Paraquat disrupts KIF5A-mediated axonal mitochondrial transport in midbrain neurons and its antagonism by melatonin.

Paraquat (PQ) is a broad-spectrum herbicide used worldwide and is a hazardous chemical to human health. Cumulative evidence strengthens the association between PQ exposure and the development of Parkinson's disease (PD). However, the underlying mechanism and effective interventions against PQ-induced neurotoxicity remain unclear. In this study, C57BL/6 J mice were treated with PQ (i.p., 10 mg/kg, twice a week) and melatonin (i.g., 20 mg/kg, twice a week) for 8 weeks. Results showed that PQ-induced motor deficits and midbrain dopaminergic neuronal damage in C57BL/6 J mice were protected by melatonin pretreatment. In isolated primary midbrain neurons and SK-N-SH cells, reduction of cell viability, elevation of total ROS levels, axonal mitochondrial transport defects and mitochondrial dysfunction caused by PQ were attenuated by melatonin. After screening of expression of main motors driving axonal mitochondrial transport, data showed that PQ-decreased KIF5A expression in mice midbrain and in SK-N-SH cell was antagonized by melatonin. Using the in vitro KIF5A-overexpression model, it was found that KIF5A overexpression inhibited PQ-caused neurotoxicity and mitochondrial dysfunction in SK-N-SH cells. In addition, application of MTNR1B (MT2) receptor antagonist, 4-P-PDOT, significantly counteracted the protection of melatonin against PQ-induced neurotoxicity. Further, Kif5a-knockdown diminished melatonin-induced alleviation of motor deficits and neuronal damage against PQ in C57BL/6 J mice. The present study establishes a causal link between environmental neurotoxicants exposure and PD etiology and provides effective interventive targets in the pathogenesis of PD.

Chronic cadmium exposure triggered ferroptosis by perturbing the STEAP3-mediated glutathione redox balance linked to altered metabolomic signatures in humans.

Cadmium (Cd), a predominant environmental pollutant, is a canonical toxicant that acts on the kidneys. However, the nephrotoxic effect and underlying mechanism activated by chronic exposure to Cd remain unclear. In the present study, male mice (C57BL/6J, 8 weeks) were treated with 0.6 mg/L cadmium chloride (CdCl2) administered orally for 6 months, and tubular epithelial cells (TCMK-1 cells) were treated with low-dose (1, 2, and 3 µM) CdCl2 for 72 h (h). Our study results revealed that environmental Cd exposure triggered ferroptosis and renal dysfunction. Spatially resolved metabolomics enabled delineation of metabolic profiles and visualization of the disruption to glutathione homeostasis related to ferroptosis in mouse kidneys. Multiomics analysis revealed that chronic Cd exposure induced glutathione redox imbalance that depended on STEAP3-driven lysosomal iron overload. In particular, glutathione metabolic reprogramming linked to ferroptosis emerged as a metabolic hallmark in the blood of Cd-exposed workers. In conclusion, this study provides the first evidence indicating that chronic Cd exposure triggers ferroptosis and renal dysfunction that depend on STEAP3-mediated glutathione redox imbalance, greatly increasing our understanding of the metabolic reprogramming induced by Cd exposure in the kidneys and providing novel clues linking chronic Cd exposure to nephrotoxicity.

Cadmium exposure disturbs myocardial lipid signature and induces inflammation in C57BL/6J mice.

Cadmium is a highly ubiquitous environmental pollutant that poses a serious threat to human health. In this study, we assessed the cardiotoxicity of Cd exposure and explored the possible mechanisms by which Cd exerts its toxic effects. The results demonstrated that exposure to Cd via drinking water containing CdCl2 10 mg/dL for eight consecutive weeks induced cardiac injury in C57BL/6J mice. The histopathological changes of myocardial hemolysis, widening of myocardial space, and fracture of myocardial fiber were observed. Meanwhile, elevated levels of cardiac enzyme markers and up-regulation of pro-apoptotic genes also indicated cardiac injury after Cd exposure. Non-targeted lipidomic analysis demonstrated that Cd exposure altered cardiac lipid metabolism, resulted in an increase in pro-inflammatory lipids, and changed lipid distribution abundance. In addition, Cd exposure affected the secretion of inflammatory cytokines by activating the NF-κB signaling pathway, leading to cardiac inflammation in mice. Taken together, results of our present study expand our understanding of Cd cardiotoxicity at the lipidomic level and provide new experimental evidence for uncovering the association of Cd exposure with cardiovascular diseases.

Chronic cadmium exposure induces Parkinson-like syndrome by eliciting sphingolipid disturbance and neuroinflammation in the midbrain of C57BL/6J mice.

Cadmium (Cd) is known as a widespread environmental neurotoxic pollutant. Cd exposure is recently recognized as an etiological factor of Parkinson's disease (PD) in humans. However, the mechanism underlying Cd neurotoxicity in relation to Parkinsonism pathogenesis is unclear. In our present study, C57BL/6 J mice were exposed to 100 mg/L CdCl2 in drinking water for 8 weeks. It was found Cd exposure caused motor deficits, decreased DA neurons and induced neuropathological changes in the midbrain. Non-targeted lipidomic analysis uncovered that Cd exposure altered lipid profile, increased the content of proinflammatory sphingolipid ceramides (Cer), sphingomyelin (SM) and ganglioside (GM3) in the midbrain. In consistency with increased proinflammatory lipids, the mRNA levels of genes encoding sphingolipids biosynthesis in the midbrain were dysregulated by Cd exposure. Neuroinflammation in the midbrain was evinced by the up-regulation of proinflammatory cytokines at mRNA and protein levels. Blood Cd contents and lipid metabolites in Parkinsonism patients by ICP-MS and LC-MS/MS analyses demonstrated that elevated blood Cd concentration and proinflammatory lipid metabolites were positively associated with the score of Unified Parkinson's Disease Rating Scale (UPDRS). 3 ceramide metabolites in the blood showed good specificity as the candidate biomarkers to predict and monitor Parkinsonism and Cd neurotoxicity (AUC>0.7, p < 0.01). In summary, our present study uncovered that perturbed sphingomyelin lipid metabolism is related to the Parkinsonism pathogenesis and Cd neurotoxicity, partially compensated for the deficiency in particular metabolic biomarkers for Parkinsonism in relation to Cd exposure, and emphasized the necessity of reducing Cd exposure at population level.

Characteristics of the oropharyngeal microbiota among infants with pneumonia and their effects on immune response and subsequent respiratory morbidity.

Changes in airway microbiota among infants with pneumonia and their impact on subsequent respiratory health are largely unknown. The present study aimed to analyze the oropharyngeal microbiota of infants with pneumonia and to explore the impact of disturbances of the microbiota on disease severity and long-term respiratory morbidities. The oropharyngeal microbiome was characterized using 16S ribosomal RNA-based sequencing, while serum immune mediators were assessed using cytometric bead array, and invariant natural killer T (iNKT) cells were detected using flow cytometry in infants with pneumonia < 6 months of age. Patients were followed up to 3 years of age, and clinical and respiratory morbidity data were collected. A total of 106 infants with pneumonia were enrolled in this study. Diversity of the respiratory microbiota was inversely correlated with the severity of pneumonia and length of hospitalization. Patients who experienced wheezing during pneumonia exhibited lower percentages of total iNKT cells, CD8-positive ( +), and CD4-CD8- subsets, and higher CD4 + subsets than those without. The relative abundances of Prevotella and Veillonella species were lower in patients with severe pneumonia. The abundance of Veillonella was higher in patients who experienced wheezing during pneumonia and in those with subsequent recurrent wheezing than in those without wheezing. The relative abundance and total counts of Bifidobacterium, Lactobacillus, and Neisseria were higher in patients who did not experience subsequent recurrent wheezing. CONCLUSIONS: Diversity of the respiratory microbiota was inversely associated with pneumonia severity, and the percentage of iNKT cells was associated with wheezing during pneumonia. Several species may be associated with subsequent respiratory morbidities and warrant further investigation. WHAT IS KNOWN: • Early life airway microbiota symbiosis affects the severity of respiratory infection and the risk for the development of asthma. • Changes in airway microbiota among infants with pneumonia and their impact on subsequent respiratory health are largely unknown. WHAT IS NEW: • The diversity of the airway microbiome was inversely associated with the severity of pneumonia and length of hospitalization. • The abundance of Veillonella was higher in patients who experienced wheezing during pneumonia and in those with subsequent recurrent wheezing.

Cadmium exposure impairs skeletal muscle function by altering lipid signature and inducing inflammation in C57BL/6J mice.

Cadmium (Cd) is a well-known environmental pollutant with high toxicity. Despite a variety of studies have demonstrated that Cd exposure induces multiple organ damages in humans, there is still a lack of knowledge of Cd induced skeletal muscle impairment. Exercise is a non-invasive, effective intervention to improve human health and combat diseases. In this study, we aimed to evaluate the toxic effects of Cd exposure on skeletal muscle function and explore the possibility of exercise for attenuating skeletal muscle toxicity of chronic Cd exposure. C57BL/6J mice were exposed to Cd via drinking water containing CdCl2 10 mg/dL for 8 weeks while a moderate exercise was daily induced by a motorized treadmill to mice. It was found that Cd exposure significantly reduced the ratio of gastrocnemius and body weight, decreased mouse exercise capacity, weakened muscle strength, promoted lipid accumulation and up-regulated pro-apoptotic genes in the skeletal muscle. Non-targeted lipidomics analysis indicated that Cd exposure disturbed lipid metabolism, altered lipid signatures and elevated pro-inflammatory lipid species in the skeletal muscle. Moreover, Cd exposure evoked an intense inflammatory response in the skeletal muscle by up-regulating pro-inflammatory cytokine production such as Eotaxin (CCL11), TNF-α, IL-1ß, IL-6, RANTES (CCL5) and so on. Notably, treadmill exercise effectively protected against Cd induced skeletal muscle impairment indicated by the effects of inhibiting lipid metabolism disturbance, suppressing pro-inflammatory cytokine production and preserving skeletal muscle function. These results demonstrated that environment relevant Cd exposure impairs skeletal muscle function and exercise effectively antagonizes the Cd toxicity in the skeletal muscle and preserves skeletal muscle function. This study provided the novel evidence for unraveling Cd toxicity on the skeletal muscle function and highlighted the possibility of considering exercise as a countermeasure for Cd induced skeletal muscle impairment at population level.

Heterogeneity and Memory Effect in the Sluggish Dynamics of Vacancy Defects in Colloidal Disordered Crystals and Their Implications to High-Entropy Alloys.

Vacancy dynamics of high-density 2D colloidal crystals with a polydispersity in particle size are studied experimentally. Heterogeneity in vacancy dynamics is observed. Inert vacancies that hardly hop to other lattice sites and active vacancies that hop frequently between different lattice sites are found within the same samples. The vacancies show high probabilities of first hopping from one lattice site to another neighboring lattice site, then staying at the new site for some time, and later hopping back to the original site in the next hop. This back-returning hop probability increases monotonically with the increase in packing fraction, up to 83%. This memory effect makes the active vacancies diffuse sluggishly or even get trapped in local regions. Strain-induced vacancy motion on a distorted lattice is also observed. New glassy properties in the disordered crystals are discovered, including the dynamical heterogeneity, the presence of cooperative rearranging regions, memory effect, etc. Similarities between the colloidal disordered crystals and the high-entropy alloys (HEAs) are also discussed. Molecular dynamics simulations further support the experimental observations. These results help to understand the microscopic origin of the sluggish dynamics in materials with ordered structures but in random energy landscapes, such as high-entropy alloys.

Paraquat exposure induces Parkinsonism by altering lipid profile and evoking neuroinflammation in the midbrain.

Paraquat (PQ) is the most widely used herbicide in the world and a well-known potent neurotoxin for humans. PQ exposure has been linked to increase the risk of Parkinson's disease (PD). However, the mechanism underlying its neurotoxic effects in PD pathogenesis is unclear. In our present study, C57BL/6J mice treated with PQ manifested severe motor deficits indicated by the significant reductions in suspension score, latency to fall from rotarod, and grip strength at 8 weeks after PQ exposure. Pathological hallmarks of Parkinsonism in the midbrain such as dopaminergic neuron loss, increased α-synuclein protein, and dysregulated PD-related genes were observed. Non-targeted lipidome analysis demonstrated that PQ exposure alters lipid profile and abundance, increases pro-inflammatory lipids.27 significantly altered subclasses of lipids belonged to 6 different lipid categories. Glycerophospholipids, sphingolipids, and glycerides were the most abundant lipids. Abundance of pro-inflammatory lipids such as Cer, LPC, LPS, and LPI was significantly increased in the midbrain. mRNA expressions of genes regulating ceramide biosynthesis in the midbrain were markedly up-regulated. Moreover, PQ exposure increased serum pro-inflammatory cytokines and provoked neuroinflammation in the midbrain. Pro-inflammatory lipids and cytokines in the midbrain were positively correlated with motor deficits. PQ poisoning in humans significantly also elevated serum pro-inflammatory cytokines and induced an intense systemic inflammation. In summary, we presented initial investigations of PQ induced molecular events related to the PD pathogenesis, capturing aspects of disturbed lipid metabolism, neuroinflammation, impairment of dopaminergic neurons in the midbrain, and an intense systemic inflammation. These neurotoxic effects of PQ exposure may mechanistically contribute to the pathogenesis of PQ induced Parkinsonism. Results of this study also strongly support the hypothesis that ever-increasing prevalence of Parkinson's disease is etiologically linked to the health risk of exposure to neurotoxic environmental pollutants.

Cadmium induces ferroptosis mediated inflammation by activating Gpx4/Ager/p65 axis in pancreatic ß-cells.

Cadmium (Cd) is a widely distributed endocrine disruptor and has been reported to be closely correlated to the pathogenesis of diabetes. Since pancreatic ß-cells loss and dysfunction are central to pathogenesis of diabetes, studying Cd toxicity on pancreatic ß-cells and its molecular mechanism is an important scientific issue. However, less attention has been payed to study how Cd induces pancreatic ß-cells death and dysfunction in recent years. Thus, our study aims to explore the toxic mechanism of Cd treatment on pancreatic ß-cells using both cellular and animal models. Firstly, it was confirmed that Cd induced decreased cell viability and insulin secretion in a dose-and time-dependent manner in MIN6 cells. To explore the underlying mechanism, transcriptomic analysis was employed to screen the differentially expressed genes and disturbed metabolic pathways. Go and KEGG analysis showed that Cd exposure triggered ferroptosis process in MIN6 cells. We further validated that Cd led to GSH depletion, Gpx4 reduction, lipid peroxidation, mitochondrial membrane potential loss and ultrastructural damage at mitochondrial level. Since immune system process was also perturbed based on GO analysis, we found that Cd activated Ager/Pkc/p65 inflammatory process. Moreover, ferroptosis inhibitor Fer-1 could effectively antagonized the activation of Ager-mediated immune process. It was also revealed that Cd induced iron accumulation as well as decreased Gpx4 expression in mice islets. We also uncovered that Cd led to systemic and pancreatic inflammation as early as third week after Cd exposure. Our study emphasizes the importance of ferroptotic cell death on Cd-induced systemic chronic inflammation. A novel target is provided to prevent Cd-induced pancreatic ß-cells dysfunction and improve the chronic inflammatory state for prediabetes prevention.

Cadmium perturbed metabolomic signature in pancreatic beta cells correlates with disturbed metabolite profile in human urine.

Cd exposure has been demonstrated to induce a variety of metabolic disorders accompanied with imbalance of glucose and lipid homeostasis. The metabolic toxicity of Cd exposure at metabolome-wide level remains elusive. In our study, we demonstrated that Cd exposure via drinking water increased blood glucose levels, decreased serum insulin levels, led to glucose intolerance and suppressed insulin expression in the pancreas of C57/6J mice. Cd exposure significantly inhibited cell viability and suppressed insulin secretion in MIN6 cells in vitro. Since pancreatic ß-cells are the only source of insulin production in the body and play a pivotal role in modulating glucose and lipid metabolisms, we further delineated the metabolomic signatures of Cd exposure in insulin-secreting MIN6 cells by using non-target metabolomics. PCA and OPLS-DA analysis clearly suggested that Cd exposure led to a marked metabolic alteration in MIN6 cells. 76 perturbed metabolites were identified after Cd exposure. Classification of metabolites suggested that Cd perturbed metabolites belong to nucleosides, nucleotides and analogues, organic acids and derivatives, and lipids and lipid-like molecules. 28 perturbed metabolites existed in mitochondrion, suggesting mitochondrion as the major target organelle in metabolic toxicity of Cd exposure. KEGG pathway analysis revealed that 20 metabolic pathways were disturbed by Cd exposure. Mitochondrial TCA cycle and glycerophospholipid metabolism were remarkably disturbed. The mRNA expressions of genes in mitochondrial TCA cycle and fatty acid oxidation in pancreas and MIN6 cells were significantly dysregulated by Cd exposure. Disturbances in mitochondrial TCA cycle and glycerophospholipid metabolism result in producing perturbed metabolites in pancreatic ß-cells. Moreover, 14 perturbed metabolites identified in MIN6 cells co-existed in the urine of Cd exposed workers. 11 biomarkers of diabetes mellitus were also found to be significantly altered in the urine of Cd exposed workers. In conclusion, findings of this study greatly extend our understanding of metabolic toxicity of Cd exposure in pancreatic ß-cells at metabolome-wide level and offer some new clues for linking Cd exposure to development of diabetes mellitus. Results of this study also support the notion that Cd induced metabolic toxicity could be monitored by examining perturbed urinary metabolites in humans and highlight the significance of reducing Cd exposure via drinking water at population level.

Cadmium exposure suppresses insulin secretion through mtROS-mediated mitochondrial dysfunction and inflammatory response in pancreatic beta cells.

BACKGROUND: Cadmium (Cd) exposure is a worldwide environmental threat to the public health and participates in the pathogenesis of multiple diseases. Epidemiologic research have established a direct relation between Cd exposure and diabetes development in humans. Although pancreatic ß-cell dysfunction has been considered as the major culprit in the pathogenesis of diabetes, there is a paucity of studies to elucidate the molecular mechanism of Cd toxicity on ß-cells. METHODS: To unveil the toxic effect and its underlying mechanism of Cd exposure on ß-cells, we used an in vitro MIN6 cell model of environment-relevant Cd exposure to elucidate the crucial role of mtROS-mediated mitochondrial dysfunction and inflammatory response in suppression of pancreatic ß-cell insulin secretion. RESULTS: We uncovered that Cd treatment suppresses cell viability and induces insulin secretion dysfunction in a dose-dependent manner. Moreover, Cd exposure elicits the inflammatory response, as indicated by increased IL-1ß, IL-6 and TNF-α expressions. Significant elevations of intracellular ROS and mitochondrial ROS levels were detected as early as 3 h after Cd treatment. In mitochondrial function analysis, we demonstrated that Cd treatment induced mitochondrial dysfunction and disorder of mitochondrial fission indicated by the significant decline in ATP production, the marked depolarization of mitochondrial membrane potential, the decrease in mtDNA copy numbers, the suppressions of mitochondrial transcription factor A (Tfam) and mitochondrial fission-related gene Drp1 expressions. Pretreatment with TEMPO, a specific mitochondrial ROS (mtROS) scavenger, efficiently antagonizes Cd cytotoxicity, which is indicated by attenuating Cd-induced mitochondrial dysfunction, suppressing IL-1ß, IL-6 and TNF-α expressions, ameliorating insulin production dysfunction and preserving cell viability in MIN6 cells. CONCLUSION: Our study demonstrates that Cd exposure induces an inflammatory response through mtROS-mediated mitochondrial dysfunction. Antagonism of mtROS production might be an effective strategy to prevent pancreatic toxicity from environment-relevant Cd exposure.

Cadmium exposure impairs pancreatic ß-cell function and exaggerates diabetes by disrupting lipid metabolism.

Cadmium is known as an environmental pollutant that contributes to pancreatic damage and the pathogenesis of diabetes. However, less attention has been devoted to elucidating the mechanisms underlying Cd-induced pancreatic ß-cell dysfunction and the role of Cd toxicity in the development of diabetes. In this study, we demonstrated that exposure to Cd caused remarkable pancreatic ß-cell dysfunction and death, both in vitro and in vivo. Lipidomic analysis of Cd-exposed pancreatic ß-cells using high-resolution mass spectrometry revealed that Cd exposure altered the profile and abundance of lipids. Cd exposure induced intracellular lipid accumulation, promoted lipid biogenesis, elevated pro-inflammatory lipid contents and inhibited lipid degradation. Furthermore, Cd exposure upregulated the expression levels of TNF-α, IL-1ß and IL-6 in pancreatic ß-cells and elevated the TNF-α, IL1-ß and IL-6 levels in the serum and pancreas. Taken together, the results of our study demonstrated that environmental relevant Cd exposure causes pro-inflammatory lipids elevation and insulin secretion dysfunction in ß-cells and hence exaggerates diabetes development. Combined exposure to environmental hazardous chemicals might markedly increase the probability of developing diabetes in humans. This study provides new metabolic and pharmacological targets for antagonizing Cd toxicity.

Inhibition of SERPINA3N-dependent neuroinflammation is essential for melatonin to ameliorate trimethyltin chloride-induced neurotoxicity.

Trimethyltin chloride (TMT) is a potent neurotoxin that causes neuroinflammation and neuronal cell death. Melatonin is a well-known anti-inflammatory agent with significant neuroprotective activity. Male C57BL/6J mice were intraperitoneally injected with a single dose of melatonin (10 mg/kg) before exposure to TMT (2.8 mg/kg, ip). Thereafter, the mice received melatonin (10 mg/kg, ip) once a day for another three consecutive days. Melatonin dramatically alleviated TMT-induced neurotoxicity in mice by attenuating hippocampal neuron loss, inhibiting epilepsy-like seizures, and ameliorating memory deficits. Moreover, melatonin markedly suppressed TMT-induced neuroinflammatory responses and astrocyte activation, as shown by a decrease in inflammatory cytokine production as well as the downregulation of neurotoxic reactive astrocyte phenotype markers. Mechanistically, serine peptidase inhibitor clade A member 3N (SERPINA3N) was identified as playing a central role in the protective effects of melatonin based on quantitative proteome and bioinformatics analysis. Most importantly, melatonin significantly suppressed TMT-induced SERPINA3N upregulation at both the mRNA and protein levels. The overexpression of Serpina3n in the mouse hippocampus abolished the protective effects of melatonin on TMT-induced neuroinflammation and neurotoxicity. Melatonin protected cells against TMT-induced neurotoxicity by inhibiting SERPINA3N-mediated neuroinflammation. Melatonin may be a promising and practical agent for reducing TMT-induced neurotoxicity in clinical practice.

Association between X-ray repair cross-complementing group 1(XRCC1) Arg399Gln polymorphism and endometriosis: A systematic review and meta-analysis.

OBJECTIVE(S): X-ray repair cross-complementing group 1(XRCC1) gene is one of the DNA repair pathway genes playing a vital role in endometriosis risk. Various studies have explored the association between them, however, the results remained inconsistent. So to confirm the association between XRCC1 Arg399Gln polymorphism and the risk of endometriosis, a meta-analysis was conducted. STUDY DESIGN: PubMed, Web of Science, Science Director, Cochrane Library, Google Scholar, China National Knowledge Infrastructure (CNKI) and Wanfang Data databases were searched to identify the all relevant studies before Sep. 30, 2016 focusing on the association between XRCC1 Arg399Gln polymorphism and the risk of endometriosis. Summary odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated and analyzed by Review Manager 5.2 and Stata 12 to assess the strength of the association. Meanwhile, Begg's test was used to check the publication bias. RESULTS: The present meta-analysis identified 6 studies with 646 cases and 616 controls. The overall analysis revealed that the AA genotype exhibited a significant association with a decreased risk for endometriosis compared with GG (OR=0.43, 95%CI=0.20-0.94, P=0.03), GA (OR=0.57, 95%CI=0.35-0.95, P=0.03) and GG+GA (OR=0.54, 95%CI=0.31-0.96, P=0.04) respectively. In addition, subgroup analyses based on varied regions indicated that a total comparisons of allelic and various genetic models had statistical significances among Asians (A allele vs. G allele: OR=0.62, 95%CI=0.48-0.81, P=0.0004; AA vs. GG: OR=0.22, 95%CI=0.11-0.46, P<0.0001; AA vs. GA: OR=0.32, 95%CI=0.16-0.63, P=0.001; AA vs. GG+GA: OR=0.28, 95%CI=0.14-0.54, P=0.0002; AA+GA vs. GG: OR=0.28, 95%CI=0.14-0.54, P=0.008) but not among Middle Eastern. The Begg's test did not reveal any obvious publication bias in the present study. CONCLUSION(S): Our meta-analysis suggested that Arg399Gln in XRCC1 was associated with endometriosis risk. And especially in Asians, the A allele might be a preventive factor for this disease. Further well-designed researches with larger sample size and various regions are required to validate our conclusion.

Associations of C677T polymorphism in methylenetetrahydrofolate reductase (MTHFR) gene with male infertility risk: A meta-analysis.

PURPOSE: Methylenetetrahydrofolate reductase is one of the key enzymes in folate metabolism. But the association between polymorphism and the risk of male infertility is still controversial. Therefore, this study used a meta-analysis on the collection of data to analyze MTHFR gene C677T polymorphism (known as c.665 C>T, rs1801133, p.Ala222Val). METHODS: PubMed, EMBASE, China National Knowledge Infrastructure (CNKI), and Wan fang. Data were searched to identify eligible studies. We sifted the data collection by Hardy-Weinberg equilibrium calculator and used odds ratios (ORs) and 95% confidence intervals (95% CIs) to conduct data through RevMan5.0 and StataSE12.0 software. RESULTS: A total of 15 studies have 3853 patients with infertility and 3613 healthy controls in this meta-analysis. Our results showed that T variant of MTHFR C677T gene polymorphism was significantly associated with an increased risk of male infertility (forT vs. C: OR=1.38, 95% CI=1.18-1.63; for TT vs. CC: OR=1.86, 95% CI=1.36-2.54; for CT vs. CC: OR=1.34, 95% CI=1.03-1.74; for TT vs. CT: OR=1.52, 95% CI=1.26-1.84; for TT vs. CT+CC: OR=1.42, 95% CI=1.19-1.70; for TT+CT versus CC: OR=1.46, 95%CI=1.05-2.04). In addition, the results indicated that T allele had the positive association which was driven by East-asian populations (random: OR=1.44, 95% CI=1.2-1.74; fixed: OR=1.39, 95% CI=1.20-1.61), Middle-eastern populations (random: OR=1.30, 95% CI=1.05-1.63; fixed: OR=1.30, 95% CI=1.05-1.63) and Mixed-race (random: OR=1.96, 95% CI=1.35-2.85; fixed: OR=1.31, 95% CI=1.20-1.43). CONCLUSION: This meta-analysis suggests that MTHFR C677T polymorphism is associated with male infertility.