Cystic fibrosis transmembrane conductance regulator (CFTR) is an anion channel, mutations of which cause cystic fibrosis, a disease characterized by defective Cl ؊ and HCO3 ؊ transport. Although >95% of all CF male patients are infertile because of congenital bilateral absence of the vas deferens (CBAVD), the question whether CFTR mutations are involved in other forms of male infertility is under intense debates. Here we report that CFTR is detected in both human and mouse sperm. CFTR inhibitor or antibody significantly reduces the sperm capacitation, and the associated HCO 3 ؊ -dependent events, including increases in intracellular pH, cAMP production and membrane hyperpolarization. The fertilizing capacity of the sperm obtained from heterozygous CFTR mutant mice is also significantly lower compared with that of the wild-type. These results suggest that CFTR in sperm may be involved in the transport of HCO 3 ؊ important for sperm capacitation and that CFTR mutations with impaired CFTR function may lead to reduced sperm fertilizing capacity and male infertility other than CBAVD.

Oxidative stress (OS) has received extensive attention in the last two decades, because of the discovery that abnormal oxidation status was related to patients with chronic diseases, such as diabetes, cardiovascular, polycystic ovary syndrome (PCOS), cancer, and neurological diseases. OS is considered as a potential inducing factor in the pathogenesis of PCOS, which is one of the most common complex endocrine disorders and a leading cause of female infertility, affecting 4%–12% of women in the world, as OS has close interactions with PCOS characteristics, just as insulin resistance (IR), hyperandrogenemia, and chronic inflammation. It has also been shown that DNA mutations and alterations induced by OS are involved in cancer pathogenesis, tumor cell survival, proliferation, invasion, angiogenesis, and so on. Furthermore, recent studies show that the females with PCOS are reported to have an increasing risk of cancers. As a result, the more serious OS in PCOS is regarded as an important potential incentive for the increasing risk of cancers, and this study aims to analyze the possibility and potential pathogenic mechanism of the above process, providing insightful thoughts and evidences for preventing cancer potentially caused by PCOS in clinic.

CFTR is a key regulator of male fertility, a defect of which may result in different forms of male infertility other than CBAVD. It would be worthwhile to further investigate the potential of developing novel diagnostic and contraceptive methods targeting CFTR.

The cystic fibrosis transmembrane conductance regulator (CFTR) is an anion channel regulated by cAMP-dependent phosphorylation, which is expressed in epithelial cells of a wide variety of tissues including the reproductive tracts. Mutations in the gene encoding CFTR cause cystic fibrosis, a common genetic disease in Caucasian populations with a multitude of clinical manifestations including infertility/subfertility in both sexes. However, the physiological role of CFTR in reproduction and its involvement in the pathogenesis of reproductive diseases remain largely unknown. This review discusses the role of CFTR in regulating fluid volume and bicarbonate secretion in the reproductive tracts and their importance in various reproductive events. We also discuss the contribution of CFTR dysfunction to a number of pathological conditions. The evidence presented is consistent with an important role of CFTR in reproductive health and disease, suggesting that CFTR might be a potential target for the diagnosis and treatment of reproductive diseases including infertility.

Proper physiological function of the ovaries is very important for the entire female reproductive system and overall health. Reactive oxygen species (ROS) are generated as by-products during ovarian physiological metabolism, and antioxidants are indicated as factors that can maintain the balance between ROS production and clearance. A disturbance in this balance can induce pathological consequences in oocyte maturation, ovulation, fertilization, implantation, and embryo development, which can ultimately influence pregnancy outcomes. However, our understanding of the molecular and cellular mechanisms underlying these physiological and pathological processes is lacking. This article presents up-to-date findings regarding the effects of antioxidants on the ovaries. An abundance of evidence has confirmed the various significant roles of these antioxidants in the ovaries. Some animal models are discussed in this review to demonstrate the harmful consequences that result from mutation or depletion of antioxidant genes or genes related to antioxidant synthesis. Disruption of antioxidant systems may lead to pathological consequences in women. Antioxidant supplementation is indicated as a possible strategy for treating reproductive disease and infertility by controlling oxidative stress (OS). To confirm this, further investigations are required and more antioxidant therapy in humans has to been performed. BackgroundReactive oxygen species (ROS) are formed during normal metabolism of oxygen and are produced as by-products of aerobic metabolism. A certain amount of ROS production is necessary for gene expression [1], cell signalling [2,3], and redox homeostasis. Scavenging antioxidant systems are indispensable for maintaining an adequate amount of ROS. The balance between the generation and elimination of ROS is a key factor required for almost every metabolic function in mammals. Maintenance of this balance is an important constitutive process and has a particular influence on cell proliferation, differentiation, apoptosis, and death [4]. When ROS production overwhelms the scavenging ability of antioxidants, oxidative stress (OS) occurs. Unfortunately, disruption of this balance can easily result from either an increase in the concentration of ROS or a decrease in scavenging ability. Excessive ROS levels are harmful to the human body and can result in accumulation of oxidative damage in distinct subcellular compartments that exert very toxic effects on DNA, proteins, and lipids. ROS-mediated damage can ultimately influence physiological functions, such as cell signalling pathways and redox-sensitive signalling pathways, and lead to pathological conditions [5].Regarding the female reproductive system, ROS and antioxidants have been recognized as key factors involved in ovarian physiological metabolism. Many studies have investigated the presence of antioxidants and their transcripts in the female reproductive tract [6][7][8]. Previous studies have reported that the balance between ROS and antioxidants greatly influences th...

Our previous study demonstrated the involvement of cystic fibrosis transmembrane conductance regulator (CFTR) in transporting bicarbonate that is necessary for sperm capacitation; however, whether its involvement is direct or indirect remains unclear. The present study investigated the possibility of a Cl-/HCO3- exchanger (solute carrier family 26, number 3 [SLC26A3]) operating with CFTR during guinea pig sperm capacitation. Incubating sperm in media with various concentrations of Cl- resulted in varied percentages of capacitated sperm in a concentration-dependent manner. Depletion of Cl-, even in the presence of HCO3-, abolished sperm capacitation and vice versa, indicating the involvement of both anions in the process. Capacitation-associated HCO3--dependent events, including increased intracellular pH, cAMP production, and protein tyrosine phosphorylation, also depend on Cl- concentrations. Similar Cl- dependence and inhibitor sensitivity were observed for sperm-hyperactivated motility and for sperm-egg fusion. The expression and localization of CFTR and SLC26A3 were demonstrated using immunostaining and Western blot analysis. Taken together, our results indicate that Cl- is required for the entry of HCO3- that is necessary for sperm capacitation, implicating the involvement of SLC26A3 in transporting HCO3-, with CFTR providing the recycling pathway for Cl-.

Gestational diabetes mellitus (GDM), a high-risk pregnancy complication of great effect on the perinatal health of women and newborns, may cause changes of gut microbiota in mothers and further affect gut microbiota in newborns. This study aimed to investigate the potential effect of mother GDM on newborns’ gut microbiota. Meconium DNA was extracted from a total of 34 full-term and C-sectioned newborns, in which 20 newborns had mothers diagnosed with GDM, while 14 had unaffected mothers. Sequencing and bioinformatics analysis of 16S rRNA indicated that the gut microbiota of GDM newborns showed differences compared to control newborns. The taxonomy analyses suggested that the overall bacterial content significantly differed by maternal diabetes status, with the microbiome of the GDM group showing lower alpha-diversity than that of control group. The phyla of Proteobacteria and Actinobacteria in GDM newborns increased, while that of Bacteroidetes significantly reduced (P<0.05). Moreover, several unique gut microbiota in phylum of Proteobacteria, Firmicutes, Actinobacteria, Bacteroidetes, Chloroflexi, Acidobacteria, and Planctomycetes found in control newborns were absent in GDM ones. At genus level, the relative abundance of Prevotella and Lactobacillus significantly decreased (P<0.05) in GDM newborns. Correlation analysis indicated that maternal fasting glucose levels were positively correlated with the relative abundance of phylum Actinobacteria and genus Acinetobacter, while negatively correlated with that of phylum Bacteroidetes and genus Prevotella. However, bacteria in GDM grade A2 (GDM_A2) newborns did not show any statistical variation compared to those from control newborns, which might be attributed to the additional intervention by insulin. The results of this study have important implications for understanding the potential effects of GDM on the gut microbiota of newborns and thus possibly their metabolism at later stages in their lives.

Recent studies have suggested that the etiology of autism spectrum disorder (ASD) may be caused by immunological factors, particularly abnormalities in the innate immune system. However, it is still unclear which specific cytokines may be of most importance. The current study therefore investigated which cytokines showed altered concentrations in blood in ASD compared with healthy control children and which were also correlated with symptom severity. Our study sample included 32 children diagnosed with ASD and 28 age and sex-matched typically developing children. Autism symptoms were measured using the Autistic Behavior Checklist (ABC) and blood samples were taken from all subjects. We used Milliplex cytokine kits to determine serum concentrations of 11 Th1, Th2 and Th17 related cytokines. Additionally, expression of THRIL (TNFα and hnRNPL related immunoregulatory LincRNA), a long non-coding RNA involved in the regulation of tumor necrosis factor- α (TNF-α), was determined using real–time PCR. Of the 11 cytokines measured only concentrations of TNF-α (p=0.002), IL-1β (p=0.02) and IL-17a (p=0.049) were significantly increased in ASD children compared to typically developing controls, but only TNF-α concentrations were positively correlated with severity of ASD symptoms on all 5 different ABC sub-scales and were predictive of an ASD phenotype (area under the curve = 0.74). Furthermore, THRIL RNA expression was significantly decreased in ASD children. Our results provide further support for altered innate immunity being an important autism pathogenic factor, with autistic children showing increased blood TNF-α concentrations associated with symptom severity, and decreased expression of the THRIL gene involved in regulating TNF-α.