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INVITED RESEARCH HIGHLIGHT
Year : 2015  |  Volume : 17  |  Issue : 2  |  Page : 219-220

Reduced fetal androgen exposure compromises Leydig cell function in adulthood


Department of Animal Sciences, Human and Animal Physiology, Wageningen University, De Elst 1, 6709 WD Wageningen, The Netherlands

Date of Web Publication14-Nov-2014

Correspondence Address:
Katja J Teerds
Department of Animal Sciences, Human and Animal Physiology, Wageningen University, De Elst 1, 6709 WD Wageningen
The Netherlands
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1008-682X.143249

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  Abstract 

Disruption of normal fetal development can influence functioning of organs and cells in adulthood. Circumstantial evidence suggests that subtle reductions in fetal androgen production may be the cause of adult male reproductive disorders due to reduced testosterone production. The mechanisms through which these fetal events affect adult testosterone levels are largely unknown. A recent paper of Kilcoyne et al. provides evidence that fetal reduction in androgen production or signaling results in a reduced Leydig stems cell number after birth and concomitant Leydig cell failure in adulthood. This implies that fetal androgen deficiency can lead to negative programming of adult Leydig cell (ALC) function, which may have implications for general health, aging, and longevity.


How to cite this article:
Teerds KJ, Keijer J. Reduced fetal androgen exposure compromises Leydig cell function in adulthood. Asian J Androl 2015;17:219-20

How to cite this URL:
Teerds KJ, Keijer J. Reduced fetal androgen exposure compromises Leydig cell function in adulthood. Asian J Androl [serial online] 2015 [cited 2019 Dec 16];17:219-20. Available from: http://www.ajandrology.com/text.asp?2015/17/2/219/143249 - DOI: 10.4103/1008-682X.143249

Leydig cells are the main producer of androgens in the body and not only play an essential role in the paracrine regulation of spermatogenesis in the testis, but also have various systemic endocrine effects, androgenic and anabolic. Knowledge about the origin of the ALC population and the regulation of Leydig cell function is important for reproductive and metabolic performance. It will also help to understand the aging-related gradual decline in testosterone levels with consequences for not only sperm production and libido but also for general well-being as it affects for instance muscle mass and bone mineral density.

Androgen production in fetal life is initiated with the formation of the fetal Leydig cell (FLC) population, and plays a crucial role in masculinization of the male fetus. After birth, the FLC population regresses and androgen production is low until puberty, when a new population of Leydig cells starts to develop, the ALC population. The definitive origin of the ALC stem cell has not been conclusively defined. Although both ALC and FLC have a common function in androgen production, ALC are not derived from preexisting FLC [1] but have their origin in a stem cell population in the interstitium of the postnatal testes. In 2006 Ge et al. [2] were the first to identify and characterize the potential stem cell for the ALC, being a steroidogenically inactive spindle-shaped cell that expresses receptors for platelet-derived growth factor receptor-α and leukemia inhibiting factor, but does not express the luteinizing hormone (LH) receptor or steroidogenic enzymes. There are indications that the stem cells from which the ALCs develop find their origin in the fetal testis, [3],[4] but no definitive proof for this hypothesis was available until the publication of Kilcoyne et al. [5] in the Proceedings of the National Academy of Sciences USA.

Chicken ovalbumin upstream promoter transcription factor II (Coup-tfII), an orphan nuclear receptor of the steroid/thyroid hormone receptor superfamily, has been implicated as an important factor in the development of the ALC population. Based on the studies by Qin et al. [3] Kilcoyne et al. [5] hypothesize that the Coup-tfII expressing cells in the fetal testis that are negative for Leydig cell markers such as LH receptor and 3β-hydroxysteroid dehydrogenase (Hsd3b), may be the stem cells for the ALC. The authors further suggest that these stem cells might be susceptible to programming by androgens produced by FLCs during fetal life.

As a first step to prove their hypothesis Kilcoyne et al. investigated whether Leydig stem cells are present in the adult testis, using the ethane dimethyl sulphonate (EDS) treated rat as a model. EDS is a compound that specifically destroys Leydig cells in the adult rat testis, followed by a complete regeneration of the ALC population several weeks after a single EDS administration. [6] After the ablation of the ALC population, numerous spindle-shaped Coup-tfII positive cells could be detected in the interstitium. By 2 weeks after the EDS injection the first regenerated Leydig cells were observed that expressed Coup-tf-II and Hsd3b. With progressive regeneration of the Leydig cell population the number of Coup-tfII pos/Hsd3b neg cells decreased, demonstrating that the new Leydig cells have developed from the Coup-tfII positive stem cells. The next step of the authors was to demonstrate that the Coup-tfII pos/Hsd3b neg, cells, which are also present in the fetal testis, develop into ALC after birth. Using transgenic Cre-recombinase mouse lines Kilcoyne et al. [5] are the first to show convincingly that Coup-tfII pos/Hsd3b neg cells in the fetal testis give rise to the ALC in the postnatal testis; these fetal cells also express the androgen receptor (AR).

Indirect evidence suggests that subtle reductions in fetal androgen production may be the cause of adult male reproductive disorders due to reduced testosterone production. The authors, therefore, investigated whether suppression of FLC androgen production could influence the functioning of the ALC population. To reduce fetal intratesticular testosterone levels pregnant female rats were treated with dibutyl phthalate. This treatment resulted in a 40% decrease in adult Leydig stem cell numbers at the time of birth. Although ALC numbers were normal in adulthood, Leydig cell functioning was severely affected as a consequence of a significant reduction in the expression of steroid acute regulatory protein (StAR), a protein that is responsible for the transport of cholesterol from the cytoplasm into the mitochondria of Leydig cells and therefore essential for testosterone synthesis.

In order to explain how altered fetal androgen action can reduce StAR transcription, and thus ALC function, in adulthood, epigenetic changes via histone methylation were investigated. Altered methylation of the proximal-1 promoter region of StAR is crucial for regulating the expression of this gene. The level of H3K27me3, a well-known transcriptional repressor, upstream of the coding region of StAR appeared to be significantly increased. H3K27me3 protein was present in a proportion of the ALC of rats in which fetal androgen production was repressed, whereas this epigenetic mark was virtually absent in ALC of control animals. H3K27me3 protein also appeared to be present in the Coup-tfII pos/Hsd3b neg stem Leydig cells in the adult testis, implicating a possible mechanism through which deficiency in fetal androgen action on stem cells can reprogram ALC function by influencing the transcription of StAR. These data fit with increasing evidence from studies in humans, in whom reduced fetal androgen production is shown to be associated with reduced adult sperm count. [7] In line with this assumption, men with reduced sperm count commonly exhibit compromised Leydig cell function. The publication by Kilcoyne et al. is the first to show that there may indeed be a relationship between deficits in fetal androgen exposure and ALC function, with consequences for fertility, but also a range of other disorders in men related to inadequate androgen production such as decreased bone mineral density, chronic fatigue, cancer and coronary heart disease. [8] Moreover, since fetal testosterone levels correlate with maternal testosterone levels, [9] this publication potentially adds to scientific literature on the importance of maternal physiology on later life health, in this case reproductive health, of the offspring.


  Competing Interests Top


All authors declare no competing interests.

 
  References Top

1.
Habert R, Lejeune H, Saez JM. Origin, differentiation and regulation of fetal and adult Leydig cells. Mol Cell Endocrinol 2001; 179: 47-74.  Back to cited text no. 1
    
2.
Ge RS, Dong Q, Sottas CM, Papadopoulos V, Zirkin BR, et al. In search of rat stem Leydig cells: identification, isolation, and lineage-specific development. Proc Natl Acad Sci U S A 2006; 103: 2719-24.  Back to cited text no. 2
    
3.
Qin J, Tsai MJ, Tsai SY. Essential roles of COUP-TFII in Leydig cell differentiation and male fertility. PLoS One 2008; 3: e3285.  Back to cited text no. 3
    
4.
Barsoum IB, Kaur J, Ge RS, Cooke PS, Yao HH. Dynamic changes in fetal Leydig cell populations influence adult Leydig cell populations in mice. FASEB J 2013; 27: 2657-66.  Back to cited text no. 4
    
5.
Kilcoyne KR, Smith LB, Atanassova N, Macpherson S, McKinnell C, et al. Fetal programming of adult Leydig cell function by androgenic effects on stem/progenitor cells. Proc Natl Acad Sci U S A 2014; 111: E1924-32.  Back to cited text no. 5
    
6.
Sharpe RM, Maddocks S, Kerr JB. Cell-cell interactions in the control of spermatogenesis as studied using Leydig cell destruction and testosterone replacement. Am J Anat 1990; 188: 3-20.  Back to cited text no. 6
    
7.
Dean A, Sharpe RM. Clinical review: anogenital distance or digit length ratio as measures of fetal androgen exposure: relationship to male reproductive development and its disorders. J Clin Endocrinol Metab 2013; 98: 2230-8.  Back to cited text no. 7
    
8.
Traish AM, Miner MM, Morgentaler A, Zitzmann M. Testosterone deficiency. Am J Med 2011; 124: 578-87.  Back to cited text no. 8
    
9.
Gitau R, Adams D, Fisk NM, Glover V. Fetal plasma testosterone correlates positively with cortisol. Arch Dis Child Fetal Neonatal Ed 2005; 90: F166-9.  Back to cited text no. 9
    




 

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