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Title: New Insights on Sperm Function in Male Infertility of Unknown Origin: A Multimodal Approach
Authors: Pacheco, Rita I. 
Cristo, Maria I. 
Anjo, Sandra I. 
Silva, Andreia F. 
Sousa, Maria Inês 
Santos Tavares, Renata 
Sousa, Ana Paula 
Santos, Teresa Almeida 
Moura-Ramos, Mariana 
Caramelo, Francisco 
Manadas, Bruno 
Santos, João Ramalho 
Amaral, Sandra Gomes 
Keywords: idiopathic male infertility; unexplained male infertility; sperm function; sperm proteomics; biomarker
Issue Date: 27-Sep-2023
Publisher: MDPI
Project: This work was financed by the European Regional Development Fund (ERDF), through the COMPETE 2020—Operational Program for Competitiveness and Internationalization and Portuguese national funds via Fundação para a Ciência e Tecnologia (FCT), under the projects POCI- 01-0145-FEDER-028599 (ref: PTDC/MEC-AND/28599/2017-INFERT2EXPLAIN), POCI-01-0145- FEDER-029311 (ref.: PTDC/BTM-TEC/29311/2017), UIDB/04539/2020, UIDP/04539/2020 and LA/P/0058/2020 and also by the National Mass Spectrometry Network (RNEM) [POCI-01-0145- FEDER-402-022125 Ref. ROTEIRO/0028/2013). RT was a doctoral researcher hired at the scope of INFERT2EXPLAIN project. MIC and AFS were supported by FCT, through PhD scholarships: 2021.05170.BD and SFRH/BD/129429/2017, respectively, at the scope of the PhD Programme in Experimental Biology and Biomedicine. 
Serial title, monograph or event: Biomolecules
Volume: 13
Issue: 10
Abstract: 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.
ISSN: 2218-273X
DOI: 10.3390/biom13101462
Rights: openAccess
Appears in Collections:I&D CINEICC - Artigos em Revistas Internacionais
FMUC Medicina - Artigos em Revistas Internacionais
FCTUC Ciências da Vida - Artigos em Revistas Internacionais
IIIUC - Artigos em Revistas Internacionais
I&D CNC - Artigos em Revistas Internacionais

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