CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal.
IIIUC-Institute for Interdisciplinary Research, University of Coimbra, 3030-789 Coimbra, Portugal.
Biomolecules. 2023 Sep 27;13(10):1462. doi: 10.3390/biom13101462.
The global trend of rising (male) infertility is concerning, and the unidentifiable causes in half of the cases, the so-called unknown origin male infertility (UOMI), demands a better understanding and assessment of both external/internal factors and mechanisms potentially involved. In this work, it was our aim to obtain new insight on UOMI, specifically on idiopathic (ID) and Unexplained male infertility (UMI), relying on a detailed evaluation of the male gamete, including functional, metabolic and proteomic aspects. For this purpose, 1114 semen samples, from males in couples seeking infertility treatment, were collected at the Reproductive Medicine Unit from the Centro Hospitalar e Universitário de Coimbra (CHUC), from July 2018-July 2022. Based on the couples' clinical data, seminal/hormonal analysis, and strict eligibility criteria, samples were categorized in 3 groups, control (CTRL), ID and UMI. Lifestyle factors and anxiety/depression symptoms were assessed via survey. Sperm samples were evaluated functionally, mitochondrially and using proteomics. The results of Assisted Reproduction Techniques were assessed whenever available. According to our results, ID patients presented the worst sperm functional profile, while UMI patients were similar to controls. The proteomic analysis revealed 145 differentially expressed proteins, 8 of which were specifically altered in ID and UMI samples. Acrosin (ACRO) and sperm acrosome membrane-associated protein 4 (SACA4) were downregulated in ID patients while laminin subunit beta-2 (LAMB2), mannose 6-phosphate isomerase (MPI), ATP-dependent 6-phosphofructokinase liver type (PFKAL), STAR domain-containing protein 10 (STA10), serotransferrin (TRFE) and exportin-2 (XPO2) were downregulated in UMI patients. Using random forest analysis, SACA4 and LAMB2 were identified as the sperm proteins with a higher chance of distinguishing ID and UMI patients, and their function and expression variation were in accordance with the functional results. No alterations were observed in terms of lifestyle and psychological factors among the 3 groups. These findings obtained in an experimental setting based on 3 well-defined groups of subjects, might help to validate new biomarkers for unknown origin male infertility (ID and UMI) that, in the future, can be used to improve diagnostics and treatments.
全球男性不育症（male）发病率上升的趋势令人担忧，而其中一半病例的病因尚不明确，即所谓的不明原因男性不育症（unknown origin male infertility，UOMI），这需要我们更好地理解和评估潜在的内外因素和机制。在这项工作中，我们旨在通过详细评估男性配子的功能、代谢和蛋白质组学方面，获得对 UOMI 的新认识，特别是对特发性（idiopathic，ID）和不明原因男性不育症（unexplained male infertility，UMI）的认识。为此，我们收集了 2018 年 7 月至 2022 年 7 月期间在科英布拉大学中心医院生殖医学科（Centro Hospitalar e Universitário de Coimbra，CHUC）寻求不孕治疗的夫妇的 1114 份精液样本。根据夫妇的临床数据、精液/激素分析和严格的入选标准，样本被分为三组：对照组（CTRL）、ID 和 UMI。通过问卷调查评估了生活方式因素和焦虑/抑郁症状。评估了精子的功能、线粒体和蛋白质组学。只要有条件，就评估辅助生殖技术的结果。根据我们的结果，ID 患者的精子功能谱最差，而 UMI 患者与对照组相似。蛋白质组学分析显示 145 种差异表达蛋白，其中 8 种在 ID 和 UMI 样本中特异性改变。ID 患者的顶体酶（acrosin，ACRO）和精子顶体膜相关蛋白 4（sperm acrosome membrane-associated protein 4，SACA4）下调，而 UMI 患者的层粘连蛋白亚基β-2（laminin subunit beta-2，LAMB2）、甘露糖 6-磷酸异构酶（mannose 6-phosphate isomerase，MPI）、ATP 依赖性 6-磷酸果糖激酶肝型（ATP-dependent 6-phosphofructokinase liver type，PFKAL）、STA 域包含蛋白 10（STAR domain-containing protein 10，STA10）、转铁蛋白（serotransferrin，TRFE）和 exportin-2（XPO2）下调。使用随机森林分析，SACA4 和 LAMB2 被确定为区分 ID 和 UMI 患者的可能性更高的精子蛋白，其功能和表达变化与功能结果一致。三组患者的生活方式和心理因素无差异。这些在基于三组明确界定的受试者的实验环境中获得的发现，可能有助于验证不明原因男性不育症（ID 和 UMI）的新生物标志物，这些标志物将来可用于改善诊断和治疗。
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