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Richard E. Peterson - One of the best experts on this subject based on the ideXlab platform.
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in uteroand lactational exposure to 2 3 7 8 tetrachlorodibenzo ρ dioxin effects on development of the male and female reproductive system of the mouse
Toxicology and Applied Pharmacology, 1997Co-Authors: H M Theobald, Richard E. PetersonAbstract:To evaluate effects of in utero and lactational 2,3,7,8-tetrachlorodibenzo-rho-dioxin (TCDD) exposure on male and female reproductive system development of the mouse, the offspring of pregnant ICR mice administered 0, 15, 30, or 60 microg TCDD/kg on Gestation Day (GD) 14 were examined at the postweanling, pubertal, young adult, and adult stages of development. Dam and offspring body weights and prenatal and postnatal mortality were unaffected by TCDD exposure. The most sensitive endpoints in male offspring were decreased ventral prostate, coagulating gland, and thymus weights, accelerated eye opening, and hydronephrosis. Decreases in pituitary gland weight and epididymal sperm numbers were also found in TCDD-exposed male offspring. Testis, epididymis, and dorsolateral prostate weights, anogenital distance, latencies to Testis Descent and to preputial separation, and serum testosterone concentrations were unaffected. At the highest maternal TCDD dose uterus weights were decreased in female offspring evaluated during estrus and diestrus. No morphologic changes in the external genitalia of female offspring were found, nor were there alterations in ovary or pituitary gland weights. Cross-species comparisons showed that the mouse was not as sensitive to TCDD-induced developmental reproductive toxicity as the rat and hamster. Many endpoints affected by TCDD in rat and hamster offspring were either not affected or were less sensitive in mouse offspring. Endpoints of androgenic status were not affected in the mouse, decreases in accessory sex organ weights were restricted to fewer organs in the mouse, and decreases in daily sperm production were not found in the mouse. The only developmental reproductive endpoint observed in all three species was a reduction in epididymal sperm numbers.
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reproductive toxicity of 2 3 7 8 tetrachlorodibenzo p dioxin in male rats different effects of in utero versus lactational exposure
Toxicology and Applied Pharmacology, 1994Co-Authors: Donald L Bjerke, Richard E. PetersonAbstract:The male rat reproductive system is highly sensitive to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) when exposure occurs during fetal and neonatal development. Our objective was to determine the relative contributions of in utero versus lactational TCDD exposure to effects on male reproductive function. Pregnant Holtzman rats were treated on Day 15 of gestation with TCDD (1.0 micrograms/kg) or vehicle (control). At birth litters were standardized to five males and five females and fostered to dams of the same treatment or cross-fostered to dams of the opposite treatment. Four treatment groups were assessed: male offspring not exposed to TCDD by either route (control) and male offspring exposed to TCDD in utero (IU), via lactation (L), or in utero and via lactation (IUL). During early postnatal development, two androgen sensitive end points, relative anogenital distance and time to Testis Descent, were not affected by TCDD. However, end points evaluated later during development were altered. Time to separation of the prepuce from the glans penis (an index of pubertal development) was delayed, plasma testosterone concentrations and accessory sex organ weights were reduced, daily sperm production and epididymal sperm reserves were decreased, and sexual behavior was feminized. Certain responses were only produced by IU exposure whereas other responses only occurred following L exposure. Only IU TCDD exposure delayed pubertal development and decreased daily sperm production, while only L TCDD exposure feminized the sexual behavior of male offspring. For most male reproductive end points both IU and L TCDD exposure produced the same responses. Decreases in plasma testosterone concentrations, reductions in weights, protein, and DNA contents of ventral prostate and seminal vesicles, and decreases in epididymal sperm reserves were caused in young adult rats by either IU or L exposure to TCDD. We conclude that the route and timing of TCDD exposure during fetal and neonatal development of the rat determine the profile of male reproductive effects observed and that all effects in the present study, with the notable exception of feminized sexual behavior, can be caused by low level exposure to TCDD via the IU route alone.
A O Brinkmann - One of the best experts on this subject based on the ideXlab platform.
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involvement of insulin like factor 3 insl3 in diethylstilbestrol induced cryptorchidism
Endocrinology, 2000Co-Authors: Judith M A Emmen, Ibrahim M Adham, Anke Mcluskey, Wolfgang Engel, Anton J Grootegoed, Miriam Verhoefpost, Axel P N Themmen, A O BrinkmannAbstract:Recently, it has been shown that targeted inactivation of the Insl3 gene in male mice results in cryptorchidism. The Insl3 gene encodes insulin-like factor 3 (Insl3), which is expressed in fetal Leydig cells. The testicular factor Insl3 appears to play an important role in the transabdominal phase of Testis Descent, which involves development of the gubernaculum. Other studies have demonstrated that in utero exposure to diethylstilbestrol (DES), a synthetic estrogen, can lead to cryptorchidism both in humans and in animal models. The present study was undertaken to investigate whether prenatal DES-exposure might interfere with testicular Insl3 mRNA expression. Furthermore, the effect of DES on steroidogenic factor 1 (SF-1) mRNA expression level was determined, since it has been shown that SF-1 plays an essential role in transcriptional activation of the Insl3 gene promoter. Timed pregnant mice were treated with DES (100 μg/kg body weight) or vehicle alone on days E9 (gestational day 9) through E17. Contro...
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hormonal control of gubernaculum development during Testis Descent gubernaculum outgrowth in vitro requires both insulin like factor and androgen
Endocrinology, 2000Co-Authors: Judith M A Emmen, Ibrahim M Adham, Anke Mcluskey, Wolfgang Engel, Anton J Grootegoed, A O BrinkmannAbstract:The gubernaculum connects the gonad to the inguinoscrotal region and is involved in Testis Descent. It rapidly develops in the male fetus, whereas development in the female fetus is lacking. Possible factors involved in gubernaculum development are androgens, anti-Mullerian hormone (AMH), and insulin-like factor (Insl3). Sexual dimorphism in gubernaculum development correlated with the mitotic activity of cells in the gubernacular bulbs from male and female fetuses. Androgen receptor expression was restricted to the mesenchymal core of the gubernacular bulb, whereas skeletal muscle was detected in its outer layer. In an organ culture system devised to further study gubernaculum development in vitro, morphology of gubernacular explants grown in the presence of testes was comparable with that of gubernacula developed in vivo. Testicular tissue or medium containing R1881, a synthetic androgen, had a growth stimulatory effect on gubernacular explants compared with ovarian tissue or basal medium only. Moreover...
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hormonal control of gubernaculum development during Testis Descent gubernaculum outgrowth in vitro requires both insulin like factor and androgen
Endocrinology, 2000Co-Authors: Judith M A Emmen, Ibrahim M Adham, Anke Mcluskey, Wolfgang Engel, Anton J Grootegoed, A O BrinkmannAbstract:The gubernaculum connects the gonad to the inguinoscrotal region and is involved in Testis Descent. It rapidly develops in the male fetus, whereas development in the female fetus is lacking. Possible factors involved in gubernaculum development are androgens, anti-Mullerian hormone (AMH), and insulin-like factor (Insl3). Sexual dimorphism in gubernaculum development correlated with the mitotic activity of cells in the gubernacular bulbs from male and female fetuses. Androgen receptor expression was restricted to the mesenchymal core of the gubernacular bulb, whereas skeletal muscle was detected in its outer layer. In an organ culture system devised to further study gubernaculum development in vitro, morphology of gubernacular explants grown in the presence of testes was comparable with that of gubernacula developed in vivo. Testicular tissue or medium containing R1881, a synthetic androgen, had a growth stimulatory effect on gubernacular explants compared with ovarian tissue or basal medium only. Moreover, Amh-/-, Amh+/-, and Insl3+/- testes stimulated the growth of gubernacular explants to the same extent as control testes. Insl3-/- testes, however, did not produce such an activity. This study reveals an essential role for both androgen and Insl3 in the gubernaculum outgrowth during transabdominal Testis Descent.
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Androgen action during male sex differentiation includes suppression of cranial suspensory ligament development.
Human reproduction (Oxford England), 1998Co-Authors: Judith M A Emmen, Anke Mcluskey, J. A. Grootegoed, A O BrinkmannAbstract:The cranial suspensory ligament is located on the border of the cranial (mesonephric) mesentery in adult female mammals, which runs between the cranial pole of the internal genitalia and the dorsal abdominal wall. Absence of the cranial suspensory ligament in male mammals depends upon exposure of its primordium to fetal testicular androgens and is a prerequisite for Testis Descent. Female rats were exposed to 5alpha-dihydrotestosterone propionate at different stages of genital development, and cranial suspensory ligament development was studied in neonatal and in adult animals. Androgens suppressed cranial suspensory ligament development when exposure started during the early stages of genital development, until day 19 postconception (pc). Androgen receptor expression was immunohistochemically detected in the cranial mesentery of both sexes from day 16 pc onwards. A decrease of androgen receptor expression in female fetuses from day 18 pc onwards coincided with the appearance of a differentiated cranial suspensory ligament, as evidenced by the expression of two cell differentiation markers: alpha-smooth muscle (alpha-SM) actin and desmin. alpha-SM actin was located on the outer border of the cranial mesentery of both sexes at day 17 pc, and expression increased only in female fetuses. On day 19 pc, desmin expression was also detectable in the a-SM actin-positive cells. Proliferation and apoptosis indices of cells in the cranial mesentery, as analysed by 5'-bromodeoxyuridine incorporation and by detection of DNA strand breaks (TUNEL method) respectively, did not show any difference between the sexes, neither on day 17 nor on day 18 pc. Since primordial cells of the cranial suspensory ligament highly express the androgen receptor during the period of gestation when androgens can suppress cranial suspensory development, altered morphogenesis of these cells may be a direct consequence of androgen action.
Judith M A Emmen - One of the best experts on this subject based on the ideXlab platform.
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Printed in U.S.A. Copyright © 2000 by The Endocrine Society Hormonal Control of Gubernaculum Development during Testis Descent: Gubernaculum Outgrowth in Vitro Requires Both Insulin-Like Factor and Androgen*
2013Co-Authors: Judith M A Emmen, Ibrahim M Adham, Anke Mcluskey, Wolfgang Engel, Anton J Grootegoed, O. BrinkmannAbstract:The gubernaculum connects the gonad to the inguinoscrotal region and is involved in Testis Descent. It rapidly develops in the male fetus, whereas development in the female fetus is lacking. Possible factors involved in gubernaculum development are androgens, anti-Müllerian hormone (AMH), and insulin-like factor (Insl3). Sexual dimorphism in gubernaculum development correlated with the mitotic activity of cells in the gubernacular bulbs from male and female fetuses. Androgen receptor expression was restricted to the mesenchymal core of the gubernacular bulb, whereas skeletal muscle was detected in its outer layer. In an organ culture system devised to further study Testis Descent IS the process by which the developing Testis moves from its initial position high in the abdomen into the scrotum. The process is generally subdivided into two phases (1). During the first or transabdominal phase
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involvement of insulin like factor 3 insl3 in diethylstilbestrol induced cryptorchidism
Endocrinology, 2000Co-Authors: Judith M A Emmen, Ibrahim M Adham, Anke Mcluskey, Wolfgang Engel, Anton J Grootegoed, Miriam Verhoefpost, Axel P N Themmen, A O BrinkmannAbstract:Recently, it has been shown that targeted inactivation of the Insl3 gene in male mice results in cryptorchidism. The Insl3 gene encodes insulin-like factor 3 (Insl3), which is expressed in fetal Leydig cells. The testicular factor Insl3 appears to play an important role in the transabdominal phase of Testis Descent, which involves development of the gubernaculum. Other studies have demonstrated that in utero exposure to diethylstilbestrol (DES), a synthetic estrogen, can lead to cryptorchidism both in humans and in animal models. The present study was undertaken to investigate whether prenatal DES-exposure might interfere with testicular Insl3 mRNA expression. Furthermore, the effect of DES on steroidogenic factor 1 (SF-1) mRNA expression level was determined, since it has been shown that SF-1 plays an essential role in transcriptional activation of the Insl3 gene promoter. Timed pregnant mice were treated with DES (100 μg/kg body weight) or vehicle alone on days E9 (gestational day 9) through E17. Contro...
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hormonal control of gubernaculum development during Testis Descent gubernaculum outgrowth in vitro requires both insulin like factor and androgen
Endocrinology, 2000Co-Authors: Judith M A Emmen, Ibrahim M Adham, Anke Mcluskey, Wolfgang Engel, Anton J Grootegoed, A O BrinkmannAbstract:The gubernaculum connects the gonad to the inguinoscrotal region and is involved in Testis Descent. It rapidly develops in the male fetus, whereas development in the female fetus is lacking. Possible factors involved in gubernaculum development are androgens, anti-Mullerian hormone (AMH), and insulin-like factor (Insl3). Sexual dimorphism in gubernaculum development correlated with the mitotic activity of cells in the gubernacular bulbs from male and female fetuses. Androgen receptor expression was restricted to the mesenchymal core of the gubernacular bulb, whereas skeletal muscle was detected in its outer layer. In an organ culture system devised to further study gubernaculum development in vitro, morphology of gubernacular explants grown in the presence of testes was comparable with that of gubernacula developed in vivo. Testicular tissue or medium containing R1881, a synthetic androgen, had a growth stimulatory effect on gubernacular explants compared with ovarian tissue or basal medium only. Moreover...
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hormonal control of gubernaculum development during Testis Descent gubernaculum outgrowth in vitro requires both insulin like factor and androgen
Endocrinology, 2000Co-Authors: Judith M A Emmen, Ibrahim M Adham, Anke Mcluskey, Wolfgang Engel, Anton J Grootegoed, A O BrinkmannAbstract:The gubernaculum connects the gonad to the inguinoscrotal region and is involved in Testis Descent. It rapidly develops in the male fetus, whereas development in the female fetus is lacking. Possible factors involved in gubernaculum development are androgens, anti-Mullerian hormone (AMH), and insulin-like factor (Insl3). Sexual dimorphism in gubernaculum development correlated with the mitotic activity of cells in the gubernacular bulbs from male and female fetuses. Androgen receptor expression was restricted to the mesenchymal core of the gubernacular bulb, whereas skeletal muscle was detected in its outer layer. In an organ culture system devised to further study gubernaculum development in vitro, morphology of gubernacular explants grown in the presence of testes was comparable with that of gubernacula developed in vivo. Testicular tissue or medium containing R1881, a synthetic androgen, had a growth stimulatory effect on gubernacular explants compared with ovarian tissue or basal medium only. Moreover, Amh-/-, Amh+/-, and Insl3+/- testes stimulated the growth of gubernacular explants to the same extent as control testes. Insl3-/- testes, however, did not produce such an activity. This study reveals an essential role for both androgen and Insl3 in the gubernaculum outgrowth during transabdominal Testis Descent.
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Androgen action during male sex differentiation includes suppression of cranial suspensory ligament development.
Human reproduction (Oxford England), 1998Co-Authors: Judith M A Emmen, Anke Mcluskey, J. A. Grootegoed, A O BrinkmannAbstract:The cranial suspensory ligament is located on the border of the cranial (mesonephric) mesentery in adult female mammals, which runs between the cranial pole of the internal genitalia and the dorsal abdominal wall. Absence of the cranial suspensory ligament in male mammals depends upon exposure of its primordium to fetal testicular androgens and is a prerequisite for Testis Descent. Female rats were exposed to 5alpha-dihydrotestosterone propionate at different stages of genital development, and cranial suspensory ligament development was studied in neonatal and in adult animals. Androgens suppressed cranial suspensory ligament development when exposure started during the early stages of genital development, until day 19 postconception (pc). Androgen receptor expression was immunohistochemically detected in the cranial mesentery of both sexes from day 16 pc onwards. A decrease of androgen receptor expression in female fetuses from day 18 pc onwards coincided with the appearance of a differentiated cranial suspensory ligament, as evidenced by the expression of two cell differentiation markers: alpha-smooth muscle (alpha-SM) actin and desmin. alpha-SM actin was located on the outer border of the cranial mesentery of both sexes at day 17 pc, and expression increased only in female fetuses. On day 19 pc, desmin expression was also detectable in the a-SM actin-positive cells. Proliferation and apoptosis indices of cells in the cranial mesentery, as analysed by 5'-bromodeoxyuridine incorporation and by detection of DNA strand breaks (TUNEL method) respectively, did not show any difference between the sexes, neither on day 17 nor on day 18 pc. Since primordial cells of the cranial suspensory ligament highly express the androgen receptor during the period of gestation when androgens can suppress cranial suspensory development, altered morphogenesis of these cells may be a direct consequence of androgen action.
Jacques J. Tremblay - One of the best experts on this subject based on the ideXlab platform.
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Commentary What Signals Testis Descent?
2016Co-Authors: Jacques J. TremblayAbstract:Proper migration of the testes, from their original position adjacent to the kidneys to their final location within the scrotum, constitutes a normal and obligatory step of the male sex differentiation process. In humans and other mammals, the developing Testis is connected to the abdominal wall by the cranial suspensory ligament and the gubernaculum. A peptide hormone called insulin-like 3 (INSL3) was found to be a master regulator of gonadal positioning in mammals by controlling gubernacular growth [1], but key questions remained. How does INSL3 do it? What pathways are activated by this hormone? In this issue of Biology of Reproduction, Johnson et al. [2] have achieved an important advance in our understandings of Testis Descent by identifying several pathways activated by INSL3 in the gubernaculum. Theories Behind Testis Descen
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COMMENTARY--What signals Testis Descent?
2016Co-Authors: Jacques J. TremblayAbstract:Proper migration of the testes, from their original position adjacent to the kidneys to their final location within the scrotum, constitutes a normal and obligatory step of the male sex differentiation process. In humans and other mammals, the developing Testis is connected to the abdominal wall by the cranial suspensory ligament and the gubernaculum. A peptide hormone called insulin-like 3 (INSL3) was found to be a master regulator of gonadal positioning in mammals by controlling gubernacular growth [1]. But key questions remained: How does INSL3 do it? What are the pathways activated by this hormone? In this issue of Biology of Reproduction, Johnson et al. have achieved an important advance in our understandings of Testis Descent by identifying several pathways activated by INSL3 in the gubernaculum. Theories behind Testis Descent In 1762 John Hunter published the first description of a structure, the gubernaculum, that "connects the Testis with the scrotum and directs its course in its Descent " [2]. Several hypotheses have been proposed over the past two centuries to explain the mechanism of testicular Descent [3]. These theories included gravity, traction where growth of the gubernaculum pulls the Testis down, propulsion where the Testis is expelled from the abdomen by increased intra-abdomina
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klf6 cooperates with nur77 and sf1 to activate the human insl3 promoter in mouse ma 10 leydig cells
Journal of Molecular Endocrinology, 2016Co-Authors: Maxime Tremblay, Raifish E Mendozavillarroel, Nicholas M. Robert, Francis Bergeron, Jacques J. TremblayAbstract:Insulin-like 3 (INSL3), a Leydig cell-specific hormone, is essential for Testis Descent during foetal life and bone metabolism in adults. Despite its essential roles in male reproductive and bone health, very little is known regarding its transcriptional regulation in Leydig cells. To date, few transcription factors have been shown to activate INSL3 promoter activity: the nuclear receptors AR, NUR77, COUP-TFII and SF1. To identify additional regulators, we have isolated and performed a detailed analysis of a 1.1 kb human INSL3 promoter fragment. Through 5' progressive deletions and site-directed mutagenesis, we have mapped a 10 bp element responsible for about 80% of INSL3 promoter activity in Leydig cells. This element is identical to the CPE element of the placental-specific glycoprotein-5 (PSG5) promoter that is recognized by the developmental regulator Kruppel-like factor 6 (KLF6). Using PCR and western blotting, we found that KLF6 is expressed in several Leydig and Sertoli cell lines. Furthermore, immunohistochemistry on adult mouse Testis revealed the presence of KLF6 in the nuclei of both Leydig and Sertoli cells. KLF6 binds to the 10 bp KLF element at -108 bp and activates the -1.1 kb human, but not the mouse, INSL3 promoter. KLF6-mediated activation of the human INSL3 promoter required an intact KLF element as well as Leydig/Sertoli-enriched factors because KLF6 did not stimulate the human INSL3 promoter activity in CV-1 fibroblast cells. Consistent with this, we found that KLF6 transcriptionally cooperates with NUR77 and SF1. Collectively, our results identify KLF6 as a regulator of human INSL3 transcription.
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molecular regulation of steroidogenesis in endocrine leydig cells
Steroids, 2015Co-Authors: Jacques J. TremblayAbstract:Steroid hormones regulate essential physiological processes and inadequate levels are associated with various pathological conditions. Consequently, the process of steroid hormone biosynthesis is finely regulated. In the Testis, the main steroidogenic cells are the Leydig cells. There are two distinct populations of Leydig cells that arise during development: fetal and adult Leydig cells. Fetal Leydig cells are responsible for masculinizing the male urogenital tract and inducing Testis Descent. These cells atrophy shortly after birth and do not contribute to the adult Leydig cell population. Adult Leydig cells derive from undifferentiated precursors present after birth and become fully steroidogenic at puberty. The differentiation of both Leydig cell populations is controlled by locally produced paracrine factors and by endocrine hormones. In fully differentially and steroidogenically active Leydig cells, androgen production and hormone-responsiveness involve various signaling pathways and downstream transcription factors. This review article focuses on recent developments regarding the origin and function of Leydig cells, the regulation of their differentiation by signaling molecules, hormones, and structural changes, the signaling pathways, kinases, and transcription factors involved in their differentiation and in mediating LH-responsiveness, as well as the fine-tuning mechanisms that ensure adequate production steroid hormones.
Anke Mcluskey - One of the best experts on this subject based on the ideXlab platform.
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Printed in U.S.A. Copyright © 2000 by The Endocrine Society Hormonal Control of Gubernaculum Development during Testis Descent: Gubernaculum Outgrowth in Vitro Requires Both Insulin-Like Factor and Androgen*
2013Co-Authors: Judith M A Emmen, Ibrahim M Adham, Anke Mcluskey, Wolfgang Engel, Anton J Grootegoed, O. BrinkmannAbstract:The gubernaculum connects the gonad to the inguinoscrotal region and is involved in Testis Descent. It rapidly develops in the male fetus, whereas development in the female fetus is lacking. Possible factors involved in gubernaculum development are androgens, anti-Müllerian hormone (AMH), and insulin-like factor (Insl3). Sexual dimorphism in gubernaculum development correlated with the mitotic activity of cells in the gubernacular bulbs from male and female fetuses. Androgen receptor expression was restricted to the mesenchymal core of the gubernacular bulb, whereas skeletal muscle was detected in its outer layer. In an organ culture system devised to further study Testis Descent IS the process by which the developing Testis moves from its initial position high in the abdomen into the scrotum. The process is generally subdivided into two phases (1). During the first or transabdominal phase
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involvement of insulin like factor 3 insl3 in diethylstilbestrol induced cryptorchidism
Endocrinology, 2000Co-Authors: Judith M A Emmen, Ibrahim M Adham, Anke Mcluskey, Wolfgang Engel, Anton J Grootegoed, Miriam Verhoefpost, Axel P N Themmen, A O BrinkmannAbstract:Recently, it has been shown that targeted inactivation of the Insl3 gene in male mice results in cryptorchidism. The Insl3 gene encodes insulin-like factor 3 (Insl3), which is expressed in fetal Leydig cells. The testicular factor Insl3 appears to play an important role in the transabdominal phase of Testis Descent, which involves development of the gubernaculum. Other studies have demonstrated that in utero exposure to diethylstilbestrol (DES), a synthetic estrogen, can lead to cryptorchidism both in humans and in animal models. The present study was undertaken to investigate whether prenatal DES-exposure might interfere with testicular Insl3 mRNA expression. Furthermore, the effect of DES on steroidogenic factor 1 (SF-1) mRNA expression level was determined, since it has been shown that SF-1 plays an essential role in transcriptional activation of the Insl3 gene promoter. Timed pregnant mice were treated with DES (100 μg/kg body weight) or vehicle alone on days E9 (gestational day 9) through E17. Contro...
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hormonal control of gubernaculum development during Testis Descent gubernaculum outgrowth in vitro requires both insulin like factor and androgen
Endocrinology, 2000Co-Authors: Judith M A Emmen, Ibrahim M Adham, Anke Mcluskey, Wolfgang Engel, Anton J Grootegoed, A O BrinkmannAbstract:The gubernaculum connects the gonad to the inguinoscrotal region and is involved in Testis Descent. It rapidly develops in the male fetus, whereas development in the female fetus is lacking. Possible factors involved in gubernaculum development are androgens, anti-Mullerian hormone (AMH), and insulin-like factor (Insl3). Sexual dimorphism in gubernaculum development correlated with the mitotic activity of cells in the gubernacular bulbs from male and female fetuses. Androgen receptor expression was restricted to the mesenchymal core of the gubernacular bulb, whereas skeletal muscle was detected in its outer layer. In an organ culture system devised to further study gubernaculum development in vitro, morphology of gubernacular explants grown in the presence of testes was comparable with that of gubernacula developed in vivo. Testicular tissue or medium containing R1881, a synthetic androgen, had a growth stimulatory effect on gubernacular explants compared with ovarian tissue or basal medium only. Moreover...
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hormonal control of gubernaculum development during Testis Descent gubernaculum outgrowth in vitro requires both insulin like factor and androgen
Endocrinology, 2000Co-Authors: Judith M A Emmen, Ibrahim M Adham, Anke Mcluskey, Wolfgang Engel, Anton J Grootegoed, A O BrinkmannAbstract:The gubernaculum connects the gonad to the inguinoscrotal region and is involved in Testis Descent. It rapidly develops in the male fetus, whereas development in the female fetus is lacking. Possible factors involved in gubernaculum development are androgens, anti-Mullerian hormone (AMH), and insulin-like factor (Insl3). Sexual dimorphism in gubernaculum development correlated with the mitotic activity of cells in the gubernacular bulbs from male and female fetuses. Androgen receptor expression was restricted to the mesenchymal core of the gubernacular bulb, whereas skeletal muscle was detected in its outer layer. In an organ culture system devised to further study gubernaculum development in vitro, morphology of gubernacular explants grown in the presence of testes was comparable with that of gubernacula developed in vivo. Testicular tissue or medium containing R1881, a synthetic androgen, had a growth stimulatory effect on gubernacular explants compared with ovarian tissue or basal medium only. Moreover, Amh-/-, Amh+/-, and Insl3+/- testes stimulated the growth of gubernacular explants to the same extent as control testes. Insl3-/- testes, however, did not produce such an activity. This study reveals an essential role for both androgen and Insl3 in the gubernaculum outgrowth during transabdominal Testis Descent.
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Androgen action during male sex differentiation includes suppression of cranial suspensory ligament development.
Human reproduction (Oxford England), 1998Co-Authors: Judith M A Emmen, Anke Mcluskey, J. A. Grootegoed, A O BrinkmannAbstract:The cranial suspensory ligament is located on the border of the cranial (mesonephric) mesentery in adult female mammals, which runs between the cranial pole of the internal genitalia and the dorsal abdominal wall. Absence of the cranial suspensory ligament in male mammals depends upon exposure of its primordium to fetal testicular androgens and is a prerequisite for Testis Descent. Female rats were exposed to 5alpha-dihydrotestosterone propionate at different stages of genital development, and cranial suspensory ligament development was studied in neonatal and in adult animals. Androgens suppressed cranial suspensory ligament development when exposure started during the early stages of genital development, until day 19 postconception (pc). Androgen receptor expression was immunohistochemically detected in the cranial mesentery of both sexes from day 16 pc onwards. A decrease of androgen receptor expression in female fetuses from day 18 pc onwards coincided with the appearance of a differentiated cranial suspensory ligament, as evidenced by the expression of two cell differentiation markers: alpha-smooth muscle (alpha-SM) actin and desmin. alpha-SM actin was located on the outer border of the cranial mesentery of both sexes at day 17 pc, and expression increased only in female fetuses. On day 19 pc, desmin expression was also detectable in the a-SM actin-positive cells. Proliferation and apoptosis indices of cells in the cranial mesentery, as analysed by 5'-bromodeoxyuridine incorporation and by detection of DNA strand breaks (TUNEL method) respectively, did not show any difference between the sexes, neither on day 17 nor on day 18 pc. Since primordial cells of the cranial suspensory ligament highly express the androgen receptor during the period of gestation when androgens can suppress cranial suspensory development, altered morphogenesis of these cells may be a direct consequence of androgen action.