Steroid 17β-estradiol Research Articles

Internal exposure of whitefish ( Coregonus lavaretus) to estrogens

Gonad malformations have been found in fish all over the world. Particularly in Lake Thun (Switzerland) a high prevalence of gonad deformations in whitefish has been observed. Very often, a link between exposure to endocrine disrupting compounds and altered gonad morphology exists. Hence, we analyzed the estrogenic burden in bile and muscle from whitefish (coregonids) from Lake Thun and linked it to observed gonad malformations. Estrogenicity in bile, measured with the yeast estrogen screen (YES) was exclusively caused by the natural steroids estrone and 17β-estradiol. Estrogenicity determined in muscle tissue using YES was similar in cases and controls, and between the sexes. Furthermore, endocrine active compounds in the lake water were investigated using passive sampling devices to monitor tributaries and the main outflow of Lake Thun. Here, we found accumulated estrogenicity. With target chemical analysis small amounts of estrone and bisphenol A were determined. We conclude, that the whitefish from Lake Thun are not suffering from (xeno)estrogens. The present study contributed substantially to the search for the cause for gonad malformations in Lake Thun whitefish, even though the cause of the malformations remains yet to be discovered.

Endometrial stromal cells from women with endometriosis reveal peculiar migratory behavior in response to ovarian steroids

To evaluate differences in endometrial stromal cell (ESC) migration between patients with and without endometriosis. Differences in ESC migration, cellular morphology, and cytoskeletal-actin dynamics were evaluated in response to platelet-derived growth factor-BB (PDGF-BB) and steroid hormones (17beta-estradiol and progesterone). Medical school research laboratory. Endometrial biopsy samples obtained from 43 women: 23 as controls (endometriosis excluded by laparoscopy), 20 with severe or moderate endometriosis (diagnosed by laparoscopy). ESCs were treated with and without PDGF-BB, 17beta-estradiol, and progesterone. Cellular migration was evaluated by means of chemotaxis experiments in a Boyden chamber. Cellular morphology and cytoskeletal-actin dynamics were evaluated by immunofluorescence. Progesterone stimulated the migratory behavior of ESCs derived from women with endometriosis, while 17beta-estradiol could stimulate motility of ESCs derived from both controls and women with endometriosis, with a greater effect observed in the latter group. No difference in ESC migratory behavior after PDGF-BB treatment was observed between women with and without the disease. Also, PDGF-BB and steroid hormones could modify the organization of actin cytoskeletal structures. Ovarian steroids differently affect the migration of ESCs derived from women with and without endometriosis. This effect is likely to involve cytoskeletal reorganization. Nongenomic signaling pathways induced by steroid hormones might have a role in this phenomenon.

Soy Phytoestrogens and Breast Cancer Chemoprevention: Molecular Mechanisms

Breast cancer is an important public health problem worldwide and it represents the second leading cause of cancer-related deaths among women in most industrialized countries. Epidemiological studies suggest a much lower incidence of breast cancer in women from countries with high soy phytoestrogen consumption such as China and Japan than the Western world. Phytoestrogens are a group of plant-derived polyphenol compounds that exhibit structural and functional similarities to the human steroid hormone 17β-estradiol. Genistein and daidzein, the main soy phytoestrogens, are two estrogen-mimicking compounds which can bind to estrogen receptors and exert weak estrogenic effects. There are several possible mechanisms by which these phytochemicals may reduce the risk of breast cancer; however their precise mechanisms of action remain to be elucidated. This review will summarize the properties of genistein and daidzein as phytoestrogens, and their chemopreventive effects in breast carcinogenesis including their antioxidant properties, antiinflammatory activities as well as their antiprogression abilities, and their importance in xenobiotic metabolism. Because the use of soy phytoestrogens is increasing, it is important from a public health perspective and a mechanistic understanding to study the potential links existing between soy phytoestrogens and breast cancer prevention.

Monthly day/night changes and seasonal daily rhythms of sexual steroids in Senegal sole ( Solea senegalensis) under natural fluctuating or controlled environmental conditions

In this paper we attempted to investigate the existence of daily fluctuations on plasma sexual steroids (17β-estradiol, E 2 and testosterone, T) in Senegal sole ( Solea senegalensis) females. We described the monthly day/night concentrations and seasonal daily rhythms in animals reared under natural photo- and thermo-period. In addition, the influence of the natural annual fluctuation of the water temperature on the plasma concentration of these steroids was investigated, using one group of Senegal sole under a natural photoperiod, but with an attenuated thermal cycle (around 17–20 °C) for one year. Although no significant day/night differences were detected in monthly samplings, the existence of an annual rhythm of E 2 and T ( p < 0.01) with an acrophase in February was revealed by COSINOR analysis. Maximum values were reached in March for both steroids (6.1 ± 1.7 ng mL − 1 at mid-dark, MD and 4.0 ± 0.6 ng mL − 1 at mid-light, ML for E2 and 1.4 ± 0.4 ng mL − 1 at MD and 0.8 ± 0.1 ng mL − 1 at ML for T) in anticipation of the spawning season (May–June). As regards seasonal daily rhythms, the presence of daily oscillations was revealed. At the spring solstice (21st March) a daily rhythm was observed for both steroids (COSINOR, p < 0.01), with an acrophase at 20:00 h (E 2) and at 21:08 h (T). In summer, autumn and winter no daily rhythms were observed due to the low steroid levels at those seasons. When Senegal sole females were submitted to an attenuated annual thermal cycle, the steroid rhythm disappeared (there was no surge in spring, as in the control group) and these fish did not spawn, despite being subjected to natural photoperiod conditions. This result underlined the importance of the natural annual fluctuation of water temperature and photoperiod on the synchronization of the spawning season and on the onset of steroidogenesis.

Sex steroids enhance insulin receptors and glucose oxidation in Chang liver cells

Background The present study was designed to assess the effect of sex steroids (testosterone and 17β-estradiol) on insulin receptor expression, insulin binding and glucose oxidation in human liver cell line. Methods Non-malignant Chang liver cells were treated with different concentrations of testosterone and 17β-estradiol dissolved in serum free medium for 24 h to identify the effective dose of both steroids for further studies. Cells with 70–80% confluency were challenged with testosterone (0.1 µmol/l), 17β-estradiol (0.1 µmol/l) and their combination along with insulin as a positive control for 24 h. After the treatment period, insulin receptor mRNA expression, cell surface insulin binding and 14C-glucose oxidation were assessed. Results Both testosterone and 17β-estradiol significantly increased the insulin receptor mRNA expression, cell surface insulin binding and 14C-glucose oxidation compared to basal, but the increase was not at par with the effect of insulin. Compared to individual effects of testosterone and 17β-estradiol, their combination significantly increased the glucose oxidation similar to that of insulin. Conclusion It is concluded from the present study that testosterone and 17β-estradiol can directly enhance insulin receptor mRNA expression, insulin binding and glucose oxidation in Chang liver cells and thereby glucose metabolism.

Photodegradation of the steroid hormones 17β-estradiol (E2) and 17α-ethinylestradiol (EE2) in dilute aqueous solution

The photochemical transformation of natural estrogenic steroid 17β-estradiol (E2) and the synthetic oral contraceptive 17α-ethinylestradiol (EE2) has been studied in dilute non buffered aqueous solution (pH 5.5–6.0) upon monochromatic (254 nm) and polychromatic ( λ > 290 nm) irradiation. Upon irradiation at 254 nm, the quantum yields of E2 and EE2 photolysis were similar and evaluated to be 0.067 ± 0.007 and 0.062 ± 0.007, respectively. Upon polychromatic excitation, and by using phenol as chemical actinometer, the photolysis efficiencies have been determined to be 0.07 ± 0.01 and 0.08 ± 0.01 for E2 and EE2, respectively. For both estrogens, photodegradation by-products were identified with GC/MS and LC/MS. In a first step, a model compound – 5,6,7,8-tetrahydro-2-naphthol (THN) –, which represents the photoactive phenolic group, was used to obtain basic photoproduct structural informations. Numerous primary and secondary products were observed, corresponding to hydroxylated phenolic- or quinone-type compounds.

Impact of Estradiol on γ-Aminobutyric Acid- and Glutamate-Mediated Calcium Responses of Fetal Baboon (Papio anubis) Hippocampal and Cortical Neurons

High levels of maternal estrogens are likely to gain access to the fetal brain, yet little is known regarding the role of the steroid hormone 17beta-estradiol in neuronal differentiation and maturation of primate neurons. Previous research documented the presence of estrogen receptors during development in the hippocampus and cortex of the primate brain, but the functional significance of steroid exposure has not been widely investigated. Using both an in vitro preparation of primary hippocampal and frontal cortex neurons and Western blot analysis of fetal hippocampal and frontal cortex tissue, we documented the effects of in utero and acute in vitro exposure to 17beta-estradiol on the development of neuronal responsiveness to the amino acid transmitters gamma-aminobutyric acid (GABA) and glutamate in fetal baboon, Papio anubis, hippocampal, and cortical neurons. We found that in utero 17beta-estradiol exposure enhanced the excitatory action of the GABAergic system on immature cortical and hippocampal neurons, as manifest by increases in intracellular calcium after transient muscimol application and changes in the relevant ion cotransporters. Acute exposure to 17beta-estradiol in vitro had limited effect on GABAergic responses in cultured hippocampal and frontal cortex neurons. Moreover, there was limited effect of both prolonged in utero and acute estradiol on the response to glutamatergic system activation, consistent with previous findings in the rat. Along with documenting a prominent role for 17beta-estradiol in maturation of the GABAergic system, these findings increase our understanding of neuronal differentiation and maturation in the fetal primate brain.

The Role of Postoperative Neurocognitive Dysfunction on Quality of Life for Postmenopausal Women 6 Months After Cardiac Surgery

Women are prone to neurological complications after cardiac surgery. We have previously reported that treatment perioperatively with the neuroprotectant steroid 17beta-estradiol did not improve neurocognitive end-points 4 to 6 wk after surgery for elderly women. In this study, we evaluated the influence of early postoperative neurocognitive dysfunction on quality of life in postmenopausal women undergoing cardiac surgery and whether it is impacted by perioperative 17beta-estradiol treatment. One hundred seventy-four postmenopausal women randomly received 17beta-estradiol or placebo in a double-blind manner beginning the day before surgery and continued until the fifth postoperative day. The patients underwent psychometric testing using a standard battery before surgery and again 4 to 6 wk and 6 mo postoperatively. Quality of life was assessed at baseline and 6 mo after surgery with the SF-36 questionnaire and the Lawton instrumental activities of daily living scale. Complete data were available from 108 women of whom 13% demonstrated postoperative neurocognitive dysfunction. Based on multiple logistic regression analysis, a neurocognitive deficit 4 to 6 wk after surgery was an independent predictor of a lower SF-36 physical component score (P = 0.004) and lower Lawton instrumental activities of daily living scale 6 mo postoperatively (P = 0.026). Treatment with 17beta-estradiol (P = 0.003) and smoking status (P = 0.015) were predictors of worse SF-36 mental health component rating. Preoperative lower scores were independently associated with low quality of life postoperatively for all measurements. Postoperative neurocognitive dysfunction is associated with impaired quality of life in women after cardiac surgery. Perioperative treatment with 17beta-estradiol provides no benefits to postoperative quality of life. The relationship between low preoperative and postoperative self-rated health status suggests that some aspects of quality of life in postmenopausal women are not amenable to improvements with cardiac surgery.

Rainfall and tillage effects on transport of fecal bacteria and sex hormones 17β-estradiol and testosterone from broiler litter applications to a Georgia Piedmont Ultisol

Poultry litter provides nutrients for crop and pasture production; however, it also contains fecal bacteria, sex hormones (17β-estradiol and testosterone) and antibiotic residues that may contaminate surface waters. Our objective was to quantify transport of fecal bacteria, estradiol, testosterone and antibiotic residues from a Cecil sandy loam managed since 1991 under no-till (NT) and conventional tillage (CT) to which either poultry litter (PL) or conventional fertilizer (CF) was applied based on the nitrogen needs of corn ( Zea mays L) in the Southern Piedmont of NE Georgia. Simulated rainfall was applied for 60 min to 2 by 3-m field plots at a constant rate in 2004 and variable rate in 2005. Runoff was continuously measured and subsamples taken for determining flow-weighted concentrations of fecal bacteria, hormones, and antibiotic residues. Neither Salmonella, nor Campylobacter, nor antimicrobial residues were detected in litter, soil, or runoff. Differences in soil concentrations of fecal bacteria before and after rainfall simulations were observed only for Escherichia coli in the constant rainfall intensity experiment. Differences in flow-weighted concentrations were observed only for testosterone in both constant and variable intensity rainfall experiments, and were greatest for treatments that received poultry litter. Total loads of E. coli and fecal enterococci, were largest for both tillage treatments receiving poultry litter for the variable rainfall intensity. Load of testosterone was greatest for no-till plots receiving poultry litter under variable rainfall intensity. Poultry litter application rates commensurate for corn appeared to enhance only soil concentrations of E. coli, and runoff concentrations of testosterone above background levels.

Hormonal regulation of female nuptial coloration in a fish

Physiological color change in camouflage and mating is widespread among fishes, but little is known about the regulation of such temporal changes in nuptial coloration and particularly concerning female coloration. To better understand regulation of nuptial coloration we investigated physiological color change in female two-spotted gobies ( Gobiusculus flavescens). Females of this species develop an orange belly that acts as an ornament. The orange color is caused by the color of the gonads combined with the chromathophore based pigmentation and transparency of the skin. Often during courtship and female–female competition, a rapid increase in orange coloration, in combination with lighter sides and back that increases skin and body transparency, gives the belly an intense ‘glowing’ appearance. To understand how this increased orange coloration can be regulated we analysed chromatic and transparency effects of neurohumoral agents on abdominal skin biopsies in vitro. We found prolactin and α-melanocyte stimulating hormone (MSH) to increase orange coloration of the skin. By contrast, melatonin and noradrenaline increased skin transparency, but had a negative effect on orange coloration. However, mixtures of melatonin and MSH, or melatonin and prolactin, increased both orange coloration and transparency. This effect mimics the chromatic ‘glow’ effect that commonly takes place during courtship and intra sexual aggression. Notably, not only epidermal chromatophores but also internal chromatophores lining the peritoneum responded to hormone treatments. There were no chromatic effects of the sex steroids 17β-estradiol, testosterone or 11-ketotestosterone. We hypothesize that similar modulation of nuptial coloration by multiple hormones may be widespread in nature.

Steroid hormone determination in water using an environmentally friendly membrane based extraction technique

In this study, a method was developed for determination of steroid hormones (17β-estradiol, estrone, 17α-ethynylestradiol) in tap and sewage water samples from Sweden. Sample preparation and analysis were performed by a hollow-fibre microporous membrane liquid–liquid extraction (HF-MMLLE) set-up combined with gas chromatography–mass spectrometry (GC–MS). In this approach, only the organic liquid in the lumen (10 μL) of the hollow-fibre membrane was utilised for depleting extraction. Several parameters were studied, including: type of organic solvent, sample pH, salt and humic acid content. The optimised method allowed the determination of the analyte at the low ng L −1 level in tap and sewage water. A linear plot gave correlation coefficients better than 0.995 and resulted in a method limit of detection of 1.6, 3 and 10 ng L −1 for 17β-estradiol, estrone, and 17α-ethynylestradiol, respectively, in sewage water. Enrichment factors were over 1400 after derivatisation. The repeatabilities at 50 and 600 ng L −1 were better than 10% and 6%, respectively.

Estrogen Receptor α, but Not β, Is Required for Optimal Dendritic Cell Differentiation and CD40-Induced Cytokine Production

Dendritic cells (DC) are critical actors in the initiation of primary immune responses and regulation of self-tolerance. The steroid sex hormone 17beta-estradiol (E(2)) has been shown to promote the differentiation of DCs from bone marrow (BM) precursors in vitro. However, the estrogen receptor (ER) involved in this effect has not yet been characterized. Using recently generated ERalpha- or ERbeta-deficient mice, we investigated the role of ER isotypes in DC differentiation and acquisition of effector functions. We report that estrogen-dependent activation of ERalpha, but not ERbeta, is required for normal DC development from BM precursors cultured with GM-CSF. We show that reduced numbers of DCs were generated in the absence of ERalpha activation and provide evidence for a cell-autonomous function of ERalpha signaling in DC differentiation. ERalpha-deficient DCs were phenotypically and functionally distinct from wild-type DCs generated in the presence of estrogens. In response to microbial components, ERalpha-deficient DCs failed to up-regulate MHC class II and CD86 molecules, which could account for their reduced capacity to prime naive CD4(+) T lymphocytes. Although they retained the ability to express CD40 and to produce proinflammatory cytokines (e.g., IL-12, IL-6) upon TLR engagement, ERalpha-deficient DCs were defective in their ability to secrete such cytokines in response to CD40-CD40L interactions. Taken together, these results provide the first genetic evidence that ERalpha is the main receptor regulating estrogen-dependent DC differentiation in vitro and acquisition of their effector functions.

Effects of fifteen PBDE metabolites, DE71, DE79 and TBBPA on steroidogenesis in the H295R cell line

Polybrominated diphenyl ethers (PBDEs) and tetrabromobisphenol A (TBBPA) are brominated flame retardants that are produced in large quantities and are commonly used in construction materials, textiles, and as polymers in electronic equipment. Environmental and human levels of PBDEs have been increasing in the past 30 years, but the toxicity of PBDEs is not fully understood. Studies on their effects are relatively limited, and show that PBDEs are neurotoxins and potential endocrine disrupters. Hydroxylated (OH) and methoxylated (MeO) PBDEs have also been reported in the adipose tissue, blood and milk of wild animals and humans. In the present study, 15 PBDE metabolites, two BDE mixtures (DE71 and DE79), and TBBPA were studied individually to determine their effects on ten steroidogenic genes, aromatase activity, and concentrations of two steroid hormones (testosterone and 17β-estradiol) in the H295R human adrenocortical carcinoma cell line. Exposure to 0.05μM 2′-OH-BDE-68 significantly induced the expression of CYP11A, CYP11B2, CYP17, CYP21, 3βHSD2, 17βHSD1, and 17βHSD4, and the expression of StAR was induced by 6-OH-BDE-90 at the three exposure concentrations. Exposure to DE71 and DE79 resulted in dose-dependent trend towards induction, but these effects were not significant. Exposure to 0.5μM 2-OH-BDE-123 and 2-MeO-BDE-123 resulted in significantly greater aromatase activity. However, none of the compounds affected sex hormone production at the concentrations tested. Generally, OH-BDEs had a much stronger ability to affect steroidogenic gene expression than MeO-BDEs.

Soy isoflavones decrease the catechol-O-methyltransferase-mediated inactivation of 4-hydroxyestradiol in cultured MCF-7 cells

The tissue concentrations of the female sex hormone 17beta-estradiol (E2) and its reactive catechol metabolites such as 4-hydroxyestradiol (4-HO-E2) play important roles in hormonal carcinogenesis. They are influenced by the activity of local enzymes involved in the metabolic activation and inactivation of E2. In the mammary gland, catechol estrogens are predominately inactivated by catechol-O-methyltransferase (COMT). Food supplements containing the soy isoflavones genistein and daidzein are consumed because they are believed to protect from breast cancer; however, this proposed benefit is controversial. The aim of the present study was to investigate the influence of soy isoflavones on the gene expression and activity of COMT in cultured human mammary adenocarcinoma MCF-7 cells. Levels of COMT messenger RNA (mRNA) were determined by reverse transcription/competitive polymerase chain reaction and COMT activity was determined by high-performance liquid chromatography analysis of the methylation products of both the model substrate quercetin and the physiological relevant substrate 4-HO-E2. Our study demonstrates for the first time that soy isoflavones at hormonally active concentrations cause a significant reduction of both COMT mRNA levels and COMT activity as well as of the methylation of 4-HO-E2. Experiments using the estrogen receptor (ER) antagonist ICI 182,780 support a role of the ER in the isoflavone-induced down-regulation of COMT expression. Thus, this study not only demonstrates that hormonally active concentrations of soy isoflavones inhibit the detoxification of catechols in this human breast cancer cell line but also implies that diet might influence COMT activity to a greater extent than heretofore recognized.

The Serum Levels of 17β-estradiol, Progesterone and Triiodothyronine Correlate with Brown Adipose Tissue Thermogenic Parameters During Aging

Sex and thyroid hormones are among the factors modulating energy metabolism through regulation of mitochondrial oxidative capacity. Brown adipose tissue (BAT) in old female rats has been shown to maintain, better than males, the ability to produce heat when exposed to cold. Considering the decline that takes place in gonadal and thyroid function during aging, the aim of this work was to test whether the age-related hormonal status may be a potential mediator of the gender differences in BAT decline. COX activity, UCP1, mitochondrial respiration rate, mitochondrial DNA (mtDNA), levels of mitochondrial transcription factor A (TFAM), as well as the serum levels of sex steroids (17β-estradiol, progesterone and testosterone) and thyroid hormones (T3 and T4) were measured in 6-, 18-, and 24-month (mo) old male and female rats kept at 22 °C. Six mo-old female rats showed higher thermogenic features than males. Male rats at 18-mo showed a decrease in uncoupling activity compared to females. Both genders showed marked signs of atrophy in BAT of 24-mo-old rats, characterized by a decrease in total DNA, mitochondrial protein, COX and UCP1, whereas mtDNA was found to increase. Sex steroid hormones were well correlated with BAT parameters when both genders were considered, however, T3 was the hormone with the strongest positive correlations in female rats. In conclusion, our findings provide evidence suggesting that T3 may be a potential mediator of the sexual dimorphism in the effect of aging on the functional decline of BAT.

17β-Estradiol protects the neonatal brain from hypoxia–ischemia

Hypoxia–ischemia is relatively common in human infants. Hypoxia–ischemia can occur as a result of complications associated with prematurity or birth, frequently leading to altered brain development and cognitive and behavioral deficits that persist throughout life. Despite the relative frequency of neonatal hypoxic–ischemic encephalopathy, the immature brain sustains relatively less damage than an adult who experiences a similar crisis of oxygen and nutrient deprivation. Therefore, factors may be present that protect the developing brain. During late gestation, the infant brain encounters high levels of the steroid hormone 17β-estradiol. This observation, combined with evidence supporting 17β-estradiol as a neuroprotective agent, led us to hypothesize that increasing the basal level of 17β-estradiol would reduce the amount of hypoxia–ischemia induced injury to the neonatal brain. To test that hypothesis we administered 17β-estradiol using either a repeated dosing paradigm or a single dose paradigm to immature male and female rats. Here we show that the repeated dosing paradigm (three doses of 17β-estradiol) provided approximately 70% protection of the hippocampus, basal ganglia, and amygdala. By contrast, a single administration of 17β-estradiol 24 h prior to hypoxia–ischemia conferred little protection. The only exception was the pyramidal layer of the female hippocampus, which was modestly protected (16% reduction in damage). The protection afforded by the multiple administrations of 17β-estradiol was similar for females and males, with the only exception being the male amygdala, which displayed less damage than the female amgydala. We conclude that 17β-estradiol acts as a potent neuroprotective agent against hypoxia–ischemia induced damage to the developing brain, and that pretreating infants at risk for hypoxic–ischemic injury may be advisable.

Sexual dimorphism in airway responsiveness to sex hormones in rabbits

LETTERS TO THE EDITORSexual dimorphism in airway responsiveness to sex hormones in rabbitsVassiliki Kouloumenta, Apostolia Hatziefthimiou, Efrosyni Paraskeva, Konstantinos Gourgoulianis, and Paschalis Adam MolyvdasVassiliki Kouloumenta, Apostolia Hatziefthimiou, Efrosyni Paraskeva, Konstantinos Gourgoulianis, and Paschalis Adam MolyvdasPublished Online:01 Aug 2007https://doi.org/10.1152/ajplung.00192.2007MoreSectionsPDF (30 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInEmailWeChat to the editor: Recently, Massaro and Massaro (4) demonstrated a sexual dimorphism of alveolar size in male and female adult rats and mice and that estrogen receptor (ER)-α and ER-β are required for this sexual dimorphism.Our group recently showed that a similar phenomenon of sexual dimorphism presents in airway responsiveness to sex hormones in rabbits. We studied the direct effect of sex hormones (testosterone and 17β-estradiol) on airway smooth muscle (ASM) at rest and precontracted with acetylcholine or carbachol. Testosterone induced a concentration-dependent (10−12 M to 10−4 M) contraction of ASM at rest and a concentration-dependent (10−12 M to 10−4 M) relaxation of ASM precontracted with 10−5 M acetylcholine or carbachol (3). This action of testosterone was observed only in male rabbits, whereas testosterone had no effect in female rabbits. Mechanical removal of the airway epithelium abolished significantly (P < 0.05) the relaxing effect of testosterone (10−7 M to 10−4 M). In contrast to testosterone, 17β-estradiol had an epithelium-independent relaxing effect on ASM from male rabbits precontracted with acetylcholine, only in the concentration of 10−6 M (P = 0.005). Similar results have been obtained in a previous study demonstrating that in male rabbits, β-estradiol caused an epithelial-independent relaxation of tracheal muscle strips precontracted with either acetylcholine or KCl (5). Indirect immunofluorescence with an anti-human androgen receptor (AR) monoclonal antibody revealed that ASM cells express AR. However, in culture of epithelium-intact ASM, the presence of testosterone (10−8 M or 10−4 M) for 24 or 48 h did not alter their responsiveness to acetylcholine. Besides, the testosterone effect was not influenced by the presence of the specific AR antagonist flutamide or the inhibitor of DNA transcription actinomycin D in the perfusing medium.Nevertheless, there are not many studies in airways. There are studies on vessels suggesting this phenomenon of sexual dimorphism. Many clinical and epidemiological studies show a bigger frequency of cardiovascular diseases in men than in pre-menopause women (1), whereas studies in rabbits demonstrated a different effect of testosterone in male and female animals in the development of athiromatic plaque (2).The results above suggest that in our experiments, sexual dimorphism was not due to classic steroid receptors. It remains to be investigated whether the action of testosterone on rabbit trachea is mediated by nonclassic membrane receptors that also exist in tracheal smooth muscle cells.REFERENCES1 Barrett-Connor E. Sex differences in coronary heart diseases. Why are women so superior? The 1995 Ancel Keys Lecture. Circulation 95: 252–264, 1997.Crossref | PubMed | ISI | Google Scholar2 Hanke H, Lenz C, Hess B, Spindler KD, Weidemann W. Effect of testosterone on plaque development and androgen receptor expression in the arterial vessel wall. Circulation 103: 1382–1385, 2001.Crossref | PubMed | ISI | Google Scholar3 Kouloumenta V, Hatziefthimiou A, Paraskeva E, Gourgoulianis K, Molyvdas PA. Non-genomic effect of testosterone on airway smooth muscle. Br J Pharmacol 149: 1083–1091, 2006.Crossref | PubMed | ISI | Google Scholar4 Massaro D, Massaro GD. Estrogen receptor regulation of pulmonary alveolar dimensions: alveolar sexual dimorphism in mice. Am J Physiol Lung Cell Mol Physiol 290: L866–L870, 2006.Link | ISI | Google Scholar5 Pang JJ, Xu XB, Li HF, Zhang XY, Zheng TZ, Qu SY. Inhibition of b-estradiol on trachea smooth muscle contraction in vitro and in vivo. Acta Pharmacol Sin 23: 273–277, 2002.PubMed | ISI | Google ScholarAUTHOR NOTESAddress for reprint requests and other correspondence: A. Hatziefthimiou, Univ. of Thessaly, Medical School, Larissa, Greece (e-mail: [email protected]) Download PDF Previous Back to Top FiguresReferencesRelatedInformationCited ByMenopause, lung function and obstructive lung disease outcomes: a systematic review6 November 2017 | Climacteric, Vol. 21, No. 1Emerging concepts in smooth muscle contributions to airway structure and function: implications for health and diseaseY. S. Prakash12 December 2016 | American Journal of Physiology-Lung Cellular and Molecular Physiology, Vol. 311, No. 6Seasonal changes in testosterone levels in wild Mexican cottontails Sylvilagus cuniculariusMammalian Biology - Zeitschrift für Säugetierkunde, Vol. 79, No. 4The mitogenic effect of testosterone and 17β-estradiol on airway smooth muscle cellsSteroids, Vol. 76, No. 4 More from this issue > Volume 293Issue 2August 2007Pages L516-L516 Copyright & PermissionsCopyright © 2007 the American Physiological Societyhttps://doi.org/10.1152/ajplung.00192.2007PubMed17666738History Published online 1 August 2007 Published in print 1 August 2007 Metrics

Female Gender-specific Inhibition of KCNQ1 Channels and Chloride Secretion by 17β-Estradiol in Rat Distal Colonic Crypts

The estrogen sex steroid 17beta-estradiol rapidly inhibits secretagogue-stimulated cAMP-dependent Cl(-) secretion in the female rat distal colonic crypt by the inhibition of basolateral K(+) channels. In Ussing chamber studies, both the anti-secretory response and inhibition of basolateral K(+) current was shown to be attenuated by pretreatment with rottlerin, a PKCdelta-specific inhibitor. In whole cell patch-clamp analysis, 17beta-estradiol inhibited a chromanol 293B-sensitive KCNQ1 channel current in isolated female rat distal colonic crypts. Estrogen had no effect on KCNQ1 channel currents in colonic crypts isolated from male rats. Female distal colonic crypts expressed a significantly higher amount of PKCdelta in comparison to male tissue. PKCdelta and PKA were activated at 5 min in response to 17beta-estradiol in female distal colonic crypts only. Both PKCdelta- and PKA-associated with the KCNQ1 channel in response to 17beta-estradiol in female distal colonic crypts, and no associations were observed in crypts from males. PKA activation, association with KCNQ1, and phosphorylation of the channel were regulated by PKCdelta as the responses were blocked by pretreatment with rottlerin. Taken together, our experiments have identified the molecular targets underlying the anti-secretory response to estrogen involving the inhibition of KCNQ1 channel activity via PKCdelta- and PKA-dependent signaling pathways. This is a novel gender-specific mechanism of regulation of an ion channel by estrogen. The anti-secretory response described in this study provides molecular insights whereby estrogen causes fluid retention effects in the female during periods of high circulating plasma estrogen levels.

Acceleration of Autoimmunity by Organochlorine Pesticides: A Comparison of Splenic B-Cell Effects of Chlordecone and Estradiol in (NZBxNZW)F1 Mice

The weakly estrogenic organochlorine pesticide chlordecone can accelerate the development of systemic lupus erythematosus (SLE) in ovariectomized (NZBxNZW)F1 mice, with a shortened time to appearance of autoantibodies and disease similar to that produced by treatment with the sex hormone 17beta-estradiol (E2). It is unclear whether chlordecone and E2 share the same pathways in mediating this effect. The effects of chlordecone and E2 treatment on splenic germinal center (GC) and marginal zone B cells were examined. Both chlordecone and E2 activated splenic B cells and enhanced GC reactions, as shown by upregulated protein expression of GL7, CXCR5, and CXCR4. Both treatments increased B-cell bcl-2 and shp-1 gene expression and enhanced ICAM-1 and VCAM-1 protein levels in GC B cells. Chlordecone reduced total B cell and GC B-cell apoptosis without affecting proliferation, another feature shared by E2 treatment. However, chlordecone treatment did not alter the composition of splenic B-cell subsets in marked contrast to the decrease in transitional B cells and increase in marginal zone B cells seen in E2-treated mice. The differences in effects between chlordecone and E2 indicate that chlordecone is not functioning simply as an estrogen mimic with respect to effects on the immune system. Similarities in the effects of chlordecone and E2 on specific immune functions, such as diminished apoptosis in GC B cells, may provide valuable clues regarding key events in the acceleration of autoimmunity by E2, chlordecone, and other agents.

Leaching of Estrogenic Hormones from Manure-Treated Structured Soils

The threat to the aquatic environment posed by root zone leaching of estrogens from manure-treated fields has hitherto been overlooked. The steroid hormones 17beta-estradiol (E2) and its degradation product estrone (E1) are of particular environmental concern as both are abundant in slurryfrom pregnant and cycling pigs and both are potential endocrine disruptors (lowest observable effect level (LOEL) 14 and 3.3 ng/L, respectively). The present one-year study examines the transport of E1 and E2 from manure to tile drainage systems at two field sites on structured, loamy soil. The estrogens leached from the root zone to tile drainage water in concentrations exceeding the LOEL for as long as 3 months after application, with the maximum recorded concentration of E1 and E2 being 68.1 and 2.5 ng/ L, respectively. Transport of estrogens from the soil to the aquatic environment was governed by pronounced macropore flow and consequent rapid movement of the estrogens to the tile drains. These findings suggest that the application of manure to structured soils poses a potential contamination risk to the aquatic environment with estrogen, particularly when manure is applied to areas where the majority of streamwater derives from drainage water.