Increased Exposure to Estrogens Disturbs Maturation, Steroidogenesis, and Cholesterol Homeostasis via Estrogen Receptor α in Adult Mouse Leydig Cells

Strauss, Leena; Kallio, Johanna; Desai, Nimisha; Pakarinen, Pirjo; Miettinen, Tatu A.; Gylling, Helena; Albrecht, Martín; Mäkelä, Sari; Mayerhofer, Artur; Poutanen, Matti

doi:10.1210/en.2008-1311

Cited by 68 publications

(66 citation statements)

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“…The expression of Insl3 in MA-10 Leydig cells is similar to what has been reported in primary Leydig cell cultures and in rodents. For instance, Insl3 expression is known to be repressed by estradiol in vivo in mice and rats (Nef et al 2000, Cederroth et al 2007, Strauss et al 2009, Zhou et al 2011) and this repression was also observed in MA-10 Leydig cells ). Insl3 expression is upregulated by androgens in vivo (Zhou et al 2010) as well as in primary Leydig cells and in MA-10 Leydig cells (Laguë & Tremblay 2008).…”

Section: Cell Culture Transfections and Reporter Assaysmentioning

confidence: 94%

The INSL3 gene is a direct target for the orphan nuclear receptor, COUP-TFII, in Leydig cells

Mendoza-Villarroel¹,

Di-Luoffo²,

Camiré³

et al. 2014

Journal of Molecular Endocrinology

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Insulin-like 3 (INSL3), a hormone produced by Leydig cells, regulates testicular descent during foetal life and bone metabolism in adults. Despite its importance, little is known about the molecular mechanisms controlling INSL3 expression. Reduced Insl3 mRNA levels were reported in the testis of mice deficient for chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII), an orphan nuclear receptor known to play critical roles in cell differentiation and lineage determination in several tissues. Although COUP-TFII-deficient mice had Leydig cell dysfunction and impaired fertility, it remained unknown whether Insl3 expression was directly regulated by COUP-TFII. In this study, we observed a significant decrease in Insl3 mRNA levels in MA-10 Leydig cells depleted of COUP-TFII. Furthermore, a K1087 bp mouse Insl3 promoter was activated fourfold by COUP-TFII in MA-10 Leydig cells. Using 5 0 progressive deletions, the COUP-TFII-responsive element was located between K186 and K79 bp, a region containing previously uncharacterised direct repeat 0-like (DR0-like) and DR3 elements. The recruitment and direct binding of COUP-TFII to the DR0-like element were confirmed by chromatin immunoprecipitation and DNA precipitation assay respectively. Mutation of the DR0-like element, which prevented COUP-TFII binding, significantly decreased COUP-TFII-mediated activation of the K1087 bp Insl3 reporter in CV-1 fibroblast cells but not in MA-10 Leydig cells. Finally, we found that COUP-TFII cooperates with the nuclear receptor steroidogenic factor 1 (SF1) to further enhance Insl3 promoter activity. Our results identify Insl3 as a target for COUP-TFII in Leydig cells and revealed that COUP-TFII acts through protein-protein interactions with other DNA-bound transcription factors, including SF1, to activate Insl3 transcription in these cells.

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Section: Cell Culture Transfections and Reporter Assaysmentioning

confidence: 94%

The INSL3 gene is a direct target for the orphan nuclear receptor, COUP-TFII, in Leydig cells

Mendoza-Villarroel¹,

Di-Luoffo²,

Camiré³

et al. 2014

Journal of Molecular Endocrinology

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“…Several studies also indicated a role for E2 as a paracrine/autocrine factor in the regulation of steroidogenesis in the Leydig cells from rodents (33). A recent study has demonstrated that the chronic imbalance of the androgen-estrogen ratio in the aromatase transgenic animal leads to severe abnormalities in the development, structure, and function of mouse Leydig cells, and these effects seem to be mediated by ESR1 (34).…”

Section: Testismentioning

confidence: 99%

Estrogen receptors and function in the male reproductive system

Lazari

Lucas

Yasuhara

et al. 2009

Arq Bras Endocrinol Metab

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A substantial advance in our understanding on the estrogen signaling occurred in the last decade. Estrogens interact with two receptors, ESR1 and ESR2, also known as ERα and ERβ, respectively. ESR1 and ESR2 belong to the nuclear receptor family of transcription factors. In addition to the well established transcriptional effects, estrogens can mediate rapid signaling, triggered within seconds or minutes. These rapid effects can be mediated by ESRs or the G protein-coupled estrogen receptor GPER, also known as GPR30. The effects of estrogen on cell proliferation, differentiation and apoptosis are often mediated by growth factors. The understanding of the cross-talk between androgen, estrogen and growth factors signaling pathways is therefore essential to understand the physiopathological mechanisms of estrogen action. In this review we focused on recent discoveries about the nature of the estrogen receptors, and on the signaling and function of estrogen in the male reproductive system. Arq Bras Endocrinol Metab. 2009;53(8):923-33 Keywords Estrogens; receptors, estrogen; reproduction; male resumo Durante a última década, ocorreu um avanço substancial no conhecimento da sinalização do estrógeno. Estrógenos interagem com dois receptores, ESR1 e ESR2, também conhecidos como ERα e ERβ, respectivamente. ESR1 e ESR2 pertencem à família de receptores nucleares, que funcionam como fatores de transcrição. Além dos bem estabelecidos efeitos transcricionais, os estrógenos medeiam a sinalização rápida, desencadeada dentro de segundos ou minutos. Esses efeitos rápidos podem ser mediados por ESRs ou pelo receptor de estrógeno acoplado à proteína G, GPER, também conhecido como GPR30. Os efeitos de estrógenos sobre a proliferação celular, diferenciação e apoptose são, muitas vezes, mediados por fatores de crescimento. Portanto, a compreensão da interação entre as vias de sinalização de andrógeno, estrógeno e fatores de crescimento é essencial para entender os mecanismos fisiopatológicos envolvidos na ação estrogênica. Nesta revisão, foram abordadas descobertas recentes sobre a estrutura dos receptores, a sinalização e a função do estrógeno no sistema reprodutor masculino. Arq Bras Endocrinol Metab. 2009;53(8):923-33

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“…Only recently have a few studies of changes in global testicular gene expression after increased exposure to estrogens been reported [46][47][48]. One of these studies [48] involved a 10-day E2 exposure to normal adult rats, and the results may be compared with those of the present study.…”

Section: Estrogen-regulated Genes In Irradiated Rat Testes 829mentioning

confidence: 87%

Estrogen Regulated Genes in Rat Testes and Their Relationship to Recovery of Spermatogenesis after Irradiation.

Zhou

Bolden-Tiller

Shao

et al. 2011

Biology of Reproduction

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Despite numerous observations of the effects of estrogens on spermatogenesis, identification of estrogen-regulated genes in the testis is limited. Using rats in which irradiation had completely blocked spermatogonial differentiation, we previously showed that testosterone suppression with gonadotropinreleasing hormone-antagonist acyline and the antiandrogen flutamide stimulated spermatogenic recovery and that addition of estradiol (E2) to this regimen accelerated this recovery. We report here the global changes in testicular cell gene expression induced by the E2 treatment. By minimizing the changes in other hormones and using concurrent data on regulation of the genes by these hormones, we were able to dissect the effects of estrogen on gene expression, independent of gonadotropin or testosterone changes. Expression of 20 genes, largely in somatic cells, was up-or downregulated between 2-and 5-fold by E2. The unexpected and striking enrichment of transcripts not corresponding to known genes among the E2-downregulated probes suggested that these might represent noncoding mRNAs; indeed, we have identified several as miRNAs and their potential target genes in this system. We propose that genes for which expression levels are altered in one direction by irradiation and in the opposite direction by both testosterone suppression and E2 treatment are candidates for controlling the block in differentiation. Several genes, including insulin-like 3 (Insl3), satisfied those criteria. If they are indeed involved in the inhibition of spermatogonial differentiation, they may be candidate targets for treatments to enhance recovery of spermatogenesis following gonadotoxic exposures, such as those resulting from cancer therapy.

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Increased Exposure to Estrogens Disturbs Maturation, Steroidogenesis, and Cholesterol Homeostasis via Estrogen Receptor α in Adult Mouse Leydig Cells

Cited by 68 publications

References 66 publications

The INSL3 gene is a direct target for the orphan nuclear receptor, COUP-TFII, in Leydig cells

The INSL3 gene is a direct target for the orphan nuclear receptor, COUP-TFII, in Leydig cells

Estrogen receptors and function in the male reproductive system

Estrogen Regulated Genes in Rat Testes and Their Relationship to Recovery of Spermatogenesis after Irradiation.

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