ArticlePloS one2012
Proposed role for COUP-TFII in regulating fetal Leydig cell steroidogenesis, perturbation of which leads to masculinization disorders in rodents.
Article in PloS one, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 44 papers.
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Who cites it
44 citing papers in PubMed, 90 citations in OpenAlex.
- Post-translational modification of proteins in the human testis development pathway.Human reproduction update · 2026Review
- Article
- Single-cell resolution uncovers neighboring cell subtypes that share steroidogenic capacity during fetal testis development.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Evaluation of the endocrine disrupting potential of Di-isononyl phthalate.Current research in toxicology · 2025Article
- Evidence for NR2F2/COUP-TFII involvement in human testis development.Scientific reports · 2024Article
- Mechanistic screening of reproductive toxicity in a novel 3D testicular co-culture model shows significant impairments following exposure to low-dibutyl phthalate concentrations.Archives of toxicology · 2024Article
- Fetal Leydig cells: What we know and what we don't.Molecular reproduction and development · 2024Review
- COUP-TFII regulates early bipotential gonad signaling and commitment to ovarian progenitors.Cell & bioscience · 2024Article
- Testicular differentiation in 46,XX DSD: an overview of genetic causes.Frontiers in endocrinology · 2024Review
- Nuclear Receptor Gene Variants Underlying Disorders/Differences of Sex Development through Abnormal Testicular Development.Biomolecules · 2023Review
- Steroid hormone signaling: multifaceted support of testicular function.Frontiers in cell and developmental biology · 2023Review
- Emerging concepts on Leydig cell development in fetal and adult testis.Frontiers in endocrinology · 2022Review
- Expression and Role of INSL3 in the Fetal Testis.Frontiers in endocrinology · 2022Review
- Cisplatin Effects on the Human Fetal Testis - Establishing the Sensitive Period for (Pre)Spermatogonial Loss and Relevance for Fertility Preservation in Pre-Pubertal Boys.Frontiers in endocrinology · 2022Article
- REPRODUCTIVE TOXICOLOGY: Environmental exposures, fetal testis development and function: phthalates and beyond.Reproduction (Cambridge, England) · 2021Review
- Development of a putative adverse outcome pathway network for male rat reproductive tract abnormalities with specific considerations for the androgen sensitive window of development.Current research in toxicology · 2021Article
- Endosialin defines human stem Leydig cells with regenerative potential.Human reproduction (Oxford, England) · 2020Article
- Use of the Adverse Outcome Pathway (AOP) framework to evaluate species concordance and human relevance of Dibutyl phthalate (DBP)-induced male reproductive toxicity.Reproductive toxicology (Elmsford, N.Y.) · 2020Review
- Application of a combined aggregate exposure pathway and adverse outcome pathway (AEP-AOP) approach to inform a cumulative risk assessment: A case study with phthalates.Toxicology in vitro : an international journal published in association with BIBRA · 2020Article
- Analysis of variants in GATA4 and FOG2/ZFPM2 demonstrates benign contribution to 46,XY disorders of sex development.Molecular genetics & genomic medicine · 2020Article
Corrections and comments
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Authors and funding
11 authors at 3 institutions in 1 country.
Funding
Abstract
Reproductive disorders that are common/increasing in prevalence in human males may arise because of deficient androgen production/action during a fetal 'masculinization programming window'. We identify a potentially important role for Chicken Ovalbumin Upstream Promoter-Transcription Factor II (COUP-TFII) in Leydig cell (LC) steroidogenesis that may partly explain this. In rats, fetal LC size and intratesticular testosterone (ITT) increased ~3-fold between e15.5-e21.5 which associated with a progressive decrease in the percentage of LC expressing COUP-TFII. Exposure of fetuses to dibutyl phthalate (DBP), which induces masculinization disorders, dose-dependently prevented the age-related decrease in LC COUP-TFII expression and the normal increases in LC size and ITT. We show that nuclear COUP-TFII expression in fetal rat LC relates inversely to LC expression of steroidogenic factor-1 (SF-1)-dependent genes (StAR, Cyp11a1, Cyp17a1) with overlapping binding sites for SF-1 and COUP-TFII in their promoter regions, but does not affect an SF-1 dependent LC gene (3β-HSD) without overlapping sites. We also show that once COUP-TFII expression in LC has switched off, it is re-induced by DBP exposure, coincident with suppression of ITT. Furthermore, other treatments that reduce fetal ITT in rats (dexamethasone, diethylstilbestrol (DES)) also maintain/induce LC nuclear expression of COUP-TFII. In contrast to rats, in mice DBP neither causes persistence of fetal LC COUP-TFII nor reduces ITT, whereas DES-exposure of mice maintains COUP-TFII expression in fetal LC and decreases ITT, as in rats. These findings suggest that lifting of repression by COUP-TFII may be an important mechanism that promotes increased testosterone production by fetal LC to drive masculinization. As we also show an age-related decline in expression of COUP-TFII in human fetal LC, this mechanism may also be functional in humans, and its susceptibility to disruption by environmental chemicals, stress and pregnancy hormones could explain the origin of some human male reproductive disorders.
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