277,323 research outputs found

    Steroid Hormones and Endocrine Disruptors: Recent Advances in Receptor–Mediated Actions

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    It has been accepted that receptor-mediated action of steroid hormones depends on both the receptor and the hormonal level. The mechanism of transcription by steroid receptors is mediated by cofactors, which function as co-activators or co-repressors, while their non-genomic actions depend on receptors localized to the cell membrane. Recently, a number of environmental chemicals, which are now termed as endocrine disruptors, have been identified, and their unwanted effects on our lives have become serious problems all over the world. Their adverse effects on endocrine systems in animals, mostly estrogenic or anti-estrogenic, have resulted in reproductive malfunction and developmental disorders. Although aryl hydrocarbons exhibit estrogenic or anti- estrogenic activity through specific interaction with aryl hydrocarbon receptors, other chemicals seem to interact directly with estrogen receptors, α and β forms. In this paper, we surveyed the most recent understanding of endocrine disruptors from the viewpoint of steroid receptor systems. We suggest two potential mechanisms of action for endocrine disruptors. Endocrine distruptors i) directly associate with steroid receptor systems and/or ii) associate with the growth factor or the neurotransmitter receptor systems, and then upregulate the mitogen-activated protein kinase signaling cascades, leading to the ligand-independent activation of steroid receptor systems. Using these steroid receptor-dependent mechanisms, it appears that endocrine disruptors disorder our endocrine systems. We have proposed future suggestions to further understand endocrine disruptors from the viewpoint of steroid receptor systems. Key words: endocrine disruptors; receptor-mediated actions; steroid hormone

    Nrf2 deficiency influences susceptibility to steroid resistance via HDAC2 reduction

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    Abnormal lung inflammation and oxidant burden are associated with a significant reduction in histone deacetylase 2 (HDAC2) abundance and steroid resistance. We hypothesized that Nrf2 regulates steroid sensitivity via HDAC2 in response to inflammation in mouse lung. Furthermore, HDAC2 deficiency leads to steroid resistance in attenuating lung inflammatory response, which may be due to oxidant/antioxidant imbalance. Loss of antioxidant transcription factor Nrf2 resulted in decreased HDAC2 in lung, and increased inflammatory lung response which was not reversed by steroid. Thus, steroid resistance or inability of steroids to control lung inflammatory response is dependent on Nrf2-HDAC2 axis. These findings have implications in steroid resistance, particularly during the conditions of oxidative stress when the lungs are more susceptible to inflammatory response, which is seen in patients with chronic obstructive pulmonary disease, asthma, rheumatoid arthritis, and inflammatory bowel disease

    Unraveling the functional role of the orphan solute carrier, SLC22A24 in the transport of steroid conjugates through metabolomic and genome-wide association studies.

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    Variation in steroid hormone levels has wide implications for health and disease. The genes encoding the proteins involved in steroid disposition represent key determinants of interindividual variation in steroid levels and ultimately, their effects. Beginning with metabolomic data from genome-wide association studies (GWAS), we observed that genetic variants in the orphan transporter, SLC22A24 were significantly associated with levels of androsterone glucuronide and etiocholanolone glucuronide (sentinel SNPs p-value <1x10-30). In cells over-expressing human or various mammalian orthologs of SLC22A24, we showed that steroid conjugates and bile acids were substrates of the transporter. Phylogenetic, genomic, and transcriptomic analyses suggested that SLC22A24 has a specialized role in the kidney and appears to function in the reabsorption of organic anions, and in particular, anionic steroids. Phenome-wide analysis showed that functional variants of SLC22A24 are associated with human disease such as cardiovascular diseases and acne, which have been linked to dysregulated steroid metabolism. Collectively, these functional genomic studies reveal a previously uncharacterized protein involved in steroid homeostasis, opening up new possibilities for SLC22A24 as a pharmacological target for regulating steroid levels

    Steroid Hormones and Endocrine Disruptors: Recent Advances in Receptor–Mediated Actions

    Get PDF
    It has been accepted that receptor-mediated action of steroid hormones depends on both the receptor and the hormonal level. The mechanism of transcription by steroid receptors is mediated by cofactors, which function as co-activators or co-repressors, while their non-genomic actions depend on receptors localized to the cell membrane. Recently, a number of environmental chemicals, which are now termed as endocrine disruptors, have been identified, and their unwanted effects on our lives have become serious problems all over the world. Their adverse effects on endocrine systems in animals, mostly estrogenic or anti-estrogenic, have resulted in reproductive malfunction and developmental disorders. Although aryl hydrocarbons exhibit estrogenic or anti- estrogenic activity through specific interaction with aryl hydrocarbon receptors, other chemicals seem to interact directly with estrogen receptors, α and β forms. In this paper, we surveyed the most recent understanding of endocrine disruptors from the viewpoint of steroid receptor systems. We suggest two potential mechanisms of action for endocrine disruptors. Endocrine distruptors i) directly associate with steroid receptor systems and/or ii) associate with the growth factor or the neurotransmitter receptor systems, and then upregulate the mitogen-activated protein kinase signaling cascades, leading to the ligand-independent activation of steroid receptor systems. Using these steroid receptor-dependent mechanisms, it appears that endocrine disruptors disorder our endocrine systems. We have proposed future suggestions to further understand endocrine disruptors from the viewpoint of steroid receptor systems. Key words: endocrine disruptors; receptor-mediated actions; steroid hormone

    Freedom of Information

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    OBJECTIVE: It has previously been shown that a combination of inhaled nitric oxide (iNO) and intravenous (IV) steroid attenuates endotoxin-induced organ damage in a 6-hour porcine endotoxemia model. We aimed to further explore these effects in a 30-hour model with attention to clinically important variables. DESIGN: Randomized controlled trial. SETTING: University animal laboratory. SUBJECTS: Domestic piglets (n = 30). INTERVENTIONS: Animals were randomized into 5 groups (n = 6 each): 1) Controls, 2) LPS-only (endotoxin/lipopolysaccharide (LPS) infusion), 3) LPS + iNO, 4) LPS + IV steroid, 5) LPS + iNO + IV steroid. MEASUREMENTS AND MAIN RESULTS: Exposure to LPS temporarily increased pulmonary artery mean pressure and impeded renal function with elevated serum creatinine and acidosis compared to a control group over the 30-hour study period. Double treatment with both iNO and IV steroid tended to blunt the deterioration in renal function, although the only significant effect was on Base Excess (p = 0.045). None of the LPS + iNO + IV steroid treated animals died during the study period, whereas one animal died in each of the other LPS-infused groups. CONCLUSIONS: This study suggests that combined early therapy with iNO and IV steroid is associated with partial protection of kidney function after 30 hours of experimental LPS infusion

    3D model of amphioxus steroid receptor complexed with estradiol

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    The origins of signaling by vertebrate steroids are not fully understood. An important advance was the report that an estrogen-binding steroid receptor [SR] is present in amphioxus, a basal chordate with a similar body plan as vertebrates. To investigate the evolution of estrogen binding to steroid receptors, we constructed a 3D model of amphioxus SR complexed with estradiol. This 3D model indicates that although the SR is activated by estradiol, some interactions between estradiol and human ER[alpha] are not conserved in the SR, which can explain the low affinity of estradiol for the SR. These differences between the SR and ER[alpha] in the steroid-binding domain are sufficient to suggest that another steroid is the physiological regulator of the SR. The 3D model predicts that mutation of Glu-346 to Gln will increase the affinity of testosterone for amphioxus SR and elucidate the evolution of steroid binding to nuclear receptors

    Rapid bioconcentration of steroids in the plasma of three-spined stickleback Gasterosteus aculeatus exposed to waterborne testosterone and 17β-oestradiol

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    The relationship over time between the concentrations of two steroids, singly and in combination, in a static exposure system and in the blood of three-spined stickleback Gasterosteus aculeatus, held within the exposure system was investigated. Groups of three-spined stickleback were exposed (nominally) to either 1000 ng l1 17β-oestradiol (E2), testosterone (T) or E2 and T in combination at the same concentrations for 6 days. Both water and fish were sampled at intervals and steroid concentrations in both compartments were determined. The plasma steroid time profile revealed a rapid bioconcentration within the first 6 h of exposure. The plasma steroid levels attained at this time point (20–90 ng ml1) were up to 50-fold (E2) and 200-fold (T) greater than the actual levels of steroid measured in the exposure water, while levels in the blood of control fish did not exceed 4 ng ml1. The substantial elevation of plasma steroid levels relative to the concentrations of steroid to which the fish were exposed in the ambient water gives scope for delivery of the steroids to target endocrine tissues at levels far in excess of what might be predicted on the basis of passive branchial uptake alone. These results are discussed in relation to endocrine disruption, and in particular the occurrence of effects in fish exposed to levels of endocrine active substances that are seemingly physiologically irrelevant

    Adjuvant Migraine Medications in the Treatment of Sudden Sensorineural Hearing Loss.

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    Objectives/hypothesisTo examine the hearing outcomes of patients with sudden sensorineural hearing loss (SSNHL) treated with oral and intratympanic (IT) steroid only or a combination of steroid and migraine treatment. Our hypothesis was that adjuvant migraine medications may improve outcomes in SSNHL.MethodsA retrospective chart review at a tertiary otology center was conducted to identify patients with SSNHL who received oral steroid and IT dexamethasone injection(s) with or without migraine medications (a combination of nortriptyline and topiramate).ResultsA total of 47 patients received oral steroid and IT dexamethasone injection(s) only, and 46 patients received oral steroid and IT dexamethasone injection(s) as well as migraine lifestyle changes plus a combination of nortriptyline and topiramate. There were no significant differences in demographics and baseline audiometric data between the two groups. Both groups demonstrated improvements in pure tone average (PTA) and hearing thresholds at 250 Hz and 8000 Hz posttreatment. However, compared to steroid-only group, the adjuvant migraine medications group had significantly greater improvements in hearing thresholds at the lower frequencies (250 Hz, 500 Hz, 1000 Hz). Patients in the latter cohort also had greater improvement in PTA (P = .01) and received fewer IT injections (P = .04) PTA improvement of ≥ 10 dB was observed in 36 patients (78%) in the adjuvant migraine medications group and 22 patients (46%) in the control group (P < .001).ConclusionIn multimodal treatment of SSNHL, supplementing oral and IT steroid with migraine medications may result in greater improvements in lower frequency hearing thresholds and PTA. Furthermore, adjuvant migraine treatment can lead to decrease in number of IT injections, thus reducing procedure-related risks and complications.Level of evidence3 Laryngoscope, 131:E283-E288, 2021

    Faecal steroid measurements for the assessment of reproductive function in Japanese quail (Coturnix coturnix japonica) and kakapo (Strigops habroptilus) : a thesis presented in partial fulfilment of the requirements for the degree of Master of Science in Physiology at Massey University

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    The kakapo (Strigops habroptilus) is an endangered parrot endemic to New Zealand and little is known of its reproductive physiology. Reproductive function is conventionally determined by the measurement of reproductive steroids in plasma samples. This is impractical and invasive in endangered, free-living species. However, the measurement of reproductive steroids in avian faecal samples is practiced. Few studies have documented strong relationships between faecal and plasma steroid concentrations. The objectives of this study were to develop and validate a faecal extraction method for the measurement of oestradiol, progesterone and testosterone in Japanese quail (Coturnix coturnix japonica); determine the relationships between steroid concentrations and gonadal development in quail; and define annual faecal hormone cycles of kakapo in relation to their breeding status. Groups of male and female quail were held on different photoperiodic and temperature regimes to produce birds with a range of gonad sizes and steroid concentrations. Steroid concentrations were measured in faeces and plasma by radioimmunoassay. Positive relationships were demonstrated between plasma and faecal steroid concentrations. Faecal steroid concentrations had strong positive relationships with ovary and testis size in female and male quail respectively. The extraction method developed was then applied to faecal samples, which were collected from kakapo in their free-living environment on Whenua Hou (Codfish Island). The samples were collected from identified birds over three potential breeding seasons. There were annual cycles of hormone concentrations that corresponded with cycles of breeding activity in females and males. No significant differences were found between breeding and non-breeding years for faecal concentrations of all three hormones, suggesting that kakapo undergo a degree of gonadal development each year. Annual hormone profiles for individual birds supported this finding. This study quantifies the value of collecting multiple faecal samples in both captive and wild situations and demonstrates the power and value of faecal steroid analysis

    The fate of steroid estrogens: Partitioning during wastewater treatment and onto river sediments

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    This is the author's accepted manuscript. The final published article is available from the link below. Copyright @ 2010 Springer Science+Business Media B.V.The partitioning of steroid estrogens in wastewater treatment and receiving waters is likely to influence their discharge to, and persistence in, the environment. This study investigated the partitioning behaviour of steroid estrogens in both laboratory and field studies. Partitioning onto activated sludge from laboratory-scale Husmann units was rapid with equilibrium achieved after 1 h. Sorption isotherms and Kd values decreased in the order 17α-ethinyl estradiol > 17α-estradiol > estrone > estriol without a sorption limit being achieved (1/n >1). Samples from a wastewater treatment works indicated no accumulation of steroid estrogens in solids from primary or secondary biological treatment, however, a range of steroid estrogens were identified in sediment samples from the River Thames. This would indicate that partitioning in the environment may play a role in the long-term fate of estrogens, with an indication that they will be recalcitrant in anaerobic conditions.EPSR
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