Experimentally induced testicular dysgenesis syndrome originates in the masculinization programming window

Driesche, Sander van den; Kilcoyne, Karen; Wagner, I. Janelle; Rebourcet, Diane; Boyle, Ashley; Mitchell, Rod; McKinnell, Chris; MacPherson, Sarah E.; Donat, Roland; Shukla, Chitranjan J.; Jørgensen, Anne; Meyts, Ewa Rajpert‐De; Skakkebæk, Niels E.; Sharpe, Richard M.

doi:10.1172/jci.insight.91204

Cited by 86 publications

(74 citation statements)

References 79 publications

(133 reference statements)

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“…Taken together, these results suggest that, similar to the mouse, DMRT1 is not essential for seminiferous cord formation in the human fetal testis, but is required for subsequent maintenance of the seminiferous cords and for the prevention of trans-differentiation to an ovarian phenotype. In the context of testicular dysgenesis syndrome (TDS) disorders, the present results suggest that the focal dysgenesis which is frequently observed in the testes of patients with reproductive disorders ( Skakkebaek et al , 2016 ), could arise as the result of the breakdown of already formed seminiferous cords, as recently documented in an animal model of TDS ( Lara et al , 2017 ; van den Driesche et al , 2017 ). Moreover, the fact that DMRT1-miRNA-induced focal dysgenesis was associated with evidence for impaired Leydig cell steroidogenesis, as indicated by reduced CYP11a1 expression, fits with the clinical ( Skakkebaek et al , 2016 ) and rodent experimental ( van den Driesche et al , 2017 ) data, and this is considered to be the underlying cause of some of the TDS disorders.…”

Section: Discussionsupporting

confidence: 64%

“…Once testicular somatic cell populations are established, testosterone production from fetal Leydig cells is initiated to induce masculinization of the fetus. Failure of normal sex-determination or perturbed hormone production during fetal gonadal development in humans can result in disorders of sex development (DSD) ( Jørgensen et al , 2015a ; Hersmus et al , 2017 ) and is also implicated in the development of testicular dysgenesis syndrome (TDS; cryptorchidism, hypospadias, testicular cancer and low sperm counts; Skakkebaek et al , 2016 ; van den Driesche et al , 2017 ).…”

Section: Introductionmentioning

confidence: 99%

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DMRT1 repression using a novel approach to genetic manipulation induces testicular dysgenesis in human fetal gonads

et al. 2018

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STUDY QUESTIONDoes loss of DMRT1 in human fetal testis alter testicular development and result in testicular dysgenesis?SUMMARY ANSWERDMRT1 repression in human fetal testis alters the expression of key testicular and ovarian determining genes, and leads to focal testicular dysgenesis.WHAT IS KNOWN ALREADYTesticular dysgenesis syndrome (TDS) is associated with common testicular disorders in young men, but its etiology is unknown. DMRT1 has been shown to play a role in the regulation of sex differentiation in the vertebrate gonad. Downregulation of DMRT1 in male mice results in trans-differentiation of Sertoli cells into granulosa (FOXL2+) cells resulting in an ovarian gonadal phenotype.STUDY DESIGN, SIZE, DURATIONTo determine the effect of DMRT1 repression on human fetal testes, we developed a novel system for genetic manipulation, which utilizes a Lentivral delivered miRNA during short-term in vitro culture (2 weeks). A long-term (4–6 weeks) ex vivo xenograft model was used to determine the subsequent effects of DMRT1 repression on testicular development and maintenance. We included first and second-trimester testis tissue (8–20 weeks gestation; n = 12) in the study.PARTICIPANTS/MATERIALS, SETTING, METHODSHuman fetal testes were cultured in vitro and exposed to either of two DMRT1 miRNAs (miR536, miR641), or to scrambled control miRNA, for 24 h. This was followed by a further 14 days of culture (n = 3–4), or xenografting (n = 5) into immunocompromised mice for 4–6 weeks. Tissues were analyzed by histology, immunohistochemistry, immunofluorescence and quantitative RT-PCR. Endpoints included histological evaluation of seminiferous cord integrity, mRNA expression of testicular, ovarian and germ cell genes, and assessment of cell number and protein expression for proliferation, apoptosis and pluripotency factors. Statistical analysis was performed using a linear mixed effect model.MAIN RESULTS AND THE ROLE OF CHANCEDMRT1 repression (miR536/miR641) resulted in a loss of DMRT1 protein expression in a sub-population of Sertoli cells of first trimester (8–11 weeks gestation) human fetal testis; however, this did not affect the completion of seminiferous cord formation or morphological appearance. In second-trimester testis (12–20 weeks gestation), DMRT1 repression (miR536/miR641) resulted in disruption of seminiferous cords with absence of DMRT1 protein expression in Sertoli (SOX9+) cells. No differences in proliferation (Ki67+) were observed and apoptotic cells (CC3+) were rare. Expression of the Sertoli cell associated gene, SOX8, was significantly reduced (miR536, 34% reduction, P = 0.031; miR641 36% reduction, P = 0.026), whilst SOX9 expression was unaffected. Changes in expression of AMH (miR536, 100% increase, P = 0.033), CYP26B1 (miR641, 38% reduction, P = 0.05) and PTGDS (miR642, 30% reduction, P = 0.0076) were also observed. Amongst granulosa cell associated genes, there was a significant downregulation in R-spondin 1 expression (miR536, 76% reduction, P < 0.0001; miR641, 49% reduction, P = 0.046); howev...

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Section: Discussionsupporting

confidence: 64%

Section: Introductionmentioning

confidence: 99%

DMRT1 repression using a novel approach to genetic manipulation induces testicular dysgenesis in human fetal gonads

et al. 2018

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“…They found that DBP treatment induced reduction of anogenital distance (AGD) and compensated ALC failure. Interestingly, these effects at later stages were observed when fetuses were treated in a limited time window (they called this period the masculinization programming window) . In another study, Su et al eliminated FLCs in the rat testis by EDS treatment at neonatal stages and analyzed the effect of FLC loss on ALC function in the pubertal and adult periods.…”

Section: Developmental Link Between Fetal and Adult Leydig Cellsmentioning

confidence: 99%

Development of fetal and adult Leydig cells

Shima

2019

Reprod Medicine & Biology

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Background In mammals, two distinct Leydig cell populations, fetal Leydig cells (FLCs) and adult Leydig cells (ALCs), appear in the prenatal and postnatal testis, respectively. Although the functional differences between these cell types have been well described, the developmental relationship between FLCs and ALCs has not been fully understood. In this review, I focus on the cellular origins of FLCs and ALCs as well as the developmental and functional links between them. Methods I surveyed previous reports about FLC and/or ALC development and summarized the findings. Main findings Fetal Leydig cells and ALCs were identified to have separate origins in the fetal and neonatal testis, respectively. However, several studies suggested that FLCs and ALCs share a common progenitor pool. Moreover, perturbation of FLC development at the fetal stage induces ALC dysfunction in adults, suggesting a functional link between FLCs and ALCs. Although the lineage relationship between FLCs and ALCs remains controversial, a recent study suggested that some FLCs dedifferentiate at the fetal stage, and that these cells serve as ALC stem cells. Conclusion Findings obtained from animal studies might provide clues to the causative mechanisms of male reproductive dysfunctions such as testicular dysgenesis syndrome in humans.

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“…Under normal conditions, the distance between the anus and the genitals, the anogenital distance (AGD), becomes twice as long in males as in females (Hotchkiss & Vandenbergh, 2005;Salazar-Martinez et al, 2004). The programming of AGD occurs during a short timespan during fetal development (embryonic day 15.5-18.5 in rats and gestation week 8-14 in humans) and is often referred to as the masculinization programming window (MPW) (van den Driesche et al, 2017;Van den Driesche et al, 2012;Welsh et al, 2008). If androgen signaling is disrupted during the MPW, it can have severe consequences for androgen-dependent tissues and organs, including the AGD; a morphometric change regarded as a feminization effect (Schwartz et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Distinct Transcriptional Profiles of the Female, Male, and Finasteride-Induced Feminized Male Anogenital Region in Rat Fetuses

Schwartz

Vinggaard

Christiansen

et al. 2019

Toxicological Sciences

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show abstract

Experimentally induced testicular dysgenesis syndrome originates in the masculinization programming window

Cited by 86 publications

References 79 publications

DMRT1 repression using a novel approach to genetic manipulation induces testicular dysgenesis in human fetal gonads

DMRT1 repression using a novel approach to genetic manipulation induces testicular dysgenesis in human fetal gonads

Development of fetal and adult Leydig cells

Distinct Transcriptional Profiles of the Female, Male, and Finasteride-Induced Feminized Male Anogenital Region in Rat Fetuses

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