacts on metabolism homeostasis and underlying mechanisms remain unclear. Here we investigated bioaccumulation, metabolism disorders and mechanisms in grass carp after exposure to glyphosate. Higher accumulation of glyphosate and its major metabolite, aminomethylphosphonic acid, in the gut was detected. Intestinal inflammation, barrier damage and hepatic steatosis were caused by glyphosate exposure. Lipid metabolism disorder was confirmed by the decreased triglyceride, increased total cholesterol and lipoproteins in serum and decreased visceral fat. Metabolomics analysis found that glyphosate exposure significantly inhibited bile acids biosynthesis in liver with decreased total bile acids content, which was further supported by significant downregulations of cyp27a1, cyp8b1 and fxr. Moreover, the dysbiosis of gut microbiota contributed to the inflammation in liver and gut by increasing lipopolysaccharide, as well as to the declined bile acids circulation by reducing secondary bile acids. These results indicated that exposure to environmental levels of glyphosate generated higher bioaccumulation in gut, where evoked enterohepatic injury, intestinal microbiota dysbiosis and disturbed homeostasis of bile acids metabolism; then the functional dysregulation of the gut-liver axis possibly resulted in ultimate lipid metabolism disorder. These findings highlight the metabolism health risks of glyphosate exposure to fish in aquatic environment.

Identification and quantification of titanium nanoparticles in surface water: A case study in Lake Taihu, China.

The accurate detection and quantification of nanoparticles (NPs) in aquatic environments are essential for toxicological and ecological risk assessment. Herein, we used single particle inductively coupled mass spectroscopy (SP-ICP-MS) to quantify titanium nanoparticles (Ti-NPs) in the extraction fractions of surface waters, and transmission electron microscopy coupled with an energy dispersive X-ray spectrometer (TEM-EDS) to specifically identify the nanoparticles. By using gold-NPs as reference standard, this approach achieved a Ti-NPs size detection limit in water of 25 nm with a particle number concentration limit of 102 particles/ml. We measured Ti-NPs concentrations in surface waters from Lake Taihu, China. The results revealed that the particles concentration was 2.78 × 105 particles/ml with the mean size of 67 nm in October 2016, and the particles concentration of 2.28 × 105 particles/ml with the mean size of 65 nm in April 2018, respectively. Based on TEM-EDS observation, various shapes of Ti-NPs were further identified, including regular cubes, long rods and flaky. We further measured the total organic carbon (TOC), and found that there was a positive correlation between Ti-NPs and TOC. This method enabled accurate detection and quantification of Ti-NPs concentration in environmental surface waters, which could be hugely useful for environmental risk assessment in aquatic systems.

Clinical significance of detecting survivin-expressing circulating cancer cells in patients with non-small cell lung cancer.

We previously demonstrated that the detection of circulating cancer cells (CCC) expressing survivin mRNA could provide valuable information for predicting metastasis and recurrence in breast cancer. The objective of this study was to investigate the significance of detecting survivin-expressing CCC on the clinical outcomes of patients with non-small cell lung cancer (NSCLC). Peripheral blood samples collected from 143 NSCLC patients and 177 healthy volunteers were quantitatively evaluated using a technique developed in our laboratory that detected reverse transcription-polymerase chain reaction (RT-PCR) products based on a hybridisation-enzyme linked immunosorbant essay (ELISA), which we called RT-PCR ELISA. The presence of survivin-expressing CCC was detected in 63 cancer patients (44.1%) and was significantly associated with pathological T classification, nodal status, and disease stages (all P<0.001). During a follow-up period of 36 months, patients who had positive survivin expressions at the time of the initial assay test had a higher relapse rate and shorter survival time when compared to those who had negative survivin expressions (all P<0.001). Through multivariate analysis, the detection of survivin-expressing CCC was found to be an independent predictor for cancer recurrence (HR=43.5; 95% CI=2.67-70.9; P=0.008) and survival (HR=1.35; 95% CI=1.02-4.31; P=0.049). Thus, detection of survivin-expressing CCC could be used in the prediction of disease recurrence as well as in the prognosis of NSCLC.

Neurobehavioral effects of bisphenol S exposure in early life stages of zebrafish larvae (Danio rerio).

As an alternate of bisphenol A (BPA), bisphenol S (BPS) is now widely used to produce our daily consumer goods. Some studies have shown that BPS has the potential to disrupt the reproduction and glucose homeostasis. However, the impact of BPS on the nervous system remains unclear. The purpose of this study is to investigate the impact of BPS on the nervous systems of zebrafish in their early growing stages. The 96 h-LC50 value of BPS to zebrafish larvae was 323 mg/L (95%CI: 308-339 mg/L). Zebrafish embryos were exposed to BPS at concentrations of 0, 0.03, 0.3 and 3.0 mg/L until 6 days postfertilization. Our results showed that 0.3 and 3.0 mg/L BPS exposure markedly decreased locomotor behavior, accompany by the increased oxidative stress, promoted apoptosis and altered retinal structure in zebrafish. In addition, the expression levels of six neurodevelopment genes (α1-tubulin, elavl3, gap43, mbp, syn2a and gfap) were downregulated after 3.0 mg/L BPS treatment. In conclusion, BPS may affect locomotor behavior and alter retinal structure in zebrafish larvae partially by increasing oxidative stress, and by suppressing the expression levels of neurodevelopment genes.

The change in circulating tumor cells before and during concurrent chemoradiotherapy is associated with survival in patients with locally advanced head and neck cancer.

BACKGROUND: This study aimed to evaluate the role of baseline circulating tumor cells (CTCs) before and during concurrent chemoradiotherapy and attempted to determine the impacts of CTCs on the outcomes in patients with head and neck squamous cell carcinoma. METHODS: CTCs were detected using a negative selection strategy and flow cytometry protocol. RESULTS: We observed a significant correlation between baseline CTCs and staging (P = 0.001). The CTC counts were significantly reduced within 2-4 weeks in 47 concurrent chemoradiotherapy responders (P < 0.001). Change of CTC counts correlates with progression-free survival (PFS, P = 0.01) and overall survival (OS, P = 0.01). CTC decline status was an independent prognostic factor in PFS (P = 0.03) and OS (P = 0.05) in multivariate analyses. CONCLUSION: In chemoradiotherapy responders, CTCs are significantly reduced. CTC decline within the first month indicates a longer PFS and OS, suggesting that the dynamics of CTCs could be more important than CTC number alone.

Detection of survivin-expressing circulating cancer cells (CCCs) in peripheral blood of patients with gastric and colorectal cancer reveals high risks of relapse.

BACKGROUND: We previously demonstrated that the detection of circulating cancer cells (CCCs) expressing survivin mRNA could provide valuable information for predicting metastasis and recurrence in breast cancer. The objective of this study was to investigate whether or not the detection of survivin expression in the peripheral blood could also have significant effects on the clinical outcomes of patients with gastric and colorectal cancer. METHODS: Survivin-expressing CCCs in peripheral blood samples obtained from 55 gastric cancer patients, 86 colorectal cancer patients, and 87 healthy volunteers were quantitatively examined by using a RT-PCR ELISA. Its clinical significance was statistically evaluated. RESULTS: The CCCs in the peripheral blood samples were detected in 45.4% and 44.0% of gastric and colorectal cancer patients, respectively. The presence of survivin-expressing CCCs was found to be significantly associated with the degree of tumor penetration, nodal status, and disease stages for both types of cancers. During a follow-up period of 36 months, patients who had a positive detection at the time of the initial assay test had a higher relapse rate than those who had a negative detection. As well, survivin-expressing CCCs were statistically shown to be a significant and independent predictor for cancer recurrence. The detection of survivin-expressing CCCs was also demonstrated to be more accurate in terms of predicting recurrence than traditional detection methods such as plasma carcinoembryonic antigen (CEA) measurements. CONCLUSION: The detection of CCCs expressing survivin mRNA could be used to accurately identify gastric and colorectal cancer patients with high risks of relapse.

Bisphenol analogues in surface water and sediment from the shallow Chinese freshwater lakes: Occurrence, distribution, source apportionment, and ecological and human health risk.

Compared to Bisphenol A (BPA), current knowledge on the spatial distribution, potential sources and environmental risk assessment of other bisphenol analogues (BPs) remains limited. The occurrence, distribution and sources of seven BPs were investigated in the surface water and sediment from Taihu Lake and Luoma Lake, which are the Chinese shallow freshwater lakes. Because there are many industries and living areas around Taihu Lake, the total concentrations of ∑BPs were much higher than that in Luoma Lake, which is away from the industry-intensive areas. For the two lakes, BPA was still the dominant BPs in both surface water and sediment, followed by BPF and BPS. The spatial distribution and principal component analysis showed that BPs in Luoma Lake was relatively homogeneous and the potential sources were relatively simple than that in Taihu Lake. The spatial distribution of BPs in sediment of Taihu Lake indicated that ∑BPs positively correlated with the TOC content. For both Taihu Lake and Luoma Lake, the risk assessment at the sampling sites showed that no high risk in surface water and sediment (RQt < 1.0, and EEQt < 1.0 ng E2/L).

Occurrence, spatial distribution, and ecological risks of typical hydroxylated polybrominated diphenyl ethers in surface sediments from a large freshwater lake of China.

Hydroxylated polybrominated diphenyl ethers (OH-PBDEs) have been frequently observed in marine aquatic environments; however, little information is available on the occurrence of these compounds in freshwater aquatic environments, including freshwater lakes. In this study, we investigated the occurrence and spatial distribution of typical OH-PBDEs, including 2'-OH-BDE-68, 3-OH-BDE-47, 5-OH-BDE-47, and 6-OH-BDE-47 in surface sediments of Taihu Lake. 3-OH-BDE-47 was the predominant congener, followed by 5-OH-BDE-47, 2'-OH-BDE-68, and 6-OH-BDE-47. Distributions of these compounds are drastically different between sampling site which may be a result of differences in nearby point sources, such as the discharge of industrial wastewater and e-waste leachate. The positive correlation between ∑OH-PBDEs and total organic carbon (TOC) was moderate (r = 0.485, p < 0.05), and site S3 and S15 were excluded due to point source pollution, suggesting that OH-PBDEs concentrations were controlled by sediment TOC content, as well as other factors. The pairwise correlations between the concentrations of these compounds suggest that these compounds may have similar input sources and environmental behavior. The target compounds in the sediments of Lake Taihu pose low risks to aquatic organisms. Results show that OH-PBDEs in Lake Taihu are largely dependent on pollution sources. Because of bioaccumulation and subsequent harmful effects on aquatic organisms, the concentrations of OH-PBDEs in freshwater ecosystems are of environmental concern.

Genetic variants in telomerase reverse transcriptase (TERT) and telomerase-associated protein 1 (TEP1) and the risk of male infertility.

Telomeres are critical in maintaining genomic stability and integrity, and telomerase expression in spermatogonial stem cells is responsible for the maintenance of telomere length in the human male germline. Genetic variants in telomere-associated pathway genes might affect telomere length and chromosomal stability, and subsequently disease susceptibility. Thus, we hypothesize that single nucleotide polymorphisms (SNPs) in this pathway could contribute to male infertility risk. In a case-control study of 580 male infertility cases and 580 matched controls, 8 common SNPs in telomerase reverse transcriptase (TERT) and telomerase-associated protein 1 (TEP1) were genotyped. Overall, we found that TERT rs2736100 was inversely associated with male infertility risk (adjusted odds ratio (OR)=0.66, 95% confidence interval (CI): 0.47-0.92; Ptrend=0.011), whereas TEP1 rs1713449 was positively associated with risk of male infertility (adjusted OR=1.39, 95% CI: 1.20-1.62; Ptrend<0.001). In addition, subjects carrying risk genotypes of these both loci had a two-fold (95% CI: 1.34-3.15) increase in the risk of male infertility, indicating a significant gene-gene interaction between these two loci (P for multiplicative interaction=0.009). Moreover, linear regression analysis showed that individuals carrying the TEP1 rs1713419 variants have significantly higher levels of sperm DNA fragmentation (ß=2.243, P=0.016). In conclusion, our results give the first evidence that genetic variations of TERT rs2736100 and TEP1 rs1713449 were associated with susceptibility to male infertility.

Genetic variants in nitric oxide synthase genes and the risk of male infertility in a Chinese population: a case-control study.

BACKGROUND: In recent years, oxidative stress has been studied extensively as a main contributing factor to male infertility. Nitric Oxide, a highly reactive free radical gas, is potentially detrimental to sperm function and sperm DNA integrity at high levels. Thus, the aim of this study was to investigate the associations between five polymorphisms in nitric oxide synthase genes (NOSs) and the risk of male infertility and sperm DNA damage as well. METHODS: Genotypes were determined by 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 (OR) and 95% confidence interval (CI) were estimated using unconditional logistic regression. RESULTS: Our results revealed a statistically significant difference between the cases and controls in both genotypic distribution (P<0.001) and allelic frequency (P = 0.021) only for the NOS3 rs1799983 SNP. Multivariate logistic regression analyses revealed that rs1799983 was associated with a borderline significantly increased risk of male infertility (GT vs. GG: adjusted OR = 1.30, 95% CI: 1.00-1.70; GT+TT vs. GG: adjusted OR = 1.34, 95% CI: 1.03-1.74; P trend = 0.020). Moreover, NOS3 rs1799983 was positively associated with higher levels of sperm DNA fragmentation (ß = 0.223, P = 0.044). However, the other 4 polymorphisms (NOS1 rs2682826, NOS1 rs1047735, NOS2 rs2297518, and NOS2 rs10459953) were not found to have any apparent relationships with male infertility risk. CONCLUSIONS: Of five NOS gene polymorphisms investigated in the present study, we found NOS3 rs1799983 might cause oxidative sperm DNA damage, thereby contributing to male infertility.