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Research Article

Fetal programming of adult Leydig cell function by androgenic effects on stem/progenitor cells

Karen R. Kilcoyne, Lee B. Smith, Nina Atanassova, Sheila Macpherson, Chris McKinnell, Sander van den Driesche, Matthew S. Jobling, Thomas J. G. Chambers, Karel De Gendt, Guido Verhoeven, Laura O’Hara, Sophie Platts, Luiz Renato de Franca, Nathália L. M. Lara, Richard A. Anderson, and Richard M. Sharpe
  1. aMedical Research Council Centre for Reproductive Health, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, United Kingdom;
  2. bInstitute of Experimental Morphology, Pathology and Anthropology with Museum, Bulgarian Academy of Sciences, Sofia 1113, Bulgaria;
  3. cDepartment of Clinical and Experimental Medicine, Catholic University of Leuven, B-300 Leuven, Belgium; and
  4. dLaboratory of Cellular Biology, Department of Morphology, Institute of Biological Sciences, Federal University of Minas Gerais, MG 31270-901, Belo Horizonte, Brazil

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PNAS May 6, 2014 111 (18) E1924-E1932; first published April 21, 2014; https://doi.org/10.1073/pnas.1320735111
Karen R. Kilcoyne
aMedical Research Council Centre for Reproductive Health, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, United Kingdom;
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Lee B. Smith
aMedical Research Council Centre for Reproductive Health, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, United Kingdom;
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Nina Atanassova
bInstitute of Experimental Morphology, Pathology and Anthropology with Museum, Bulgarian Academy of Sciences, Sofia 1113, Bulgaria;
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Sheila Macpherson
aMedical Research Council Centre for Reproductive Health, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, United Kingdom;
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Chris McKinnell
aMedical Research Council Centre for Reproductive Health, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, United Kingdom;
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Sander van den Driesche
aMedical Research Council Centre for Reproductive Health, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, United Kingdom;
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Matthew S. Jobling
aMedical Research Council Centre for Reproductive Health, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, United Kingdom;
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Thomas J. G. Chambers
aMedical Research Council Centre for Reproductive Health, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, United Kingdom;
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Karel De Gendt
cDepartment of Clinical and Experimental Medicine, Catholic University of Leuven, B-300 Leuven, Belgium; and
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Guido Verhoeven
cDepartment of Clinical and Experimental Medicine, Catholic University of Leuven, B-300 Leuven, Belgium; and
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Laura O’Hara
aMedical Research Council Centre for Reproductive Health, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, United Kingdom;
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Sophie Platts
aMedical Research Council Centre for Reproductive Health, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, United Kingdom;
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Luiz Renato de Franca
dLaboratory of Cellular Biology, Department of Morphology, Institute of Biological Sciences, Federal University of Minas Gerais, MG 31270-901, Belo Horizonte, Brazil
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Nathália L. M. Lara
dLaboratory of Cellular Biology, Department of Morphology, Institute of Biological Sciences, Federal University of Minas Gerais, MG 31270-901, Belo Horizonte, Brazil
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Richard A. Anderson
aMedical Research Council Centre for Reproductive Health, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, United Kingdom;
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Richard M. Sharpe
aMedical Research Council Centre for Reproductive Health, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, United Kingdom;
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  • For correspondence: r.sharpe@ed.ac.uk
  1. Edited by John J. Eppig, The Jackson Laboratory, Bar Harbor, ME, and approved March 25, 2014 (received for review November 7, 2013)

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Significance

Men are defined by androgens (testosterone), which drive fetal masculinization (male development) and puberty and maintain masculinity in adulthood, including sex drive, erectile function, and fertility. Moreover, Western cardiometabolic diseases are all associated with lowered testosterone levels in men. Therefore, influences on testosterone levels in adulthood have pervasive importance for masculinity and health. Our study shows, for the first time, to our knowledge, that testosterone levels during fetal masculinization can (re)program adult testosterone levels through effects on stem cells, which develop into adult Leydig cells (the source of testosterone) after puberty. These stem cells are present in fetal testes of humans and animals, and using the latter, we show how these cells are reprogrammed to affect adult testosterone levels.

Abstract

Fetal growth plays a role in programming of adult cardiometabolic disorders, which in men, are associated with lowered testosterone levels. Fetal growth and fetal androgen exposure can also predetermine testosterone levels in men, although how is unknown, because the adult Leydig cells (ALCs) that produce testosterone do not differentiate until puberty. To explain this conundrum, we hypothesized that stem cells for ALCs must be present in the fetal testis and might be susceptible to programming by fetal androgen exposure during masculinization. To address this hypothesis, we used ALC ablation/regeneration to identify that, in rats, ALCs derive from stem/progenitor cells that express chicken ovalbumin upstream promoter transcription factor II. These stem cells are abundant in the fetal testis of humans and rodents, and lineage tracing in mice shows that they develop into ALCs. The stem cells also express androgen receptors (ARs). Reduction in fetal androgen action through AR KO in mice or dibutyl phthalate (DBP) -induced reduction in intratesticular testosterone in rats reduced ALC stem cell number by ∼40% at birth to adulthood and induced compensated ALC failure (low/normal testosterone and elevated luteinizing hormone). In DBP-exposed males, this failure was probably explained by reduced testicular steroidogenic acute regulatory protein expression, which is associated with increased histone methylation (H3K27me3) in the proximal promoter. Accordingly, ALCs and ALC stem cells immunoexpressed increased H3K27me3, a change that was also evident in ALC stem cells in fetal testes. These studies highlight how a key component of male reproductive development can fundamentally reprogram adult hormone production (through an epigenetic change), which might affect lifetime disease risk.

  • adult Leydig stem/progenitor cells
  • compensated Leydig cell failure
  • GATA4
  • ethane dimethane sulfonate

Footnotes

  • ↵1To whom correspondence should be addressed. E-mail: r.sharpe{at}ed.ac.uk.
  • Author contributions: K.R.K., L.B.S., K.D.G., G.V., and R.M.S. designed research; K.R.K., N.A., S.M., C.M., S.v.d.D., M.S.J., T.J.G.C., K.D.G., L.O., S.P., L.R.d.F., N.L.M.L., and R.A.A. performed research; L.B.S., T.J.G.C., K.D.G., G.V., L.O., L.R.d.F., and R.A.A. contributed new reagents/analytic tools; K.R.K., N.A., and R.M.S. analyzed data; and K.R.K., L.B.S., G.V., R.A.A., and R.M.S. wrote the paper.

  • The authors declare no conflict of interest.

  • This article is a PNAS Direct Submission.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1320735111/-/DCSupplemental.

Freely available online through the PNAS open access option.

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Fetal androgen effects on adult Leydig cells
Karen R. Kilcoyne, Lee B. Smith, Nina Atanassova, Sheila Macpherson, Chris McKinnell, Sander van den Driesche, Matthew S. Jobling, Thomas J. G. Chambers, Karel De Gendt, Guido Verhoeven, Laura O’Hara, Sophie Platts, Luiz Renato de Franca, Nathália L. M. Lara, Richard A. Anderson, Richard M. Sharpe
Proceedings of the National Academy of Sciences May 2014, 111 (18) E1924-E1932; DOI: 10.1073/pnas.1320735111

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Fetal androgen effects on adult Leydig cells
Karen R. Kilcoyne, Lee B. Smith, Nina Atanassova, Sheila Macpherson, Chris McKinnell, Sander van den Driesche, Matthew S. Jobling, Thomas J. G. Chambers, Karel De Gendt, Guido Verhoeven, Laura O’Hara, Sophie Platts, Luiz Renato de Franca, Nathália L. M. Lara, Richard A. Anderson, Richard M. Sharpe
Proceedings of the National Academy of Sciences May 2014, 111 (18) E1924-E1932; DOI: 10.1073/pnas.1320735111
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