Müllerian Inhibiting Substance lowers testosterone in luteinizing hormone-stimulated rodents

Trbovich, Alexander M.; Sluss, Patrick M.; Laurich, V. Matt; O’Neill, Francis H.; MacLaughlin, David T.; Donahoe, Patricia K.; Teixeira, Jose M.

doi:10.1073/pnas.051632298

Cited by 58 publications

(47 citation statements)

References 35 publications

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“…Anti-Müllerian hormone (AMH) expression is inversely proportional to the serum concentration of testosterone in males after birth, in vitro AMH can lower testosterone production by mature rat Leydig cells and AMH-mediated down-regulation of expression of P45017α and P450scc contributes to this [37,38]. In the present study, the AMH mRNA expression level decreased in the DES 0.5 group at 6 weeks of age.…”

Section: Discussionmentioning

confidence: 56%

Effects of Maternal Exposure to Low Doses of DES on Testicular Steroidogenesis and Spermatogenesis in Male Rat Offspring

Kobayashi

Shirai

Sakaue

et al. 2009

Journal of Reproduction and Development

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Abstract.Our previous studies have demonstrated that prenatally administered diethylstilbestrol (DES) impairs testicular endocrine function in male offspring. The present study examined whether maternal DES treatment influences testicular steroidogenesis and spermatogenesis. DES was injected subcutaneously at 0.5 or 1.5 μg/kg/day (DES 0.5 and 1.5 groups, respectively) into pregnant SD rats on days 7-21 of gestation. Male offspring in the DES 0.5 and 1.5 groups were autopsied at 1, 3, 6 and 15 weeks after birth. At 1 week, DES treatment did not lead to a change in the volume of P450scc-positive cells (Leydig cells), suggesting that DES has no inhibitory effect on the development of Leydig cells. DES administration disrupted luteinizing hormone receptor (LHr) expression and exerted inhibitory effects on signal transduction from LHr to steroidogenic acute regulatory protein (StAR) in testicular steroidogenesis (P<0.05), although there were no changes in the mRNA expression levels of steroidogenic enzymes, such as P450scc, 3β-hydroxysteroid dehydrogenase (3β-HSD) and P45017α, which may have caused a decrease in the plasma testosterone level. DES treatment did not disrupt the cycle of spermatogenesis but did upregulate the expression levels of androgen receptor (AR) mRNA in both DES groups at 15 weeks (P<0.05). These results indicate that maternal DES treatment disrupts steroidogenesis but induces a high level of AR mRNA expression to counteract the low levels of testosterone during spermatogenesis. uring embryonic development, rat primordial germ cells appear in the yolk sac on embryonic day 10, and the gonadal primordium begins to develop as the genital ridge around embryonic day 11. Primordial germ cells begin to reach the genital ridge on embryonic day 12 [1]; thereafter, Sertoli and Leydig cells in the male differentiate from genital ridge cells, leading to a series of differentiation events. The duration of pregnancy is generally divided into periods of embryonic development (first trimester), organogenesis (second trimester) and organ maturation (third trimester).Diethylstilbestrol (DES), a synthetic non-steroidal estrogen, exhibits strong estrogenic activity by binding to estrogen receptors (ERs). It has been shown that the treatment of pregnant rats with DES dose-dependently (range: 10 to 300 μg/kg) suppresses testosterone levels in the blood and testes of male fetuses [2-4]. We administered doses of DES much lower (1.5 μg/kg) than those previously applied to pregnant rats at 7-21 days of gestation (in the second and third trimesters) and demonstrated that DES suppresses plasma testosterone levels in adolescent male offspring (6 weeks after birth) [5].Androgen plays an important role in the development and function of the testis and male reproductive tract via the androgen receptor (AR). Similarly, since ERs have been found in these tissues [6][7][8][9][10], estrogen may be involved in development of the male reproductive system. Nevertheless, it is apparent that male ER-or aromatase-knockout mice initially ...

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Section: Discussionmentioning

confidence: 56%

Effects of Maternal Exposure to Low Doses of DES on Testicular Steroidogenesis and Spermatogenesis in Male Rat Offspring

Kobayashi

Shirai

Sakaue

et al. 2009

Journal of Reproduction and Development

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“…MIS has been reported to decrease testosterone production in vivo and in vitro by downregulating at least the steroidogenic enzyme p450c17 (49,50).…”

Section: Mis Expression Is Downregulated By Tnf-␣mentioning

confidence: 99%

Expression ofMISin the Testis Is Downregulated by Tumor Necrosis Factor Alpha through the Negative Regulation of SF-1 Transactivation by NF-κB

Hong

Park

Seo

et al. 2003

Molecular and Cellular Biology

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The expression of Mullerian inhibiting substance (MIS),Mullerian inhibiting substance (MIS), also known as antiMullerian hormone (AMH), is essential in normal sex differentiation and reproductive function (for a review, see reference 48). Its expression is tightly regulated in tissue-specific and development-specific manners. MIS expression in the testis is restricted to Sertoli cells and is high in fetal-to-prepubertal mice, but it becomes low in pubertal-to-adult mice. Previous studies have suggested that MIS expression is regulated independently by meiotic germ cells (1, 38), androgens (39), and gonadotropins (24), although the factors that govern the complex expression of the MIS gene have not been fully understood. The MIS promoter contains a number of evolutionarily conserved elements, including those for steroidogenic factor 1 (SF-1), Sox9, and GATA-4, and these conserved elements and corresponding transcription factors have been shown to be required for the activation of MIS transcription (11, 43, 53).SF-1, an orphan nuclear receptor, plays an important role in development and differentiation of the endocrine and reproductive systems (for reviews, see references 37 and 41). Molecular studies have revealed that many genes encoding steroidogenic enzymes and regulators of endocrine function are governed by SF-1 for their expression and contain SF-1 response elements within their proximal promoters. In testicular Sertoli cells, SF-1 is required for the expression of MIS (12, 43). Diverse coregulators have been reported to modulate the effect of SF-1 on gene transcription. WT-1 and GATA-4 activate SF-1-mediated MIS expression (34, 51), whereas DAX-1 represses MIS expression (20). Other proteins, such as steroid receptor coactivator 1 (SRC-1) (7), c-Jun (26), and DP103 (35), have also been shown to modulate the transactivation activity of SF-1, although the significance of these interactions remains elusive in terms of reproductive development and function.NF-B is a pivotal transcription factor governing the expression of early response genes involved in numerous cellular responses to a wide range of signals. The major form of NF-B is a heterodimer of the p65 and p50 subunits. In the inactivated state, NF-B is sequestered in the cytoplasm through its association with the inhibitor protein IB. Activation of the NF-B signaling cascade results in phosphorylation and subsequent degradation of IB, allowing the translocation of NF-B to the nucleus, where it induces transcription by binding to specific response elements (4). Previous studies have shown that NF-B cross-talks with other proteins. The NF-B transactivation function is modulated by proteins such as C/EBP, SRC-1, glucocorticoid receptor (GR), and RXR, resulting in the regulation of promoters with B enhancer motifs (31)(32)(33)45). Furthermore, NF-B itself is able to repress the activity of steroid receptors, modulating a number of gene responses to hormonal stimuli (17,31,36).There have been reports of an inverse relationship between

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“…Four samples obtained from a whole day's medium flow were collected from 2 testis tissues in culture weeks 4 and 5. All of them showed testosterone production of 2.4 ~ 24.0 (μ g/day/g testis) which is comparable to the production by the testis in the body 26,27 . In addition, the production increased by 1.8 to 3.8-fold when luteinizing hormone (LH) was added to the culture medium (Fig.…”

Section: Molecular Diffusion Through Testis Tissuementioning

confidence: 54%

818 Long-term ex vivo maintenance of testis tissues producing fertile sperm in a microfluidic device

Komeya¹,

Hayashi²,

Yamanaka³

et al. 2016

European Urology Supplements

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Müllerian Inhibiting Substance lowers testosterone in luteinizing hormone-stimulated rodents

Cited by 58 publications

References 35 publications

Effects of Maternal Exposure to Low Doses of DES on Testicular Steroidogenesis and Spermatogenesis in Male Rat Offspring

Effects of Maternal Exposure to Low Doses of DES on Testicular Steroidogenesis and Spermatogenesis in Male Rat Offspring

Expression ofMISin the Testis Is Downregulated by Tumor Necrosis Factor Alpha through the Negative Regulation of SF-1 Transactivation by NF-κB

818 Long-term ex vivo maintenance of testis tissues producing fertile sperm in a microfluidic device

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