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Nowadays, when the nation’s temporary economic difficulties have led to a decline in the agriculture share of the overall economy, the problem of controlling weeds of agricultural land is especially urgent. Undoubtedly, in our country, with the strengthening of the economy, the use of plant protection products is growing, requiring even closer attention to the problem of the environmental impact of herbicides and the rehabilitation of soils contaminated with residues of poisonous chemicals. The general mechanism of the action affecting herbicides of different groups is the violation of redox processes, and, in particular, the increase in free radical lipid peroxidation, first of all, in gonadal cell membranes that can eventually lead to the destruction throughout the reproductive period. Moreover, they produce gonadotoxic effects leading to a decrease in steroidogenesis, and as a consequence, to impaired spermatogenesis. The aim of the study was to investigate the gonadoprotective properties of the antioxidant complex, its effect on the parameters of lipid peroxidation, morphological and functional changes in the testes of rats exposed to the toxic effect of the clopyralid herbicide. The introduction of this complex under the conditions mentioned above contributed not only to a significant decrease in free radical lipid perozidation in the blood and tissues of the testes, but also to normalization of the state of spermatogenic epithelium, quantitative sperm indicators, normalization of sperm motility. It has been proven the complex of antioxidants not only affects the level of spermatogenic epithelium, but also improves the quality of sperm, contributing to the restoration of sperm motility. The studies of morphological changes in the testes and the functional maturation of the sperm have shown that the most significant changes were registered during the correction with the antioxidant complex, emphasizing its more pronounced gonadoprotective effect. The results obtained indicate the feasibility of using this antioxidant complex as gonadoprotectant in cases of chronic intoxication with herbicides.

Summary Despite the high incidence of male infertility, only 30% of infertile men receive a causative diagnosis. To explore the regulatory mechanisms governing human germ cell function in normal and impaired spermatogenesis (crypto), we performed single-cell RNA sequencing (>30,000 cells). We find major alterations in the crypto spermatogonial compartment with increased numbers of the most undifferentiated spermatogonia (PIWIL4+). We also observe a transcriptional switch within the spermatogonial compartment driven by increased and prolonged expression of the transcription factor EGR4. Intriguingly, the EGR4-regulated chromatin-associated transcriptional repressor UTF1 is downregulated at transcriptional and protein levels. This is associated with changes in spermatogonial chromatin structure and fewer Adark spermatogonia, characterized by tightly compacted chromatin and serving as reserve stem cells. These findings suggest that crypto patients are disadvantaged, as fewer cells safeguard their germline’s genetic integrity. These identified spermatogonial regulators will be highly interesting targets to uncover genetic causes of male infertility., Graphical abstract, Highlights Crypto(zoospermic) men show increased number of PIWIL4+/EGR4+ spermatogonia Crypto undifferentiated spermatogonia over-activate the EGR4 regulatory network The predicted EGR4 target UTF1 is downregulated in crypto spermatogonia Crypto testes show reduced numbers of UTF1+ Adark reserve spermatogonia, Di Persio et al., apply single-cell RNA sequencing to testicular tissues from men with normal and impaired spermatogenesis. They find major alterations in the spermatogonial stem cell compartment with increased numbers of the most undifferentiated spermatogonia (PIWIL4+/EGR4+) and reduced numbers of the reserve spermatogonia (Adark) in impaired spermatogenesis.

Background: Our previous study confirmed the beneficial effects of chestnut polysaccharides on the spermatogenesis process, but the exact mechanism is not clear. Several studies have demonstrated the importance of a balanced gut microbiota in maintaining normal reproductive function. In this study, we investigated the biological functions of chestnut polysaccharides from the perspective of gut microbiota function, expecting to elaborate the specific mechanism of chestnut polysaccharides beneficial to spermatogenesis.Results: Compared with the Vehicle group, germ cell quantity, intestinal structure and tight junction of intestinal tissue were altered in the Busulfan-treated mice, and the intestinal microbiota was also disturbed at several levels, including phylum and genus. The Firmicutes was predominant bacteria in all group followed by Proteobacteria, Bacteroidetes, Actinobacteria, Tenericutes, Cyanobacteria and unidentified-Bacteria, however, the composition of those gut microbiota changes caused by different treatment. Busulfan disturbed the homeostasis of the intestinal microenvironment. Chestnut polysaccharides could rescue this aberrance and improve spermatogenesis via steroid hormone synthesis process. Conclusions: Chestnut polysaccharides can change gut structure and tight junctions to rescue Busulfan-impaired spermatogenesis by altering the composition of different groups of gut microbes, a rescue process that is most likely related to hormone synthesis processes. It will provide a new insight for treating the male-related infertility.

IVIRMA Group, Lisbon Clinical Group: Alberto Pacheco, Cristina González, Susana Gómez, David Amorós, Jesus Aguilar, Fernando Quintana, Carlos Calhaz-Jorge, Ana Aguiar, Joaquim Nunes, Sandra Sousa, Maria Graça Pinto, Sónia Correia Background: Severe spermatogenic failure (SpF) represents the most extreme manifestation of male infertility, as it decreases drastically the semen quality leading to either severe oligospermia (SO

Context: Zuogui Wan is a classic traditional Chinese prescription. Preliminary studies have confirmed that it could improve sperm quality significantly. Objective: To investigate the effect of Zuogui Wan on testis structure and c-kitproto-oncogeneprotein (c-Kit) and octamer-binding transcription factor-4 (Oct4) expression in a rat model of impaired spermatogenesis. Material and methods: Thirty-six Sprague-Dawley (SD) rats were divided into Blank control, Tripterygium glycosides (GTW) and Zuogui Wan groups (n = 12). GTW was used to generate models of impaired spermatogenesis. Then Zuogui Wan group was administered 6 g/kg/d of Zuogui Wan granules for 4 weeks. Changes in the pathological structure and ultrastructure were observed with optical microscope and transmission electron microscope. Expression of c-Kit and Oct4 were quantified by RT qPCR and Western blots. Results: Both the pathological damage and the damages in the ultrastructure of spermatogenic epithelium had improved in Zuogui Wan group. Compared with the GTW model group (0.47 ± 0.19; 0.38 ± 0.14), c-Kit and Oct4 protein expression increased in the Zuogui Wan group (0.75 ± 0.27; 0.65 ± 0.23). C-Kit and Oct4 mRNA expression increased in Zuogui Wan group (1.06 ± 0.16; 1.85 ± 1.04) compared to the GTW model group (0.66 ± 0.23; 0.46 ± 0.29). Conclusions: Zuogui Wan is capable of restoring the damage to the testis structure and ultrastructure and regulates the expression of c-Kit and Oct4 at protein and mRNA levels, inhibiting apoptosis and promoting proliferation of spermatogenic cells.

There is increasing data that IVS8-5T variand and TG repeats could lead to impaired spermatogenesis. To investigate this we performed Sanger sequencing on 50 Bulgarian men with a sperm count below 5 × 10

Infertility is a growing concern in developed societies. Two extreme phenotypes of male infertility are non-obstructive azoospermia (NOA) and severe oligospermia (SO), which are characterized by severe spermatogenic failure (SpF). We designed a genetic association study comprising 725 Iberian infertile men as a consequence of SpF and 1058 unaffected controls to evaluate whether five single-nucleotide polymorphisms (SNPs), previously associated with reduced fertility in Hutterites, are also involved in the genetic susceptibility to idiopathic SpF and specific clinical entities. A significant difference in the allele frequencies of USP8-rs7174015 was observed under the recessive model between the NOA group and both the control group (p = 0.0226, OR = 1.33) and the SO group (p = 0.0048, OR = 1.78). Other genetic associations for EPSTI1-rs12870438 and PSAT1-rs7867029 with SO and between TUSC1-rs10966811 and testicular sperm extraction (TESE) success in the context of NOA were observed. In silico analysis of functional annotations demonstrated cis-eQTL effects of such SNPs likely due to the modification of binding motif sites for relevant transcription factors of the spermatogenic process. The findings reported here shed light on the molecular mechanisms leading to severe phenotypes of idiopathic male infertility, and may help to better understand the contribution of the common genetic variation to the development of these conditions., Spanish Ministry of Economy and Competitiveness through the Spanish State Plan for Scientific and Technical Research and Innovation SAF201678722-R, Spanish Government RYC-2014-16458, "Juan de la Cierva Incorporacion" program IJC2018-038026-I, European Union (EU), Spanish Government FIS-ISCIII DTS18/00101, Generalitat de Catalunya 2017SGR191, "Plan Propio" program of the University of Granada ("Becas de Iniciacion a la Investigacion para estudiantes de Grado"), "Researchers Consolidation Program" from the SNS-Dpt. Salut Generalitat de Catalunya CES09/020, FCT/MCTES, through national funds attributed to Center for Toxicogenomics and Human Health-ToxOmics UIDB/00009/2020, Portuguese Foundation for Science and Technology SFRH/BPD/120777/2016, Portuguese State Budget of the Ministry for Science, Technology and High Education, European Social Fund through the Programa Operacional do Capital Humano, Portuguese Foundation for Science and Technology IF/01262/2014, FCT in the framework of the project "Institute for Research and Innovation in Health Sciences" POCI-01-0145-FEDER-007274

In the past 15 years, numerous studies have described aberrant DNA methylation of imprinted genes (e.g. MEST and H19) in sperm of oligozoospermic men, but the prevalence and genomic extent of abnormal methylation patterns have remained unknown.Using deep bisulfite sequencing (DBS), we screened swim-up sperm samples from 40 normozoospermic and 93 patients diagnosed as oligoasthenoteratozoospermic, oligoteratozoospermic or oligozoospermic, which are termed OATs throughout the manuscript, for H19 and MEST methylation. Based on this screening, we defined three patient groups: normal controls (NC), abnormally methylated oligozoospermic (AMO; n = 7) and normally methylated oligozoospermic (NMO; n = 86). Whole-genome bisulfite sequencing (WGBS) of five NC and five AMO samples revealed abnormal methylation levels of all 50 imprinting control regions in each AMO sample. To investigate whether this finding reflected epigenetic germline mosaicism or the presence of residual somatic DNA, we made a genome-wide inventory of soma-germ cell-specific DNA methylation. We found that2000 germ cell-specific genes are promoter-methylated in blood and that AMO samples had abnormal methylation levels at these genes, consistent with the presence of somatic cell DNA. The comparison between the five NC and six NMO samples revealed 19 differentially methylated regions (DMRs), none of which could be validated in an independent cohort of 40 men. Previous studies reported a higher incidence of epimutations at single CpG sites in the CTCF-binding region 6 of H19 in infertile patients. DBS analysis of this locus, however, revealed an association between DNA methylation levels and genotype (rs2071094), but not fertility phenotype.Our results suggest that somatic DNA contamination and genetic variation confound methylation studies in sperm of infertile men. While we cannot exclude the existence of rare patients with slightly abnormal sperm methylation at non-recurrent CpG sites, the prevalence of aberrant methylation in swim-up purified sperm of infertile men has likely been overestimated, which is reassuring for patients undergoing assisted reproduction.

Infertile male with small supernumerary marker chromosomes (sSMCs) were studied. Overall, 37 own patients and 166 cases from the literature were included. sSMCs of our own cases were characterized by multicolor-FISH probe sets. Available clinical data of the infertile males were also evaluated, and meta-analysis on suitability of molecular karyotyping for sSMC characterization was done. As a result, sSMCs can be optimally characterized by single-cell directed (molecular) cytogenetics. In infertile males, sSMCs derive predominantly from one of the acrocentric chromosomes, mainly chromosomes 15, 14, and 22. Interestingly, altered spermiograms were found in 62% of the males with an sSMC, while the remainder cases had infertility in connection with recurrent spontaneous abortions. Meta-analysis for detectability of sSMCs by aCGH revealed that 81-87% of the cases would have not been picked up by exclusive use of that approach. Thus, as impaired spermatogenesis is known to be indicative for gross chromosomal anomalies in infertile male patients, it can be concluded from this study that the presence of sSMCs also needs to be considered. However, sSMCs can only be reliably detected by standard karyotyping and not by modern high throughput approaches like aCGH and next-generation sequencing.

Хромосомные аномалии (ХА), в том числе, анеуплоидии, являются одной из причин спонтанного прерывания беременности, бесплодия, рождения детей с нарушениями и пороками развития. Одним из способов оценки вероятности возникновения анеуплоидных зигот является анализ родительских гамет, однако информации об уровне анеуплоидии в таких клетках недостаточно. Был проведена оценка частоты анеуплоидии, совместимой с жизнеспособностью зигот, в ядрах сперматозоидов 82 фенотипически нормальных бесплодных мужчин с нормальным и нарушенным сперматогенезом. Chromosomal abnormalities (CA), including aneuploidy, are one of the causes of spontaneous abortion, infertility, developmental disorders and malformations. One way to evaluate probability of aneuploid zygotes occurrence is the analysis of parental gametes, however, information about the level of aneuploidy in such cells is insufficient. There was evaluated the frequency of aneuploidy compatible with the viability of the zygote in sperm nuclei of 82 phenotypically normal infertile men with normal and impaired spermatogenesis.

This cohort study examines the potential association of the use of immune checkpoint inhibitors with testicular histopathologic conditions.

Diazinon (DZN) is an organophosphate insecticide that has cytotoxic and pathological effects on the reproductive system. It causes a wide variety of pathological effects on the reproductive system such as testicular atrophy, disturbance in sex hormones, impaired spermatogenesis, low quality of sperm, and fertility problems. However, molecular and cellular mechanisms of its adverse effects are not well understood. General events such as testicular damage, inflammation, mitochondrial deficiency, DNA fragmentation, disintegration of sperm plasma membrane, apoptosis, and cell death are observed in DZN-exposed animals. Oxidative stress (OS) induced by reactive oxygen species may be a main mechanism, which can be associated with sperm DNA fragmentation, reduced integrity of sperm cell membrane, apoptosis, depletion of antioxidants, and subsequently poor sperm quality and male infertility. Therefore, identification of these pathways may provide valuable information regarding the mechanisms of DZN action on the male reproductive system. In this review, we aim to discuss the proposed cellular and molecular mechanisms of DZN action on male reproductive system, the importance of OS and mechanisms by which DZN induces OS and depletion of other antioxidants.

While the incidence of clinical varicocele is common in infertile men (about 40%), the reasons why varicocele may affect sperm parameters is still unclear. In addition, the improvement of fertility after treatment of varicocele is also a subject of debate. The purpose of this review is to get new insight into the physiopathology of varicocele, its impact on sperm parameters and the effectiveness of varicocele treatment on fertility. Treatment is likely to be effective in infertile men with clinical varicocele and impaired spermatogenesis. Even if it does not systematically lead to an improvement in sperm parameters, it may prevent further sperm degradation. In case of non-obstructive azoospermia, few studies reported a slight improvement in the process of spermatogenesis. The critical role of an adequate methodology in order to establish clinical guidelines needs to be stressed. Indeed, the huge intra-individual variability in sperm production makes the usual analysis of sperm parameters inadequate to measure treatment effectiveness. Regarding the assessment of conception, it requires not only well designed and properly sized studies but also a multivariate analysis for weighing predictive factors of success. Thus, an active scientific research is needed to better identify pathogenic agents and appropriately assess the impact of varicocele treatment.

Seminal plasma is a potential source of biomarkers for many disorders of the male reproductive system including male infertility. Knowledge of the peptide and protein components of seminal fluid is accumulating especially with the appearance of highthroughput MS-based techniques. Of special interest in the field of male infertility biomarkers, is the identification and characterization of differentially expressed proteins in seminal plasma of men with normal and impaired spermatogenesis. However, the data obtained until now is still quite heterogeneous and with small percentage of overlap between independent studies. Extensive comparative analysis of seminal plasma proteome is still needed in order to establish a potential link between seminal plasma proteins and male infertility.

The concept of an increasingly common Testicular Dysgenesis Syndrome (TDS) has been widely adopted with little epidemiological appraisal. In this paper we critically review the epidemiologic evidence of the existence of a non-genetic TDS. We systematically assess and discuss the evidence of all six possible associations between the four defining conditions of TDS: impaired spermatogenesis, undescended testis, hypospadia and testicular cancer. We also evaluate whether there are common risk factors for these four conditions. We conclude that epidemiologic studies provide little support for existence of a widespread TDS because there are no consistent non-causal associations between its different manifestations. There is furthermore little evidence of shared causes between the alleged components of the syndrome.

Undescended testis is a common finding in boys, and the majority of cases have no discernible aetiology. There are unexplained geographical differences and temporal trends in its prevalence. Cryptorchidism, especially bilateral, is associated with impaired spermatogenesis and endocrine function and increases the risk of testicular cancer. There is an urgent need to identify factors that adversely affect testicular development and optimize treatment. Conclusion: Cryptorchidism may reflect a primary testicular maldevelopment with long-term consequences.

For over a century, it has been believed that once adult Sertoli cells complete differentiation, their differentiation state is fixed for life, a feature called “terminal” differentiation. However, research efforts since the early 2000s, largely in seasonal-breeding Djungarian hamsters with data from humans, reveal that the adult Sertoli cell population in vivo is capable of dedifferentiation in settings of impaired spermatogenesis and therefore is not a homogenous terminally differentiated population. This chapter discusses how the adult Sertoli cell population develops, some of the factors that regulate differentiation, and the differences between undifferentiated and differentiated Sertoli cells. The aim is to use findings from animals and, where possible, to include data from humans to build an understanding of the biology of adult Sertoli cells and perhaps their unrealized therapeutic potential.

Since the introduction of molecular biology and gene ablation technologies there have been substantial advances in our understanding of how sperm are made and fertilization occurs. There have been at least 150 different models of specifically altered gene function produced that have resulted in male infertility spanning virtually all aspects of the spermatogenic, sperm maturation and fertilization processes. While each has, or potentially will reveal, novel aspects of these processes, there is still much of which we have little knowledge. The current review is by no means a comprehensive list of these mouse models, rather it gives an overview of the potential for such models which up to this point have generally been 'knockouts'; it presents alternative strategies for the production of new models and emphasizes the importance of thorough phenotypic analysis in order to extract a maximum amount of information from each model.

Elevated testicular temperatures are a potential risk factor for impaired spermatogenesis and reduced semen quality. The development of portable devices for the measurement of scrotal temperatures closely correlating with testicular temperature offered the opportunity to identify periods with high scrotal temperatures during daily life. Notably, sleeping periods covering approximately 1/3 of the day are associated with increased scrotal temperatures to around 36 degrees C. Combining infrared video taping with scrotal temperature profiling, our study clarified that sudden drops of scrotal temperature during sleep are the consequence of changes of posture. Nocturnal scrotal temperatures were significantly higher during sleeping on the side compared with periods lying on the back (+0.65 degrees C, right scrotum, P0.001; +0.54 degrees C, left scrotum, P0.001). Median values of nocturnal scrotal temperatures did not significantly differ between 11 volunteers with normozoospermia and 22 men with oligozoospermia. Furthermore, continued scrotal temperature profiling during the following day only showed significantly higher values among men with oligozoospermia than among volunteers for the left scrotal side (+0.70 degrees C, P0.05), but not for the right scrotal side (+0.39 degrees C, P0.05). This difference could not be attributed to higher scrotal temperature values during periods with physical inactivity (median in both groups above 36 degrees C) but the duration of physical inactivity in men with oligozoospermia was 50% longer than in volunteers. Thus, in the setting of the present study it was not possible to demonstrate a close correlation between scrotal temperature and semen quality.

The incidence of heteroploid spermatozoa was studied by mono- and dual-colored fluorescence in situ hybridization in semen samples from donors and patients with normal and impaired spermatogenesis. The frequency of heteroploid sperm in the ejaculate was linearly and inversely correlated with sperm parameters (sperm concentration in the ejaculate and proportion of motile and morphologically normal spermatozoa). The level of heterploidy was the most significant in the semen samples from patients with oligoasthenoteratospermia and oligoasthenospermia.

scores associated with an RI >0.6 (p 1⁄4 0.03). Using linear regression: Johnson score 1⁄4-12.8*RI+14.5 (R1⁄40.223). CONCLUSIONS: Intratesticular RI, measured by spectral Doppler, correlates with impaired spermatogenesis on testis biopsy. Lower Johnson scores are associated with an RI of >0.6. These results validate our prior findings and underscore the importance of testicular ultrasound with spectral Doppler as a non-invasive means of assessing spermatogenesis.

We report an 18-year-old Japanese male with severe short stature and small testes. The endocrinological examination showed high plasma FSH value and normal plasma LH value, consistent with impaired spermatogenesis, and a skeletal X-ray survey suggested systemic bone dysplasia. Analysis of DAZ and FSH receptor genes was not confirmatory of the cause of defects in the seminiferous tubule maturation in this patient. The unique association of impaired spermatogenesis and skeletal dysplasia in the patient has not previously been described.

Undescended testis is a common finding in boys, and the majority of cases have no discernible aetiology. There are unexplained geographical differences and temporal trends in its prevalence. Cryptorchidism, especially bilateral, is associated with impaired spermatogenesis and endocrine function and increases the risk of testicular cancer. There is an urgent need to identify factors that adversely affect testicular development and optimize treatment.