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Spermatogenesis is precisely controlled by sophisticated gene expression programs and is driven by epigenetic reprogramming, including histone modification alterations and histone-to-protamine transition. Nuclear receptor binding SET domain protein 2 (Nsd2) is the predominant histone methyltransferase catalyzing H3K36me2 and its role in male germ cell development remains elusive. Here, we report that NSD2 protein is abundant in spermatogenic cells. Conditional loss of Nsd2 in postnatal germ cells impaired fertility owing to apoptosis of spermatocytes and aberrant spermiogenesis. Nsd2 deficiency results in dysregulation of thousands of genes and remarkable reduction of both H3K36me2 and H3K36me3 in spermatogenic cells, with H3K36me2 occupancy correlating positively with expression of germline genes. Nsd2 deficiency leads to H4K16ac elevation in spermatogenic cells, probably through interaction between NSD2 and PSMA8, which regulates acetylated histone degradation. We further reveal that Nsd2 deficiency impairs EP300-induced H4K5/8ac, recognized by BRDT to mediate the eviction of histones. Accordingly, histones are largely retained in Nsd2-deficient spermatozoa. In addition, Nsd2 deficiency enhances expression of protamine genes, leading to increased protamine proteins in Nsd2-deficient spermatozoa. Our findings thus reveal a previously unappreciated role of the Nsd2-dependent chromatin remodeling during spermatogenesis and provide clues to the molecular mechanisms in epigenetic abnormalities impacting male reproductive health.

Sperm DNA injury is one of the common causes of male infertility. Folic acid deficiency would increase the methylation level of the important genes, including those involved in DNA double-strand break (DSB) repair pathway. In the early stages, we analysed the correlation between seminal plasma folic acid concentration and semen parameters in 157 infertility patients and 91 sperm donor volunteers, and found that there was a significant negative correlation between seminal folic acid concentration and sperm DNA Fragmentation Index (DFI; r = -0.495, p 0.01). Then through reduced representation bisulphite sequencing, global DNA methylation of sperm of patients in the low folic acid group and the high folic acid group was analysed, it was found that the methylation level in Rad54 promoter region increased in the folic acid deficiency group compared with the normal folic acid group. Meanwhile, the results of animal model and spermatocyte line (GC-2) also found that folic acid deficiency can increase the methylation level in Rad54 promoter region, increased sperm DFI in mice, increased the expression of γ-H2AX, that is, DNA injury marker protein, and increased sensitivity of GC-2 to external damage and stimulation. The study indicates that the expression of Rad54 is downregulated by folic acid deficiency via DNA methylation. This may be one of the mechanisms of sperm DNA damage caused by folate deficiency.

Background Previous studies have reported lower semen quality in malignant neoplasm patients before antineoplastic treatments, but the adverse effects of malignant neoplasms on semen quality have rarely been quantitatively evaluated. In addition, due to the lack of a comparable control group and limited types of studied malignant neoplasms, the results remain inconsistent and inconclusive. Objectives To quantitatively evaluate the potential adverse effects of specific malignant neoplasms on semen quality. Materials and methods We conducted a cross-sectional study to investigate 445 malignant neoplasm patients undergoing sperm cryopreservation for fertility preservation in Guangdong province, China during 2016-2019. A propensity score matching (PSM) method was used to select a comparable control group from 9,170 sperm donation volunteers. Each subject was analyzed for semen quality. Multivariate linear regression models were employed to assess the association between malignant neoplasm and semen quality. Results Using the PSM method, 413 (92.8%) malignant neoplasm patients were successfully matched with 798 sperm donation volunteers. Overall, malignant neoplasms were significantly associated with a 0.3 ml, 17.1 × 106 /ml, 67.6 × 106 , 9.8%, 10.2% and 6.4% reduction in semen volume, sperm concentration, total sperm number, total motility, progressive motility and normal forms, respectively. Malignant neoplasm of testis, nasopharynx and digestive organs, Hodgkin lymphoma, non-Hodgkin lymphoma, and leukemia were significantly associated with reduction in sperm motility and normal forms, while malignant neoplasm of testis, Hodgkin lymphoma and leukemia were also significantly associated with reduced sperm concentration and/or total sperm number. The reduction in sperm concentration and total sperm number associated with malignant neoplasms was significantly greater in subjects Discussion and conclusion We found that malignant neoplasms were significantly associated with reduction in semen quality, which varied across type of malignant neoplasms. Our results highlight the needs to examine semen quality for young malignant neoplasm patients, especially those who are expected to conceive. This article is protected by copyright. All rights reserved.

Otogelin-like protein (encoded by Otogl) was highly structural similar to the gelforming mucin proteins. Although human OTOG mutations have been linked to deafness, the biological function of OTOGL in male germ cell development remains enigmatic. In screening 336 patients with non-obstructive azoospermia (NOA), OTOGL displays the high mutant ratio (13.99 %). Then, we examined the expression of OTOGL in developing mouse testes. Otogl mRNA and protein are continually expressed in postnatal developing testes from postnatal day 0 (P0) testes to P21 testes exhibiting a decreased trend with the age growth. We thus generated a global Otogl knockout mouse (KO) model using the CRISPR/Cas9 technology; however, Otogl KO mice displayed normal development and fertility. Further histological analysis of Otogl knockout mouse testes revealed that all types of spermatogenic cells are present in Otogl KO seminiferous tubules. Together, our study suggested that OTOGL is nonessential for male germ cell development and spermatogenesis.

Emerging evidence shows the detrimental impacts of particulate matter (PM) on poor semen quality. High-resolution estimates of PM concentrations are conducive to evaluating accurate associations between traffic-related PM exposure and semen quality.In this study, we firstly developed a random forest model incorporating meteorological factors, land-use information, traffic-related variables, and other spatiotemporal predictors to estimate daily traffic-related PM concentrations, including PMThe results showed that decreased sperm concentration was associated with PMOur results indicate that exposure to traffic-related PM

Abnormal sperm quality in men is one of the common causes of infertility. Both ambient temperature and extreme heat exposure have been shown to be associated with sperm quality, but there is no epidemiological evidence for the effect of ambient temperature variability. Our aim was to investigate the association between ambient temperature variability exposure and a decline in sperm quality at different stages of sperm development.A total of 4912 semen samples collected from the Guangdong Human Sperm Bank between 1 January 2019 and 31 December 2019 were analyzed. We selected three exposure periods: the full-stage (0-90 lag days), early-stage (34-77 lag days) and late-stage (0-37 lag days) of sperm development, and then calculated the standard deviation of daily temperature (TVSD), the maximum day-to-day temperature difference (TVDThere was a significant negative association of decreased sperm count with the exposure to temperature variability during 0-90 days prior to sperm collection. (TVDThe results indicate that exposure to temperature variability during the entire period of sperm development is significantly associated with a decline in sperm counts. We found that mean day-to-day temperature differences had a detrimental effect on sperm counts in the early-stage. Our findings provide a scientific basis for public health policy and further mechanistic studies.

Objective. To explore the risk of Ureaplasma urealyticum (UU) affecting sperm quality. Methods. Prospective cross-sectional study was conducted. In total, 340 semen samples were collected. According to whether they were infected with UU, the samples were divided into the UU-positive group (observation group) and UU-negative group (control group). The patients with UU-positive were followed up to obtain treatment and collected the semen again after treatment. The semen characteristics and sperm parameters were detected and compared, and the relationship of UU and the sperm quality was analyzed by mathematical models. Results. There were 104 UU-positive semen samples in all, with an overall infection rate of 30.6%, which was highest in 31 to 40-year-old men, and over 40-year-old men were the lowest. The pH, PR, VCL, VSL, and STR in the observation group were significantly lower than those in the control group (all P < 0.001 ), while SV, NP, and WOB were significantly higher (all P < 0.001 ). After treatment, the pH, VSL, LIN, WOB, and STR in the observation group were significantly higher than before (all P < 0.001 ), while SV and VCL were significantly lower (all P < 0.001 ). UU infection was closely correlated with pH, PR, NP, VCL, VSL, WOB, and STR. During the treatment, pH, PR, VSL, WOB, and STR increased, but NP and VCL decreased. 7 major factors that would affect SQ were extracted, of which VAP, LIN, and UU were the first three main factors. The risk of SQ declining after UU infection increased nearly twice with the change of PR and VCL and increased 0.08 times with STR. Conclusion. UU may approximately double the risk of altering the sperm’s curvilinear movement rate and straightness to affect the sperm quality.

BACKGROUND: Because of focal spermatogenesis in some nonobstructive azoospermia (NOA) patients, testicular spermatozoa can be retrieved by microdissection testicular sperm extraction (micro-TESE) for intracytoplasmic sperm injection (ICSI) to achieve successful fertilization. Currently, testicular biopsy is widely performed for the prognosis of micro-TESE; however, it might miss foci with active spermatogenesis because of the ‘blind manner’ of puncture, highlighting the needs for biomarkers that could indicate actual spermatogenesis conditions in the testis. Thus, we screened microRNAs in the seminal plasma for potential biomarkers to provide a non-invasive and reliable preoperative assessment for micro-TESE. METHODS: We screened the seminal plasma microRNAs from NOA patients with and without sperm retrieval (n=6 in each group) together with fertile men (n=6) by RNA sequencing, and the selected microRNAs were validated by quantitative polymerase chain reaction (qPCR). Next, a predictive model was established by performing ordered logistic regression using the qPCR data of 56 specimens, and the predictive accuracy of this model was evaluated using 40 more specimens in a blind manner. RESULTS: Four microRNAs (hsa-miR-34b-3p, hsa-miR-34c-3p, hsa-miR-3065-3p, and hsa-miR-4446-3p) were identified as biomarkers, and the predictive model Logit = 2.0881+ 0.13448 mir-34b-3p + 0.58679 mir-34c-3p + 0.15636 mir-3065-3p + 0.09523 mir-4446-3p was established by machine learning. The model provided a high predictive accuracy (AUC =0.927). CONCLUSIONS: We developed a predictive model with high accuracy for micro-TESE, with which NOA patients might obtain accurate assessment of spermatogenesis conditions in testes before surgery.

The influence of varicocele and microsurgical varicocelectomy on semen quality remains unclear. No previous study has investigated the relationship between semen metabolism and the abnormalities in reproductive function caused by varicocele. Here, we used the non-targeted and targeted metabolic analysis to investigate the different metabolites in seminal plasma within normal, varicocele, and varicocelectomy groups. We clearly showed that varicocele significantly affects sperm metabolism, and microsurgical varicocelectomy can reverse this metabolic abnormality. Moreover, we characterized the landscape of three dipeptides in the seminal plasma of patients with varicocele that have not been identified previously in human tissues or biofluids. Interestingly, the levels of these three dipeptides decreased after microsurgical varicocelectomy coincident with an improvement in semen quality. Western blotting confirmed the downregulation of DPEP3 (dipeptidase 3) in the varicocele group and the upregulation of DPEP3 in the varicocelectomy group. Furthermore, we found that eight metabolites may be helpful to distinguish varicocele patients from normal subjects. Our results can be applied to earlier diagnosis or to predict the outcome of microsurgery for varicocele.

Background: Depression is a potential factor affecting semen quality. However, the relationship between depression and semen quality remains to be fully elucidated. We investigated the association between depression and semen quality in men during the COVID-19 pandemic.Methods: Cross‐sectional, participants completed a questionnaire assessing lifestyle factors the Patient Health Questionnaire-9 (PHQ-9) was used to evaluate the psychological depression status of subjects. Semen quality assessment implements the requirements of the fifth edition of the World Health Organization (WHO )manual ,multivariable logistic regression analysis and linear regression analysis were conducted to assess the associations between depression and semen quality.Results: Of the 896 participants, 173 were depressed (19.30%). A Linear regression model was fitted to assess the strength and significant level of the association between depressive symptoms and semen quality. After adjusting for potential confounders, depression was significantly associated with 9.27 (95% confidence interval [CI] 3.39, 15.15), 0.57(95% CI 0.27, 0.87), 62.20 (95% CI 32.93, 91.48), and 12.96 (95% CI 10.55, 15.37) reduction in sperm concentration, sperm volume, total sperm count, and progressive motility, respectively. Which are consistent with the logistic regression analysis results. The semen concentration and total sperm count were linearly correlated with depression scores, whereas the semen volume and progressive motility of sperm were nonlinearly correlated with depression scores.Conclusions: Depression were associated with lower levels of semen concentration, semen volume, total sperm count, and progressive motility, which could affect male reproductive health.

Objectives: There is no report about association of anxiety on sperm quality during the COVID-19 epidemic. Purpose of this study was to investigate the relationship between anxiety and sperm quality during the COVID-19 outbreak in China.Methods: 896 sperm donors from 7 sperm banks in China were investigated, and passed the screening for sperm donation between 23 January 2020 and 8 June 2020. Semen quality analysis follows the standards of the WHO Fifth Edition Human Semen Examination and Processing Manual. Anxiety symptoms were assessed by the Generalized Anxiety Disorder Scal-7(GAD-7). Logistic regression and linear regression were used to identify the association between anxiety level and sperm quality.Results: Participants with anxiety status (N = 155; 17.3%) had lower sperm concentration (56.81 ± 32.70 vs. 47.21 ± 30.76 [106/mL]), sperm volume (3.58 ± 1.65 vs. 3.04 ± 1.69 [mL], P < 0.001), total sperm count (7.29 ± 1.23 vs. 6.56 ± 1.63 [106], P < 0.001), and progressive motility (50.86 ± 12.45 vs. 38.50 ± 17.00 [%], P < 0.001) than those without anxiety. Linear regression showed that anxiety symptoms was significantly associated with 8.13 (95% confidence interval [CI]: 2.51, 13.75), 0.49 (0.20, 0.79) ,51.05 (23.43, 78.68) and 12.15 (95% CI: 23.43, 78.68), reduction in sperm concentration, semen volume, and total sperm count and progressive motility respectively.Conclusions: This study revealed that anxiety symptoms were negatively associated with semen quality, and interaction was discovered between debt stress and anxiety.

Ambient PM2.5 (particulate matter ≤ 2.5 μm in aerodynamic diameter) constituents have been related to mean changes in semen quality, but focusing on the mean response may not well capture distributional and heterogeneous effects of PM2.5 constituents on semen quality. In this study, 2314 semen samples of 622 men between Jan 1, 2019 and Dec 31, 2019 from Guangdong Human Sperm Bank were subjected to semen quality analysis. Daily average concentrations of PM2.5 constituents including 4 water-soluble ions and 15 metals/metalloid were measured for 7 days per month at 3 fixed atmospheric pollutant monitoring stations. We used quantile regression for longitudinal data to examine whether the associations between PM2.5 constituents and quality indicators of semen varied across quantiles of outcome distribution. Heterogeneous associations were found between PM2.5 constituents and sperm quality across different quantiles. An interquartile range (14.0 μg/m3) increase in PM2.5 mass was negatively associated with lower tails of sperm concentration and upper tails of sperm count distribution. PM2.5 vanadium exposure was significantly related to the 90th percentile of sperm count distribution, but not to the lower quantiles. In addition, those subjects with relatively high sperm motility were more susceptible to sulfate, chromium, and manganese constituents in PM2.5. Our results indicate that PM2.5 and certain constituents were associated with sperm quality, especially sperm motility, and the associations are more pronounced in men with relatively high or low sperm motility.

Background: Exposure to residential greenness has been associated with benefits on certain reproductive health outcomes. However, its potential benefits on semen quality remain unknown. Objectives: To quantitatively explore the association between exposure to residential greenness and semen quality. Methods: We investigated 9142 sperm donation volunteers who underwent 38,682 semen examinations at Guangdong provincial human sperm bank in China during 2016–2019. Exposure to residential greenness was assessed using mean daily Normalized Difference Vegetation Index (NDVI) at each subject’s residential address with a 400 m buffer during 0–90 days before each semen collection. Multivariate linear mixed models and linear regression models were used to assess the association between exposure to residential greenness and semen quality. Results: An interquartile range increase in exposure to residential greenness was significantly associated with a 0.034 (95% confidence interval [CI]: 0.005, 0.063) ml, 4.06 (95% CI: 0.76, 7.37) × 106, and 0.32% (95% CI: 0.22%, 0.41%) increase in semen volume, total sperm number, and normal forms, respectively; similar trends were observed across quartiles of exposure to residential greenness (all p-values for liner trend