Tissue concentrations of estrogens and aromatase immunolocalization in interstitial pneumonia of human lung

Taniuchi, Shinji; Fujishima, Fumiyoshi; Miki, Yasuhiro; Abe, Keiko; Nakamura, Yasuhiro; Sato, Satoko; Kasajima, Atsuko; Fue, Misaki; Ishida, Kazuyuki; Watanabe, Mika; Sakakibara, Tomohiro; Maeda, Shin; Suzuki, Takashi; Sasano, Hironobu

doi:10.1016/j.mce.2014.05.016

Cited by 12 publications

(9 citation statements)

References 43 publications

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“…The antibody to ERα has been well characterized in mouse brain (McClellan et al , 2010), and the antibody to ERβ produced nuclear staining in the human lung (Taniuchi et al , 2014). To engender more confidence for staining in monkey, further characterization of the specificity of the commercially available ER antibodies was obtained in macaques.…”

Section: Methodsmentioning

confidence: 99%

Localization and regulation of reproductive steroid receptors in the raphe serotonin system of male macaques

Bethea

Phu

Belikova

et al. 2015

Journal of Chemical Neuroanatomy

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We previously showed that tryptophan hydroxylase 2 (TPH2) and serotonin reuptake transporter (SERT) mRNAs are increased by the androgens, testosterone (T) and dihydrotestosterone (DHT) in serotonin neurons of male macaques. In addition, we observed that serotonin in axons of a terminal region were markedly decreased by aromatase inhibition and lack of estradiol (E) from metabolism of T. These observations implicated androgen receptors (AR) and estrogen receptors (ER) in the transduction of steroid hormone actions in serotonin neurons. Due to the longer treatment period employed, the expression of the cognate nuclear receptors was sought. We used single and double immunohistochemistry to quantitate and phenotypically localize AR, ERα and ERβ in the dorsal raphe of male macaques. Male Japanese macaques (Macaca fuscata) were castrated for 5–7 months and then treated for 3 months with [1] placebo, [2] T, [3] DHT (non-aromatizable androgen) plus ATD (steroidal aromatase inhibitor), or [4] Flutamide (FLUT; androgen antagonist) plus ATD (n=5/group). After single labeling of each receptor, quantitative image analysis was applied and receptor positive neurons were counted. Double-label of raphe neurons for each receptor plus TPH2 determined whether the receptors were localized in serotonin neurons. There were significantly more AR-positive neurons in T- and DHT+ATD-treated groups (p= 0.0014) compared to placebo or FLUT+ATD-treated groups. There was no difference in the number of positive-neurons stained for ERα or ERβ. Double-immunohistochemistry revealed that serotonin neurons did not contain AR. Rather, AR-positive nuclei were found in neighboring cells that are likely neurons. However, approximately 40% of dorsal raphe serotonin neurons contained ERα or ERβ. In conclusion, the stimulatory effect of androgens on TPH2 and SERT mRNA expression is mediated indirectly by neighboring neurons containing AR. The stimulatory effect of E, derived from T metabolism, on axonal serotonin content transport is partially mediated directly via nuclear ERs.

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Section: Methodsmentioning

confidence: 99%

Localization and regulation of reproductive steroid receptors in the raphe serotonin system of male macaques

Bethea

Phu

Belikova

et al. 2015

Journal of Chemical Neuroanatomy

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“…Subtype-selective tracers would allow the assessment of the ERb/ERa ratio, offering a better characterization of tumor lesions and therefore a better assessment of the stage of the disease and its sensitivity toward different endocrine therapies. Most important, the ERb subtype tracers could be used in the assessment of the ERb in lung carcinomas (10) and lung fibrosis (11) where ERb is known to be involved in these diseases. Unfortunately, PET tracers with high subtype selectivity for ERb or ERa are currently unavailable.…”

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confidence: 99%

Synthesis and Evaluation of the Estrogen Receptor β–Selective Radioligand 2-¹⁸F-Fluoro-6-(6-Hydroxynaphthalen-2-yl)Pyridin-3-ol: Comparison with 16α-¹⁸F-Fluoro-17β-Estradiol

et al. 2016

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Estrogen receptors (ERs) are targets for endocrine treatment of estrogen-dependent cancers. The ER consists of 2 isoforms, ERα and ERβ, which have distinct biologic functions. Whereas activation of ERα stimulates cell proliferation and cell survival, ERβ promotes apoptosis. PET of ERα and ERβ levels could provide more insight in response to hormonal treatment. 16α-F-fluoro-17β-estradiol (F-FES) is a PET tracer for ER with relative selectivity for ERα. Here we report the synthesis and evaluation of a potential ERβ-selective PET tracer: 2-F-fluoro-6-(6-hydroxynaphthalen-2-yl)pyridin-3-ol (F-FHNP). F-FHNP was synthesized by fluorination of the corresponding nitro precursor, followed by acidic removal of the 2-methoxyethoxymethyl protecting group. In vitro affinity ofF-FHNP and F-FES for ER was evaluated in SKOV3 ovarian carcinoma cells. PET imaging and ex vivo biodistribution studies withF-FHNP and F-FES were conducted in athymic nude mice bearing a SKOV3 xenografts.F-FHNP had nanomolar affinity for ERs, with a 3.5 times higher affinity for ERβ. F-FHNP was obtained in 15%-40% radiochemical yield (decay-corrected), with a specific activity of 279 ± 75 GBq/μmol.F-FHNP had a dissociation constant of 2 nM and maximum binding capacity of 18 fmol/10 cells, and F-FES had a dissociation constant of 3 nM and maximum binding capacity 83 fmol/10 SKOV3 cells. Both F-FHNP andF-FES PET could clearly visualize the tumor in male mice bearing a SKOV3 xenograft. Biodistribution studies showed similar distribution of F-FHNP andF-FES in most peripheral organs. F-FES showed a 2-fold-higher tumor uptake thanF-FHNP. The tumor-to-plasma ratio of F-FES decreased 55% ( = 0.024) and 8% ( = 0.68) when administered in the presence of estradiol (nonselective) and genistein (ERβ-selective), respectively. The tumor-to-plasma ratio of F-FHNP decreased 41% ( = 0.004) and 64% ( = 0.0009) when administered with estradiol and genistein, respectively. The new PET tracerF-FHNP has suitable properties for imaging and shows relative selectivity for ERβ.

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“…The antibody to ERα has been well characterized in mouse brain (McClellan et al, 2010), and the antibody to ERβ produced nuclear staining in the human lung (Taniuchi et al, 2014). Positive controls for ERα and ERβ in this laboratory were macaque endometrium and macaque prostate gland (Brenner and Slayden, 1994; Kuiper et al, 1996).…”

Section: Methodsmentioning

confidence: 99%

Reproductive steroid receptors and actions in the locus coeruleus of male macaques: Part of an aggression circuit?

Bethea

Belikova

Phu

et al. 2016

Progress in Neuro-Psychopharmacology and Biological Psychiatry

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This study was initiated to determine whether the noradrenergic (NE) neurons of the locus coeruleus (LC) could mediate the stimulatory action of androgens on serotonin-related gene expression in male macaques. These experiments follow our observations that serotonin neurons lack androgen receptors (ARs), and yet respond to androgens. Male Japanese macaques (Macaca fuscata) were castrated for 5–7 months and then treated for 3 months with [1] placebo, [2] T (testosterone), [3] DHT (dihydrotestosterone; non-aromatizable androgen) plus ATD (steroidal aromatase inhibitor), or [4] FLUT (Flutamide; androgen antagonist) plus ATD (n = 5/group). The noradrenergic (NE) innervation of the raphe was determined with immunolabeling of axons with an antibody to dopamine-β-hydroxylase (DBH). Immunolabeling of tyrosine hydroxylase (TH) dendrites and corticotropin releasing hormone (CRH) axons innervating the LC was also determined. Due to the longer treatment period employed, the expression of the cognate nuclear receptors was sought. Androgen receptor (AR), estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ) immunostaining was accomplished. Quantitative image analysis was applied and immunopositive neurons or axons with boutons were measured. Double-label of NE neurons for each receptor plus TH determined whether the receptors were localized in NE neurons. Androgens with or without aromatase activity significantly stimulated DBH axon density in the raphe (ANOVA, p = 0.006), and LC dendritic TH (ANOVA, p < 0.0001), similar to serotonin-related mRNA expression in the raphe. There were significantly more AR-positive neurons in T- and DHT + ATD-treated groups compared to placebo or FLUT + ATD-treated groups (ANOVA, p = 0.0014). There was no difference in the number of positive-neurons stained for ERα or ERβ. The CRH axon density in the LC was significantly reduced with aromatase inhibition, suggesting that CRH depends on estrogen, not androgens (ANOVA, p = 0.0023). Double-immunohistochemistry revealed that NE neurons did not contain AR. Rather, AR-positive nuclei were found in neighboring cells that are likely neurons. However, >80% of LC NE neurons contained ERα or ERβ. In conclusion, the LC NE neurons may transduce the stimulatory effect of androgens on serotonin-related gene expression. Since LC NE neurons lack AR, the androgenic stimulation of dendritic TH and axonal DBH may be indirectly mediated by other neurons. Estrogen, either from metabolism of T or from de novo synthesis, appears necessary for robust CRH innervation of the LC, which differs from female macaques.

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Tissue concentrations of estrogens and aromatase immunolocalization in interstitial pneumonia of human lung

Cited by 12 publications

References 43 publications

Localization and regulation of reproductive steroid receptors in the raphe serotonin system of male macaques

Localization and regulation of reproductive steroid receptors in the raphe serotonin system of male macaques

Synthesis and Evaluation of the Estrogen Receptor β–Selective Radioligand 2-¹⁸F-Fluoro-6-(6-Hydroxynaphthalen-2-yl)Pyridin-3-ol: Comparison with 16α-¹⁸F-Fluoro-17β-Estradiol

Reproductive steroid receptors and actions in the locus coeruleus of male macaques: Part of an aggression circuit?

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Tissue concentrations of estrogens and aromatase immunolocalization in interstitial pneumonia of human lung

Cited by 12 publications

References 43 publications

Localization and regulation of reproductive steroid receptors in the raphe serotonin system of male macaques

Localization and regulation of reproductive steroid receptors in the raphe serotonin system of male macaques

Synthesis and Evaluation of the Estrogen Receptor β–Selective Radioligand 2-18F-Fluoro-6-(6-Hydroxynaphthalen-2-yl)Pyridin-3-ol: Comparison with 16α-18F-Fluoro-17β-Estradiol

Reproductive steroid receptors and actions in the locus coeruleus of male macaques: Part of an aggression circuit?

Contact Info

Product

Resources

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Synthesis and Evaluation of the Estrogen Receptor β–Selective Radioligand 2-¹⁸F-Fluoro-6-(6-Hydroxynaphthalen-2-yl)Pyridin-3-ol: Comparison with 16α-¹⁸F-Fluoro-17β-Estradiol