Exposure to PbSe Nanoparticles and Male Reproductive Damage in a Rat Model.
Zhou Qixing,Yue Zongkai,Li Qingzhao,Zhou Ruiren,Liu Lu
Environmental science & technology
PbSe nanoparticles (PbSe-NPs) attract ever-growing interest owing to their great promise in various fields. However, potential toxic effects of PbSe-NPs on male reproductive systems have not been reported. This study aimed to determine whether early-life exposure to PbSe-NPs could affect male reproductive systems and other related health effects in rats. The male rats were intraperitoneally injected with 10 mg/kg/week PbSe-NPs for 60 days followed by a series of reproductive-related analyses. We found that the nanoparticles could accumulate in testes in a size-dependent manner. Furthermore, accumulation of PbSe-NPs resulted in oxidative stress and disorder of normal serum sex hormones. Endoplasmic reticulum and mitochondria-mediated cell apoptosis were triggered via oxidative stress, as shown by upregulation of cytoplasmic Cyt-c, Bax, cleaved Caspase-3, GRP78, and Caspase-12. Notably, PbSe-NP administration led to reduction in the quantity and quality of sperm, which caused a great fertility decrease. In contrast, released Pb from PbSe-NPs did not result in any testis toxicity and fertility declines. These results demonstrate that PbSe-NPs could cause severe reproductive toxicity in a size-dependent manner and these toxic effects should be responsible for PbSe-NPs themselves rather than released Pb. The application of PbSe-NPs might be a double-edged sword, and corresponding measures should be taken before use.
10.1021/acs.est.9b03581
The Role of Oxidative Stress, Selected Metals, and Parameters of the Immune System in Male Fertility.
Dobrakowski Michał,Kaletka Zbigniew,Machoń-Grecka Anna,Kasperczyk Sławomir,Horak Stanisław,Birkner Ewa,Zalejska-Fiolka Jolanta,Kasperczyk Aleksandra
Oxidative medicine and cellular longevity
The aim of the study was to investigate the associations between standard semen parameters and the parameters reflecting oxidative stress intensity, antioxidant defense functions, levels of selected macro and trace elements, and parameters characterizing immune system function. The study group consisted of 103 fertile males. Based on semen volume, sperm concentration, total sperm count, and percentage of motile sperm at 1 hour postcollection, the individuals were divided into two equal groups-those with excellent (EX) semen quality and those with mediocre (ME) semen quality. The remaining measured parameters characterizing motility and the percentage of normal morphology were higher in the EX group than in the ME group; however, the seminal plasma pH did not differ between the examined groups. The phosphate level was 31% lower in the EX group than in the ME group, whereas there was a tendency toward a 25% lower level of Fe in the EX group than in the ME group ( = 0.064). The activities of enzymes involved in antioxidant defense, CuZn-SOD, CAT, and G6PD, were 14%, 63%, and 39%, respectively, higher in the EX group than in the ME group. However, the level of alpha-tocopherol was 32% lower in the EX group than in the ME group. The other measured parameters characterizing antioxidant defense and the parameters of oxidative stress intensity and immune system function were not significantly different. The value of seminal plasma pH is not related to the semen quality of fertile males. Higher fertility potential estimated based on standard semen parameters in fertile males is associated with lower levels of Fe and higher activities of some antioxidant enzymes.
10.1155/2018/6249536
Role of Oxidative Stress and Antioxidant Supplementation in Male Fertility.
Beygi Zahra,Forouhari Sedighe,Mahmoudi Elahe,Hayat Seyed M G,Nourimand Firoozeh
Current molecular medicine
Nearly 15% of couples experience infertility as a universal health issue. About 50% of infertility cases have been known to be associated with the male partner . Oxidative stress (OS) represents an imbalance in the level of reactive oxygen species (ROS) and anti-oxidants. In fact, OS has been considered as one of the popular pathologies reported in about 50% of all infertile males. Therefore, the increased level of ROS may result in infertility via DNA damages or lipid peroxidation (LPO) as well as the inactivation of enzymes and oxidation of protiens in spermatozoa. Basically, OS results from lifestyle variables. As the absence of antioxidants and the respective deficiencies in the semen cause OS, variations in the lifestyle and anti-oxidant regimes may be advantageous to treatment strategies for resolving such an issue. Actually, anti-oxidants like vitamins E and C, glutathione, coenzyme-Q10, carnitines, selenium, Nacetylcysteine, carotenoids, zinc, and pentoxifylline decline the OS-induced sperm damages. Therefore, the present review overviews the oxidative biochemistry associated with sperm health and identifies which men would be most at risk of oxidative infertility. Hence, the review would show the techniques provided to diagnose OS and diverse therapeutic options.
10.2174/1566524020999200831123553
Increased risk of metabolic dysfunction in children conceived by assisted reproductive technology.
Cui Linlin,Zhou Wei,Xi Bo,Ma Jinlong,Hu Jingmei,Fang Mei,Hu Kuona,Qin Yingying,You Li,Cao Yongzhi,Yang Lili,Yang Liu,Ma Chuanwei,Shui Wang,Wang Mingming,Zhao Min,Zhang Jun,Chen Zi-Jiang
Diabetologia
AIMS/HYPOTHESIS:Assisted reproductive technology (ART) is the most widely used treatment for infertility and has resulted in millions of births worldwide. The safety of the offspring has been of the utmost concern. Previous studies suggested an increase in metabolic disorders in offspring later in life. The aim of the present study was to investigate metabolic changes at age 6-10 years in offspring conceived as a result of in vitro fertilisation/intracytoplasmic sperm injection (IVF/ICSI). METHODS:A total of 380 children born from IVF/ICSI and a matched control group of 380 naturally conceived children, all aged 6-10 years, were recruited. Anthropometric measures, ultrasound and serum tests were performed for body mass, glucose metabolism and lipid profiles, and examination of vasculature structure. RESULTS:The children conceived by ART showed significantly higher fasting blood glucose and serum insulin levels and HOMA-IR (adjusted β [95% CI]: fasting blood glucose 0.49 [0.42, 0.55]; log-transformed insulin 0.28 [0.20, 0.35]; log-transformed HOMA-IR 0.38 [0.30, 0.46]), as well as a lower HOMA-B and serum apolipoprotein A (ApoA) levels (adjusted β [95% CI]: log-transformed HOMA-B -0.19 [-0.27, -0.11]; ApoA -0.17 [-0.21, -0.13]), when compared with the control group. Furthermore, the ultrasound scan indicated elevated carotid intima-media thickness in children conceived by ART (β 0.13 [95% CI 0.12, 0.13]). CONCLUSIONS/INTERPRETATION:Children conceived by IVF/ICSI have a less favourable glucose and cardiovascular metabolic profile in childhood when compared with naturally conceived children. The underlying mechanisms and potential long-term consequences need to be elucidated in future studies. Graphical abstract.
10.1007/s00125-020-05241-1
PHB regulates meiotic recombination via JAK2-mediated histone modifications in spermatogenesis.
Zhang Ling-Fei,Tan-Tai Wen-Jing,Li Xiao-Hui,Liu Mo-Fang,Shi Hui-Juan,Martin-DeLeon Patricia A,O Wai-Sum,Chen Hong
Nucleic acids research
Previously, we have shown that human sperm Prohibitin (PHB) expression is significantly negatively correlated with mitochondrial ROS levels but positively correlated with mitochondrial membrane potential and motility. However, the possible role of PHB in mammalian spermatogenesis has not been investigated. Here we document the presence of PHB in spermatocytes and its functional roles in meiosis by generating the first male germ cell-specific Phb-cKO mouse. Loss of PHB in spermatocytes resulted in complete male infertility, associated with not only meiotic pachytene arrest with accompanying apoptosis, but also apoptosis resulting from mitochondrial morphology and function impairment. Our mechanistic studies show that PHB in spermatocytes regulates the expression of STAG3, a key component of the meiotic cohesin complex, via a non-canonical JAK/STAT pathway, and consequently promotes meiotic DSB repair and homologous recombination. Furthermore, the PHB/JAK2 axis was found as a novel mechanism in the maintenance of stabilization of meiotic STAG3 cohesin complex and the modulation of heterochromatin formation in spermatocytes during meiosis. The observed JAK2-mediated epigenetic changes in histone modifications, reflected in a reduction of histone 3 tyrosine 41 phosphorylation (H3Y41ph) and a retention of H3K9me3 at the Stag3 locus, could be responsible for Stag3 dysregulation in spermatocytes with the loss of PHB.
10.1093/nar/gkaa203
A noncanonical role of NOD-like receptor NLRP14 in PGCLC differentiation and spermatogenesis.
Yin Yike,Cao Shiyu,Fu Huancheng,Fan Xueying,Xiong Jingfei,Huang Qiuyue,Liu Yu,Xie Kun,Meng Tie-Gang,Liu Yuliang,Tang Dan,Yang Tingting,Dong Biao,Qi Shiqian,Nie Ling,Zhang Huiyuan,Hu Hongbo,Xu Wenming,Li Fuping,Dai Lunzhi,Sun Qing-Yuan,Li Zhonghan
Proceedings of the National Academy of Sciences of the United States of America
NOD-like receptors (NLRs) are traditionally recognized as major inflammasome components. The role of NLRs in germ cell differentiation and reproduction is not known. Here, we identified the gonad-specific Nlrp14 as a pivotal regulator in primordial germ cell-like cell (PGCLC) differentiation in vitro. Physiologically, knock out of Nlrp14 resulted in reproductive failure in both female and male mice. In adult male mice, Nlrp14 knockout (KO) inhibited differentiation of spermatogonial stem cells (SSCs) and meiosis, resulting in trapped SSCs in early stages, severe oligozoospermia, and sperm abnormality. Mechanistically, NLRP14 promoted spermatogenesis by recruiting a chaperone cofactor, BAG2, to bind with HSPA2 and form the NLRP14-HSPA2-BAG2 complex, which strongly inhibited ChIP-mediated HSPA2 polyubiquitination and promoted its nuclear translocation. Finally, loss of HSPA2 protection and BAG2 recruitment by NLRP14 was confirmed in a human nonsense germline variant associated with male sterility. Together, our data highlight a unique proteasome-mediated, noncanonical function of NLRP14 in PGCLC differentiation and spermatogenesis, providing mechanistic insights of gonad-specific NLRs in mammalian germline development.
10.1073/pnas.2005533117
Function and therapeutic potential of G protein-coupled receptors in epididymis.
Zhang Daolai,Wang Yanfei,Lin Hui,Sun Yujing,Wang Mingwei,Jia Yingli,Yu Xiao,Jiang Hui,Xu Wenming,Sun Jin-Peng,Xu Zhigang
British journal of pharmacology
Infertility rates for both females and males have increased continuously in recent years. Currently, effective treatments for male infertility with defined mechanisms or targets are still lacking. G protein-coupled receptors (GPCRs) are the largest class of drug targets, but their functions and the implications for the therapeutic development for male infertility largely remain elusive. Nevertheless, recent studies have shown that several members of the GPCR superfamily play crucial roles in the maintenance of ion-water homeostasis of the epididymis, development of the efferent ductules, formation of the blood-epididymal barrier and maturation of sperm. Knowledge of the functions, genetic variations and working mechanisms of such GPCRs, along with the drugs and ligands relevant to their specific functions, provide future directions and a great arsenal for new developments in the treatment of male infertility.
10.1111/bph.15252
Spermatozoa lacking Fertilization Influencing Membrane Protein (FIMP) fail to fuse with oocytes in mice.
Fujihara Yoshitaka,Lu Yonggang,Noda Taichi,Oji Asami,Larasati Tamara,Kojima-Kita Kanako,Yu Zhifeng,Matzuk Ryan M,Matzuk Martin M,Ikawa Masahito
Proceedings of the National Academy of Sciences of the United States of America
Sperm-oocyte fusion is a critical event in mammalian fertilization, categorized by three indispensable proteins. Sperm membrane protein IZUMO1 and its counterpart oocyte membrane protein JUNO make a protein complex allowing sperm to interact with the oocyte, and subsequent sperm-oocyte fusion. Oocyte tetraspanin protein CD9 also contributes to sperm-oocyte fusion. However, the fusion process cannot be explained solely by these three essential factors. In this study, we focused on analyzing a testis-specific gene and generated mutant mice using the CRISPR/Cas9 system. Although IZUMO1 remained in knockout (KO) spermatozoa, the KO spermatozoa were unable to fuse with oocytes and the KO males were severely subfertile. 4930451I11Rik encodes two isoforms: a transmembrane (TM) form and a secreted form. Both CRISPR/Cas9-mediated TM deletion and transgenic (Tg) rescue with the TM form revealed that only the TM form plays a critical role in sperm-oocyte fusion. Thus, we renamed this TM form Fertilization Influencing Membrane Protein (FIMP). The mCherry-tagged FIMP TM form was localized to the sperm equatorial segment where the sperm-oocyte fusion event occurs. Thus, FIMP is a sperm-specific transmembrane protein that is necessary for the sperm-oocyte fusion process.
10.1073/pnas.1917060117
Sperm-specific COX6B2 enhances oxidative phosphorylation, proliferation, and survival in human lung adenocarcinoma.
Cheng Chun-Chun,Wooten Joshua,Gibbs Zane A,McGlynn Kathleen,Mishra Prashant,Whitehurst Angelique W
eLife
Cancer testis antigens (CTAs) are proteins whose expression is normally restricted to the testis but anomalously activated in human cancer. In sperm, a number of CTAs support energy generation, however, whether they contribute to tumor metabolism is not understood. We describe human COX6B2, a component of cytochrome c oxidase (complex IV). is expressed in human lung adenocarcinoma (LUAD) and expression correlates with reduced survival time. COX6B2, but not its somatic isoform COX6B1, enhances activity of complex IV, increasing oxidative phosphorylation (OXPHOS) and NAD generation. Consequently, COX6B2-expressing cancer cells display a proliferative advantage, particularly in low oxygen. Conversely, depletion of COX6B2 attenuates OXPHOS and collapses mitochondrial membrane potential leading to cell death or senescence. COX6B2 is both necessary and sufficient for growth of human tumor xenografts in mice. Our findings reveal a previously unappreciated, tumor-specific metabolic pathway hijacked from one of the most ATP-intensive processes in the animal kingdom: sperm motility.
10.7554/eLife.58108
Pathogenic Infection in Male Mice Changes Sperm Small RNA Profiles and Transgenerationally Alters Offspring Behavior.
Tyebji Shiraz,Hannan Anthony J,Tonkin Christopher J
Cell reports
Germline epigenetic factors influence transgenerational inheritance of behavioral traits upon changes in experience and environment. Immune activation due to infection can also modulate brain function, but whether this experience can be passed down to offspring remains unknown. Here, we show that infection of the male lineage with the common human parasite Toxoplasma results in transgenerational behavioral changes in offspring in a sex-dependent manner. Small RNA sequencing of sperm reveals significant transcriptional differences of infected animals compared to controls. Zygote microinjection of total small RNA from sperm of infected mice partially recapitulates the behavioral phenotype of naturally born offspring, suggesting an epigenetic mechanism of behavioral inheritance in the first generation. Our results demonstrate that sperm epigenetic factors can contribute to intergenerational inheritance of behavioral changes after pathogenic infection, which could have major public health implications.
10.1016/j.celrep.2020.107573
Novel pharmacological actions of trequinsin hydrochloride improve human sperm cell motility and function.
McBrinn Rachel C,Fraser Joanna,Hope Anthony G,Gray David W,Barratt Christopher L R,Martins da Silva Sarah J,Brown Sean G
British journal of pharmacology
BACKGROUND AND PURPOSE:Asthenozoospermia is a leading cause of male infertility, but development of pharmacological agents to improve sperm motility is hindered by the lack of effective screening platforms and knowledge of suitable molecular targets. We have demonstrated that a high-throughput screening (HTS) strategy and established in vitro tests can identify and characterise compounds that improve sperm motility. Here, we applied HTS to identify new compounds from a novel small molecule library that increase intracellular calcium ([Ca ] ), promote human sperm cell motility, and systematically determine the mechanism of action. EXPERIMENTAL APPROACH:A validated HTS fluorometric [Ca ] assay was used to screen an in-house library of compounds. Trequinsin hydrochloride (a PDE3 inhibitor) was selected for detailed molecular (plate reader assays, electrophysiology, and cyclic nucleotide measurement) and functional (motility and acrosome reaction) testing in sperm from healthy volunteer donors and, where possible, patients. KEY RESULTS:Fluorometric assays identified trequinsin as an efficacious agonist of [Ca ] , although less potent than progesterone. Functionally, trequinsin significantly increased cell hyperactivation and penetration into viscous medium in all donor sperm samples and cell hyperactivation in 22/25 (88%) patient sperm samples. Trequinsin-induced [Ca ] responses were cross-desensitised consistently by PGE but not progesterone. Whole-cell patch clamp electrophysiology confirmed that trequinsin activated CatSper and partly inhibited potassium channel activity. Trequinsin also increased intracellular cGMP. CONCLUSION AND IMPLICATIONS:Trequinsin exhibits a novel pharmacological profile in human sperm and may be a suitable lead compound for the development of new agents to improve patient sperm function and fertilisation potential.
10.1111/bph.14814
Loss of flavin adenine dinucleotide (FAD) impairs sperm function and male reproductive advantage in .
Yen Chia-An,Ruter Dana L,Turner Christian D,Pang Shanshan,Curran Sean P
eLife
Exposure to environmental stress is clinically established to influence male reproductive health, but the impact of normal cellular metabolism on sperm quality is less well-defined. Here we show that impaired mitochondrial proline catabolism, reduces energy-storing flavin adenine dinucleotide (FAD) levels, alters mitochondrial dynamics toward fusion, and leads to age-related loss of sperm quality (size and activity), which diminishes competitive fitness of the animal. Loss of the 1-pyrroline-5-carboxylate dehydrogenase enzyme that catalyzes the second step in mitochondrial proline catabolism leads to premature male reproductive senescence. Reducing the expression of the proline catabolism enzyme or FAD biosynthesis pathway genes in the germline is sufficient to recapitulate the sperm-related phenotypes observed in loss-of-function mutants. These sperm-specific defects are suppressed by feeding diets that restore FAD levels. Our results define a cell autonomous role for mitochondrial proline catabolism and FAD homeostasis on sperm function and specify strategies to pharmacologically reverse these defects.
10.7554/eLife.52899
Sperm proteins SOF1, TMEM95, and SPACA6 are required for sperm-oocyte fusion in mice.
Noda Taichi,Lu Yonggang,Fujihara Yoshitaka,Oura Seiya,Koyano Takayuki,Kobayashi Sumire,Matzuk Martin M,Ikawa Masahito
Proceedings of the National Academy of Sciences of the United States of America
Sperm-oocyte membrane fusion is one of the most important events for fertilization. So far, IZUMO1 and Fertilization Influencing Membrane Protein (FIMP) on the sperm membrane and CD9 and JUNO (IZUMO1R/FOLR4) on the oocyte membrane have been identified as fusion-required proteins. However, the molecular mechanisms for sperm-oocyte fusion are still unclear. Here, we show that testis-enriched genes, sperm-oocyte fusion required 1 (//), transmembrane protein 95 (), and sperm acrosome associated 6 (), encode sperm proteins required for sperm-oocyte fusion in mice. These knockout (KO) spermatozoa carry IZUMO1 but cannot fuse with the oocyte plasma membrane, leading to male sterility. Transgenic mice which expressed mouse , and rescued the sterility of , , and KO males, respectively. SOF1 and SPACA6 remain in acrosome-reacted spermatozoa, and SPACA6 translocates to the equatorial segment of these spermatozoa. The coexpression of SOF1, TMEM95, and SPACA6 in IZUMO1-expressing cultured cells did not enhance their ability to adhere to the oocyte membrane or allow them to fuse with oocytes. SOF1, TMEM95, and SPACA6 may function cooperatively with IZUMO1 and/or unknown fusogens in sperm-oocyte fusion.
10.1073/pnas.1922650117