title: Fetal programming of adult Leydig cell function by androgenic effects on stem/progenitor cells.
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.
authors.affiliation: Medical Research Council Centre for Reproductive Health, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, United Kingdom.
authors.forename: Karen R
authors.initials: KR
authors.lastname: Kilcoyne
authors.forename: Lee B
authors.initials: LB
authors.lastname: Smith
authors.forename: Nina
authors.initials: N
authors.lastname: Atanassova
authors.forename: Sheila
authors.initials: S
authors.lastname: Macpherson
authors.forename: Chris
authors.initials: C
authors.lastname: McKinnell
authors.forename: Sander
authors.initials: S
authors.lastname: van den Driesche
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Jobling
authors.forename: Thomas J G
authors.initials: TJ
authors.lastname: Chambers
authors.forename: Karel
authors.initials: K
authors.lastname: De Gendt
authors.forename: Guido
authors.initials: G
authors.lastname: Verhoeven
authors.forename: Laura
authors.initials: L
authors.lastname: O'Hara
authors.forename: Sophie
authors.initials: S
authors.lastname: Platts
authors.forename: Luiz
authors.initials: L
authors.lastname: Renato de Franca
authors.forename: Nathália L M
authors.initials: NL
authors.lastname: Lara
authors.forename: Richard A
authors.initials: RA
authors.lastname: Anderson
authors.forename: Richard M
authors.initials: RM
authors.lastname: Sharpe
mesh_terms: D053687:Adult Stem Cells / Q000187:drug effects / Q000502:physiology*; D000728:Androgens / Q000502:physiology*; D000818:Animals; D002144:Callithrix; D019070:Cell Lineage / Q000502:physiology; D003993:Dibutyl Phthalate / Q000633:toxicity; D005260:Female; D047109:Fetal Development / Q000187:drug effects / Q000502:physiology*; D053686:Fetal Stem Cells / Q000187:drug effects / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D007985:Leydig Cells / Q000187:drug effects / Q000502:physiology*; D007986:Luteinizing Hormone / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D023421:Models, Animal; D011247:Pregnancy; D051381:Rats; D055647:Rats, Transgenic; D017208:Rats, Wistar; D011944:Receptors, Androgen / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D012038:Regeneration; D013737:Testis / Q000196:embryology / Q000502:physiology; D013739:Testosterone / Q000172:deficiency / Q000502:physiology
chemical_list: D000728:Androgens; D011944:Receptors, Androgen; D003993:Dibutyl Phthalate; D013739:Testosterone; D007986:Luteinizing Hormone
keywords: GATA4; adult Leydig stem/progenitor cells; compensated Leydig cell failure; ethane dimethane sulfonate
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