ArticleProceedings of the National Academy of Sciences of the United States of America2014
Fetal programming of adult Leydig cell function by androgenic effects on stem/progenitor cells.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 88 papers, 1 of them a synthesis that pooled it.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
88 citing papers in PubMed, 1 synthesis or guideline pooled it, 180 citations in OpenAlex.
- Effect of environmental and pharmaceutical exposures on fetal testis development and function: a systematic review of human experimental data.Human reproduction update · 2019Pooled it
- Spatiotemporally primed coelomic epithelium and supporting-like cells establish the dual origin of granulosa cells.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Review
- Article
- Androgen signaling is dispensable for fetal testis formation: decoupling testis organogenesis from fetal masculinization programming.Molecular human reproduction · 2026Review
- Comprehensive Insight into the Male Dog Reproductive System in Health and Diseases: Developmental, Genetic, and Environmental Factors-Review on Research and Clinical Trials.Veterinary sciences · 2026Review
- A review on the epigenetic regulation of testosterone synthesis in Leydig cells.Molecular and cellular biochemistry · 2025Review
- Ovarian development is driven by early spatiotemporal priming of the coelomic epithelium.bioRxiv : the preprint server for biology · 2025Article
- Article
- NEDD4 Promotes Sertoli Cell Proliferation and Adult Leydig Cell Differentiation in the Murine Testis.Endocrinology · 2025Article
- A New Leydig Cell-Exclusive Cre Line Allows Lineage Tracing of Fetal and Adult Leydig Cell Populations in the Mouse.Endocrinology · 2025Article
- How relevant is the mouse model for understanding human sex determination?International journal of biological sciences · 2025Article
- Sertoli cells as a hub in testicular development and male reproductive.Frontiers in cell and developmental biology · 2025Review
- Endocrine disruption and male reproductive disorders: unanswered questions.Human reproduction (Oxford, England) · 2024Review
- WNT5A regulates the proliferation, apoptosis and stemness of human stem Leydig cells via the β-catenin signaling pathway.Cellular and molecular life sciences : CMLS · 2024Article
- Article
- Paternity share predicts sons' fetal testosterone.Scientific reports · 2023Article
- Effect of Fetal Pituitary-Testes Suppression on Brain Sexual Differentiation and Reproductive Function in Male Sheep.Endocrinology · 2023Article
- Nuclear Receptor Gene Variants Underlying Disorders/Differences of Sex Development through Abnormal Testicular Development.Biomolecules · 2023Review
- Effects of aging and macrophages on mice stem Leydig cell proliferation and differentiationFrontiers in endocrinology · 2023Article
28 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
16 authors at 7 institutions in 4 countries.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.