A metabolome-wide Mendelian randomization study prioritizes causal circulating metabolites for reproductive disorders including primary ovarian insufficiency, polycystic ovary syndrome, and abnormal spermatozoa.

BACKGROUND: Accumulating studies have highlighted the significant role of circulating metabolomics in the etiology of reproductive system disorders. However, the causal effects between genetically determined metabolites (GDMs) and reproductive diseases, including primary ovarian insufficiency (POI), polycystic ovary syndrome (PCOS), and abnormal spermatozoa (AS), still await thorough clarification. METHODS: With the currently most comprehensive genome-wide association studies (GWAS) data of metabolomics, systematic two-sample Mendelian randomization (MR) analyses were conducted to disclose causal associations between 1,091 blood metabolites and 309 metabolite ratios with reproductive disorders. The inverse-variance weighted (IVW) method served as the primary analysis approach, and multiple effective MR methods were employed as complementary analyses including MR-Egger, weighted median, constrained maximum likelihood (cML-MA), contamination mixture method, robust adjusted profile score (MR-RAPS), and debiased inverse-variance weighted method. Heterogeneity and pleiotropy were assessed via MR-Egger intercept and Cochran's Q statistical analysis. Outliers were detected by Radial MR and MR-PRESSO methods. External replication and metabolic pathway analysis were also conducted. RESULTS: Potential causal associations of 63 GDMs with POI were unearthed, and five metabolites with strong causal links to POI were emphasized. Two metabolic pathways related to the pathogenesis of POI were pinpointed. Suggestive causal effects of 70 GDMs on PCOS were detected, among which 7 metabolites stood out for strong causality with elevated PCOS risk. Four metabolic pathways associated with PCOS mechanisms were recognized. For AS, 64 GDMs as potential predictive biomarkers were identified, particularly highlighting two metabolites for their strong causal connections with AS. Three pathways underneath the AS mechanism were identified. Multiple assessments were conducted to further confirm the reliability and robustness of our causal inferences. CONCLUSION: By extensively assessing the causal implications of circulating GDMs on reproductive system disorders, our study underscores the intricate and pivotal role of metabolomics in reproductive ill-health, laying a theoretical foundation for clinical strategies from metabolic insights.

Genetically predicted asthma and the risk of abnormal spermatozoa.

Background: Several previous animal and human studies have found a strong association between asthma and spermatozoa quality, but whether these associations are causal or due to bias remains to be elucidated. Methods: We performed a two-sample Mendelian randomization (MR) analysis to assess the causal effect of genetically predicted asthma on the risk of abnormal spermatozoa. Asthma, childhood-onset asthma (COA), and adult-onset asthma (AOA) (sample sizes ranging from 327,670 to 408,442) were included as the exposures. Genetic information for abnormal spermatozoa was obtained from a genome-wide association study (GWAS) comprising 209,921 participants. In univariable MR (UVMR) analysis, the inverse variance weighted (IVW) method was conducted as the primary method, with the MR Egger and weighted median used as supplementary methods for causal inference. Sensitivity analyses, including the Cochran Q test, Egger intercept test, MR-PRESSO, and leave-one-out analysis, were performed to verify the robustness of the MR results. Multivariable MR (MVMR) was conducted to evaluate the direct causal effects of asthma on abnormal spermatozoa risk. Results: UVMR detected causal associations between genetically predicted asthma and an increased risk of abnormal spermatozoa (OR: 1.270, 95% CI: 1.045-1.545, p = 0.017). Moreover, we found that AOA (OR: 1.46, 95% CI: 1.051, 2.018, p = 0.024) has positive causal effects on the risk of abnormal spermatozoa rather than COA (p = 0.558). Sensitivity analysis found little evidence of bias in the current study (p > 0.05). MVMR further confirmed that asthma directly affected the risk of abnormal spermatozoa. Conclusion: Our MR study suggested that genetically predicted asthma could be associated with an increased risk of abnormal spermatozoa, and similar results were obtained in AOA. Further studies are warranted to explain the underlying mechanisms of this association and may provide new avenues for prevention and treatment.

The enigmatic interplay of immune cells and abnormal spermatozoa through Mendelian randomization.

PURPOSE: Abnormal spermatozoa significantly impact reproductive health, affecting fertility rates, potentially prolonging conception time, and increasing the risk of miscarriages. This study employs Mendelian randomization to explore their potential link with immune cells, aiming to reveal their potential causal association and wider implications for reproductive health. METHODS: We conducted forward and reverse Mendelian randomization analyses to explore the potential causal connection between 731 immune cell signatures and abnormal spermatozoa. Using publicly available genetic data, we investigated various immune signatures such as median fluorescence intensities (MFI), relative cell (RC), absolute cell (AC), and morphological parameters (MP). Robustness was ensured through comprehensive sensitivity analyses assessing consistency, heterogeneity, and potential horizontal pleiotropy. The MR study produced a statistically significant p-value of .0000684, Bonferroni-corrected for the 731 exposures. RESULTS: The Mendelian randomization analysis revealed strong indications of a reciprocal relationship between immune cell pathways and sperm integrity. When examining immune cell exposure, a potential causal link with abnormal sperm was observed in 35 different types of immune cells. Conversely, the reverse Mendelian randomization results indicated that abnormal sperm might causally affect 39 types of immune cells. These outcomes suggest a potential mutual influence between alterations in immune cell functionality and the quality of spermatozoa. CONCLUSION: This study highlights the close link between immune responses and sperm development, suggesting implications for reproductive health and immune therapies. Further research may offer crucial insights into male fertility and immune disorders.

Type 2 diabetes mellitus and the risk of abnormal spermatozoa: A Mendelian randomization study.

Abnormal spermatozoa can not only reduce the fertilization rate, but also prolong the natural conception time and even increase the risk of spontaneous miscarriage. Diabetes mellitus (DM) has become a major global health problem, and its incidence continues to rise, while affecting an increasing number of men in their reproductive years. Type 2 Diabetes Mellitus (T2DM), accounting for about 85-95% of DM, is closely related to the development of sperm. However, the exact association between T2DM and abnormal spermatozoa remains unclear. Herein, we designed a Two-sample Mendelian randomization (MR) study to explore the causal association between T2DM and abnormal spermatozoa risk in European population data which come from the GWAS summary datasets. We selected 9 single nucleotide polymorphisms (SNPs) of T2DM (exposure data) as instrumental variables (IVs), and then retrieved the suitable abnormal spermatozoa genome-wide association study (GWAS) data of European from Ieu Open GWAS Project database which includes 915 cases and 209,006 control as the outcome data. Our results indicate that strict T2DM might not result in a higher risk of abnormal spermatozoa genetically in Europeans (OR: 1.017, 95% confidence interval (CI): 0.771-1.342, p=0.902). Our findings demonstrate that only T2DM may not explain the relatively higher risk of abnormal spermatozoa in men with it in Europeans. In subsequent studies, more comprehensive and larger samples need to be studied to reveal the relationship and potential mechanism between T2DM and abnormal spermatozoa.

Hypo-Osmotic Swelling Test (HOST) for Feline Spermatozoa: The Simplified Procedure and the Aspect of Sperm Morphology.

Hypo-osmotic swelling test (HOST) is used to assess the functional integrity of sperm plasma membranes in many species. The primary aim of this study was to test a simplified HOST procedure for the evaluation of feline semen. The second objective was to check if sperm abnormalities can influence the results of this test. Urethral semen was collected from 19 male, domestic cats. In Exp. 1, HOST was performed in different media (50 mOsm/kg fructose or distilled water), temperature (37 °C or room temperature) and time (5 and 30 min). In Exp. 2, the potential effect of sperm abnormalities on HOST results was assessed by observing individual normal and abnormal spermatozoa microinjected into droplets of distilled water. The results showed no differences between the HOST results performed in different media, temperature and time. Viable abnormal spermatozoa were able to swell under hypo-osmotic conditions in the same manner as normal ones, except spermatozoa with distal droplets, which showed a higher frequency of 'despiralization'. In conclusion, HOST can be reliably performed at 0 mOsm/kg for 5 min at room temperature, which may contribute to a wider use of this test under clinical environments. Viable abnormal spermatozoa are able to swell under hypo-osmotic conditions; therefore, their presence in the ejaculate would not bias the results of HOST when total coiling is calculated.

Declining semen quality and steadying seminal plasma ions in heat-stressed boar model.

Purpose: There are increasing concerns about infertility of male exposure to high environmental temperatures. Nevertheless, the relationship between heat and accessory sex gland secretion underlying the high ambient temperature-induced poor semen quality has not yet been addressed. Methods: In the present study, five boars were used as an animal model to evaluate semen quality and the secretory function of accessory sex glands. After the boars received 3 days of heat exposure, semen collection was standardized to 18 continual times with a 3-day interval to determine the semen variables of semen volume, semen concentration, abnormal spermatozoa, seminal plasma composition, and testosterone level in the seminal plasma and serum. Results: The total sperm count was lowest by the end of week 2. The higher abnormal spermatozoa percentage were observed by the end of week 2 and persisted until week 6 after heat exposure. Additionally, there was no significant change in semen volume, testosterone level, and concentrations of ions and total protein in the seminal plasma before and after heat exposure. Conclusions: A single 3-day heat exposure caused poor semen quality, but did not disturb accessory sex gland secretion in boars. Declining semen quality might be mainly due to the damaged germ cells, which were sensitive to elevated temperature in hot summer months.