SFEBES2013 Poster Presentations Pituitary (71 abstracts)
Perinatal origins of adult Leydig cells and function: role of developmental androgens
Karen Kilcoyne 1 , Nina Atanossova 2 , Luiz Renato de Franca 3 , Nathalia Lara 3 , Karel De Gendt 4 , Guido Verhoeven 4 , Chris McKinnell 1 , Sheila Macpherson 1 , Sander van den Driesche 1 , Lee Smith 1 & Richard M Sharpe 1
1University of Edinburgh, Edinburgh, UK; 2Institute of Experimental Morphology, Sofia, Bulgaria; 3Institute of Biological Sciences, Minas Gerais, Brazil; 4Catholic University of Leuven, Leuven, Belgium.
Fetal events can affect adult testosterone levels but how this occurs is unknown, as adult Leydig cells (ALC) do not differentiate until puberty. Qin et al. 2008 (PLos ONE) identified that chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII) is essential postnatally for ALC development. We hypothesized that: i) COUP-TFII+ non-Leydig interstitial cells are progenitors for ALC and are present in the fetal testis, ii) these ‘progenitor ALC’ are regulated by fetal androgens, and this might affect testosterone levels in adulthood.
Three approaches were used: i) complete androgen receptor (AR) knockout (ARKO) mice, ii) pregnant rats treated with dibutyl phthalate (DBP; 500 mg/kg per day; e13.5–e21.5) which reduces fetal intratesticular testosterone >70%, iii) iNOS−/− mice in which intratesticular testosterone is increased. Numbers of progenitor ALC were quantified from fetal life to adulthood, and related to ALC number and function, (testosterone and LH levels, ALC-specific steroidogenic gene expression).
Presumptive progenitor ALC expressing AR (COUP-TFII+/AR+) are abundant in the fetal testis of rats, mice, marmosets and humans. In ARKOs, progenitor ALC number was reduced ~40% from birth to adulthood, paralleled by a similar shortfall in ALC; there was also compensated ALC failure. In adults progenitor and ALC numbers were correlated (P<0.0001). Fetal DBP exposure reduced progenitor ALC numbers by ~40% in fetal and postnatal life and induced compensated ALC failure and reduced steroidogenic gene expression. The iNOS−/− mice are currently under investigation.
This study suggests that COUP-TFII identifies a population of cells in the fetal testis from which ALC develop from puberty onwards, and these cells are partly regulated by androgens. Reduced fetal androgen exposure altered ALC function (mechanism unclear), presumably by altering fetal androgen action on the ALC progenitors. This adds a new dimension to growing evidence that fetal androgen exposure may determine functional competence of the adult testis and overall male reproductive health.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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