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Knockout of MCT1 results in total absence of spermatozoa, sex hormones dysregulation, and morphological alterations in the testicular tissue

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Abstract

Lactate is a key metabolite for the normal occurrence of spermatogenesis. In the testis, lactate is produced by the Sertoli cells and transported to germline cells. Monocarboxylate transporters (MCTs) are key players in that process. Among the family of MCTs, MCT1 is at least partly responsible for lactate uptake by the germ cells. We aimed to perform a first assessment of the role of MCT1 in male reproductive potential. Mct1 conditional knockout (cKO) mice were used for morphometric evaluation, testicular morphology, and sperm parameter assessment. Serum steroid hormones levels were also measured. cKO animals showed a decrease in gonadosomatic index, testis weight, and seminiferous tubular diameters. Deletion of MCT1 also causes morphological changes in the organization of the seminiferous tubules and on Sertoli cell morphology. These changes resulted in failure of spermatogenesis with depletion of germ cells and total absence of spermatozoa. MCT1 cKO animals presented also hormonal dysregulation, with a decrease in serum 17β-estradiol levels. In conclusion, MCT1 is pivotal for male reproductive potential. Absence of MCT1 results in maintenance of undifferentiated spermatogonia pool and compromised sperm production.

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Acknowledgments

The authors are thankful to Ângela Alves for the technical support.

Funding

This work was supported by “Fundação para a Ciência e a Tecnologia” (FCT) to Raquel L. Bernardino (SFRH/BD/103105/2014) and Tânia R. Dias (SFRH/BD/109284/2015). The work was co-funded by FEDER through the COMPETE/QREN, FSE/POPH to Marco G. Alves (PTDC/BIM-MET/4712/2014 and PTDC/MEC-AND/28691/2017); Pedro F. Oliveira (PTDC/BBB-BQB/1368/2014); UMIB (PEst-OE/SAU/UI0215/2014); co-funded by the EU Framework Programme for Research and Innovation H2020 (POCI/COMPETE2020).

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Authors and Affiliations

  1. Department of Microscopy, Laboratory of Cell Biology, Institute of Biomedical Sciences Abel Salazar (ICBAS) and Multidisciplinary Unit for Biomedical Research (UMIB), University of Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313, Porto, Portugal

    Raquel L. Bernardino, Tânia R. Dias, Marco G. Alves & Pedro F. Oliveira

  2. Amgen Inc., Thousand Oaks, CA, USA

    Warren N. D’Souza, Jay L. Rothstein, Daniel Chui & Sharon Wannberg

  3. University of Beira Interior, Covilhã, Portugal

    Luis Rato & Tânia R. Dias

  4. LAQV/REQUIMTE - Laboratory of Bromatology and Hydrology, Faculty of Pharmacy, University of Porto, Porto, Portugal

    Tânia R. Dias

  5. Department of Genetics, Faculty of Medicine, University of Porto, Porto, Portugal

    Pedro F. Oliveira

  6. i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal

    Pedro F. Oliveira

Authors
  1. Raquel L. Bernardino
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  2. Warren N. D’Souza
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  3. Luis Rato
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  4. Jay L. Rothstein
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  5. Tânia R. Dias
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  7. Sharon Wannberg
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  8. Marco G. Alves
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  9. Pedro F. Oliveira
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Correspondence to Pedro F. Oliveira.

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Figure 3

Murine Mct1 exon 4 was flanked by loxP sites with adjoining upstream and downstream sequences of the mouse Mct1 genomic locus. Positive (Neomycin) and negative (Herpes simplex virus thymidine kinase) selectable markers were incorporated into the targeting vector for selection during homologous recombination in mouse embryonic stem (ES) cells. Genomic southern and PCR were used to detect correctly targeted mouse ES cells. (PNG 1671 kb)

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Bernardino, R.L., D’Souza, W.N., Rato, L. et al. Knockout of MCT1 results in total absence of spermatozoa, sex hormones dysregulation, and morphological alterations in the testicular tissue. Cell Tissue Res 378, 333–339 (2019). https://doi.org/10.1007/s00441-019-03028-4

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