The Aryl Hydrocarbon Receptor Regulates Mouse Fshr Promoter Activity Through an E-Box Binding Site1

Teino, Indrek; Kuuse, Sulev; Ingerpuu, Sulev; Maimets, Toivo; Tiido, Tarmo

doi:10.1095/biolreprod.111.095596

Cited by 9 publications

(7 citation statements)

References 38 publications

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“…GC differentiation and ovarian maturation was validated by measured upregulation of Fshr, Cyp19a1 , and Lhcgr (Figure 2d–f). It is known that Ahr may regulate the expression of Fshr and Cyp19a1 [19,43,68]. In our experimental setting, however, we see no prior increase in Ahr expression compared to Fshr and Cyp19a1 .…”

Section: Discussioncontrasting

confidence: 55%

“…Previous studies have shown that the role of Ahr in the ovary may be attributed, at least partly, to regulating the expression of Cyp19a1 and thereby contributing to estradiol production [12,19]. There is also evidence that Ahr directly regulates the expression of Fshr by binding to its promoter [17,43]. According to these data, we aimed to characterize the temporal relationship between the expression of Ahr and abovementioned genes.…”

Section: Resultsmentioning

confidence: 99%

“…In combined gonadotropin treatment experiments, mice were injected in total 4 times (every 12 h) with 1.5 IU of FSH and 1.25 IU of LH. The mice were killed immediately or 12–48 h after the first injection and granulosa cells were isolated from ovaries by follicular puncture as previously described [43]. In short, murine ovaries were removed and cleared from connective tissue, washed in cold DMEM/Ham’s F-12 medium, transferred to a tube with preincubation medium (0.5 M sucrose and 10 mM EGTA in DMEM/Ham’s F-12) and incubated at 37 °C until the ovaries precipitated to the bottom of the tube.…”

Section: Methodsmentioning

confidence: 99%

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FSH/LH-Dependent Upregulation of Ahr in Murine Granulosa Cells Is Controlled by PKA Signaling and Involves Epigenetic Regulation

Matvere

Teino

Varik

et al. 2019

IJMS

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The aryl hydrocarbon receptor (Ahr) is a ligand-activated transcription factor primarily known for its toxicological functions. Recent studies have established its importance in many physiological processes including female reproduction, although there is limited data about the precise mechanisms how Ahr itself is regulated during ovarian follicle maturation. This study describes the expression of Ahr in ovarian granulosa cells (GCs) of immature mice in a gonadotropin-dependent manner. We show that Ahr upregulation in vivo requires both follicle stimulating hormone (FSH) and luteinizing hormone (LH) activities. FSH alone increased Ahr mRNA, but had no effect on Ahr protein level, implicating a possible LH-dependent post-transcriptional regulation. Also, the increase in Ahr protein is specific to large antral follicles in induced follicle maturation. We show that Ahr expression in GCs of mid-phase follicular maturation is downregulated by protein kinase A (PKA) signaling and activation of Ahr promoter is regulated by chromatin remodeling.

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Section: Discussioncontrasting

confidence: 55%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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FSH/LH-Dependent Upregulation of Ahr in Murine Granulosa Cells Is Controlled by PKA Signaling and Involves Epigenetic Regulation

Matvere

Teino

Varik

et al. 2019

IJMS

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“…showed that the E-box but not USF1 is necessary for AhR binding to the FSHR promoter in vivo. AhR activates the FSHR promoter through the region from −209 to −99 bp [13,14].…”

Section: Introductionmentioning

confidence: 99%

Correlation of the Aryl Hydrocarbon Receptor with FSHR in Ovarian Cancer Patients

Deuster

Mayr

Hester

et al. 2019

IJMS

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Expression of the aryl hydrocarbon receptor (AhR) has been described in various tumor entities from different organs. However, its role in ovarian cancer has not been thoroughly investigated. We aimed to elucidate the prognostic impact of AhR, its correlation with the follicle-stimulating hormone receptor (FSHR), and their functional role in ovarian cancer. By immunohistochemistry, AhR staining was analyzed in a subset of 156 samples of ovarian cancer patients. AhR staining was assessed in the nucleus and the cytoplasm using the semi-quantitative immunoreactive score (IRS), and the scores were grouped into high- and low-level expression. AhR expression was detected in all histological subtypes, with clear cell ovarian cancer displaying the highest staining intensity. Low cytoplasmic expression of AhR was associated with longer overall survival (median 183.46 vs. 85.07 months; p = 0.021). We found a positive correlation between AhR and FSHR (p = 0.005). Ovarian cancer patients with high cytoplasmic AhR and concurrent FSHR expression had the worst outcome (median 69.72 vs. 43.32 months; p = 0.043). Consequently, low cytoplasmic AhR expression seems to be associated with improved survival in ovarian cancer patients. Our data suggest that AhR and FSHR levels correlate with each other, and their concurrent expression was observed in ovarian cancer patients with the worst outcome. Further investigation of the interaction of both receptors and their functional role might better predict the impact of endocrine therapy in ovarian cancer.

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“…These possibilities are supported by previous studies that show that AHRKO follicles have reduced mRNA expression of FSH receptors ( Fshr ) as well as a reduced number of FSH binding sites compared to WT follicles [5,8]. Further, they are supported by studies indicating that the AHR and FSH pathways may interact to regulate transcription of the Fshr because the AHR binds to aryl hydrocarbon response elements in the promoter regions of the Fshr and an E-box binding site in the mouse ovary [5,11]. …”

Section: Introductionmentioning

confidence: 99%

Follicle-stimulating hormone responsiveness in antral follicles from aryl hydrocarbon receptor knockout mice

Hernández‐Ochoa

Gao

Peretz

et al. 2013

Reprod Biol Endocrinol

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BackgroundPrevious studies have demonstrated that pre-pubertal aryl hydrocarbon receptor knockout (AHRKO) mice have slow antral follicle growth and reduced capacity to produce estradiol compared to wild-type (WT) mice. Although previous studies have suggested that this is likely due to a reduced ability of the AHRKO follicles to respond to follicle-stimulating hormone (FSH), this possibility was not directly tested. Thus, the goal of these studies was to test the hypothesis that low FSH responsiveness is responsible for the slow growth and reduced estradiol production observed in pre-pubertal AHRKO versus WT antral follicles.MethodsAntral follicles from WT and AHRKO mice were cultured with varying amounts of FSH (0–15 IU/mL) for up to 7 days, and subjected to measurements of growth, FSH receptor and steroidogenic regulator expression, sex steroid hormone levels, and inhibin beta-A expression. General linear models (GLM) for repeated measures were used to compare follicle diameters over time among treatments. If the global tests from GLM were significant, Tukey’s tests were used for pairwise comparisons. Remaining comparisons among groups were performed using one-way analysis of variance followed by Tukey’s post hoc test.ResultsThe results indicate that FSH stimulated growth in both WT and AHRKO follicles, but that high levels of FSH (10–15 IU/mL) were required for AHRKO follicles to reach maximal growth, whereas lower levels of FSH (5 IU/mL) were required for WT follicles to reach maximal growth. Further, FSH stimulated expression of FSH receptor, steroidogenic factors, and inhibin beta-A as well as production of steroid hormones in both WT and AHRKO follicles, but the degree of stimulation differed betw een WT and AHRKO follicles. Interestingly, FSH treatment increased expression of FSH receptor, some steroidogenic regulators, inhibin beta-A, and steroid hormone production more in AHRKO follicles compared to WT follicles.ConclusionsCollectively, these data suggest that the slow growth, but not reduced steroidogenesis in AHRKO follicles, is due to their reduced ability to respond to FSH compared to WT follicles. These data also suggest that the AHR may contribute to the ability of FSH to stimulate proper follicle growth, but it may not contribute to FSH-induced steroidogenesis.

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The Aryl Hydrocarbon Receptor Regulates Mouse Fshr Promoter Activity Through an E-Box Binding Site1

Cited by 9 publications

References 38 publications

FSH/LH-Dependent Upregulation of Ahr in Murine Granulosa Cells Is Controlled by PKA Signaling and Involves Epigenetic Regulation

FSH/LH-Dependent Upregulation of Ahr in Murine Granulosa Cells Is Controlled by PKA Signaling and Involves Epigenetic Regulation

Correlation of the Aryl Hydrocarbon Receptor with FSHR in Ovarian Cancer Patients

Follicle-stimulating hormone responsiveness in antral follicles from aryl hydrocarbon receptor knockout mice

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