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‣ Avaliação in vivo do potencial estrogênico de amostra de água para consumo humano produzida por estação de tratamento do estado de São Paulo

Vaccari, Carolina
Fonte: Universidade Estadual Paulista (UNESP) Publicador: Universidade Estadual Paulista (UNESP)
Tipo: Trabalho de Conclusão de Curso
Português
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17.48117%
Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP); Introduction: The release of raw sewage into rivers and lakes has drawn attention to an important issue nowadays: the water quality. Substances with estrogenic activity (xenoestrogens) are the best known endocrine disruptors, and these, as well as other chemical substances, may remain in the water even after the conventional treatment. Objective: This study investigated the estrogenic potential of a drinking water sample from a Sao Paulo State Water Treatment Plant, using a standardized bioassay: the uterotrophic assay (OECD; nº 440), supplemented by the vaginal cornification evaluation. Materials and methods: The drinking water distributed to the population was collected and concentrated as an extract using a cartridge filter for organic substances. Water extracts were chemically evaluated for emerging contaminants and also in vitro by a bioluminescent yeast assay with estrogen/androgen human receptors (BLYES, BLYAS). In vivo assay was conducted with female 21- day old Wistar rats that were exposed by gavage to drinking water extracts during 03 days at doses of 33.3, 166.5, and 333.0 mL equivalent of water/kg body weight, modeling a daily ingestion of 2 L, 5 L and 10 L of drinking water by a 60 kg human being. Results: Traces of caffeine (21ug/L)...

‣ Biosynthesis of catalytically active rat testosterone 5 alpha-reductase in microinjected Xenopus oocytes: evidence for tissue-specific differences in translatable mRNA.

Farkash, Y; Soreq, H; Orly, J
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /08/1988 Português
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The enzyme 4-ene-3-ketosteroid-5 alpha-oxidoreductase [5 alpha-reductase; 3-oxo-5 alpha-steroid delta 4-dehydrogenase, 3-oxo-5 alpha-steroid: (acceptor) delta 4-oxidoreductase, EC 1.3.99.5] plays a key role in androgen-dependent target tissues, where it catalyzes the conversion of testosterone to the biologically active dihydrotestosterone. The regulation of 5 alpha-reductase expression has not been studied at the molecular level as the enzyme is a membrane protein that is labile in cell-free homogenates. We developed a sensitive bioassay of the enzyme activity expressed in Xenopus oocytes microinjected with rat liver and prostate mRNA. After microinjection, incubation of intact oocytes in the presence of [3H]testosterone revealed the in ovo appearance of active 5 alpha-reductase. Polyadenylated RNA was fractionated by sucrose gradient centrifugation, and the enzymatic activity was shown to be encoded by a 1600- to 2000-base-pair fraction of hepatic poly(A)+ RNA. 5 alpha-Reductase mRNA was most efficiently translated when up to 80 ng of RNA was injected per oocyte. In the injected oocytes, 5 alpha-reductase mRNA was found to be a short-lived molecule (t1/2 = 2 hr), whereas its in ovo translatable 5 alpha-reductase protein exhibited stable enzymatic activity for over 40 hr. Moreover...

‣ Androgenic and Estrogenic Response of Green Mussel Extracts from Singapore’s Coastal Environment Using a Human Cell-Based Bioassay

Bayen, Stéphane; Gong, Yinhan; Chin, Hong Soon; Lee, Hian Kee; Leong, Yong Eu; Obbard, Jeffrey Philip
Fonte: National Institue of Environmental Health Sciences Publicador: National Institue of Environmental Health Sciences
Tipo: Artigo de Revista Científica
Português
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27.101804%
In the last decade, evidence of endocrine disruption in biota exposed to environmental pollutants has raised serious concern. Human cell-based bioassays have been developed to evaluate induced androgenic and estrogenic activities of chemical compounds. However, bioassays have been sparsely applied to environmental samples. In this study we present data on sex hormone activities in the green mussel, Perna viridis, in Singapore’s coastal waters. P. viridis is a common bioindicator of marine contamination, and this study is a follow-up to an earlier investigation that reported the presence of sex hormone activities in seawater samples from Singapore’s coastal environment. Specimens were collected from eight locations around the Singapore coastline and analyzed for persistent organic pollutants (POPs) and heavy metals. Tissue extracts were then screened for activities on androgen receptors (ARs) and estrogen receptors (ER-α and ER-β) using a reporter gene bio-assay based on a HeLa human cell line. Mussel extracts alone did not exhibit AR activity, but in the presence of the reference androgenic hormone dihydrotestosterone (DHT), activities were up to 340% higher than those observed for DHT alone. Peak activities were observed in locations adjacent to industrial and shipping activities. Estrogenic activities of the mussel extract both alone and in the presence of reference hormone were positive. Correlations were statistically investigated between sex hormone activities...

‣ The OECD Program to Validate the Rat Hershberger Bioassay to Screen Compounds for in Vivo Androgen and Antiandrogen Responses. Phase 1: Use of a Potent Agonist and a Potent Antagonist to Test the Standardized Protocol

Owens, William; Zeiger, Errol; Walker, Michael; Ashby, John; Onyon, Lesley; Gray, L. Earl
Fonte: National Institute of Environmental Health Sciences Publicador: National Institute of Environmental Health Sciences
Tipo: Artigo de Revista Científica
Português
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27.94484%
The Organisation for Economic Cooperation and Development (OECD) has completed phase 1 of the Hershberger validation intended to identify in vivo activity of suspected androgens and anti-androgens. Seventeen laboratories from 7 countries participated in phase 1, and results were collated and evaluated by the OECD with the support of an international committee of experts. Five androgen-responsive tissues (ventral prostate, paired seminal vesicles and coagulating glands, levator ani and bulbocavernosus muscles, glans penis, and paired Cowper’s or bulbourethral glands) were evaluated. The standardized protocols used selected doses of a reference androgen, testosterone propionate (TP), and an antiandrogen, flutamide (FLU). All laboratories successfully detected TP-stimulated increases in androgen-responsive tissue weight and decreases in TP-stimulated tissue weights when FLU was co-administered. The standardized protocols performed well under a variety of conditions (e.g., strain, diet, housing protocol, bedding). There was good agreement among laboratories with regard to the TP doses inducing significant increases in tissue weights and the FLU doses decreasing TP-stimulated tissue weights. Several additional procedures (e.g., weighing of the dorsolateral prostate and fixation of tissues before weighing) and serum component measurements (e.g....

‣ A new highly specific and robust yeast androgen bioassay for the detection of agonists and antagonists

Bovee, Toine F. H.; Helsdingen, Richard J. R.; Hamers, Astrid R. M.; van Duursen, Majorie B. M.; Nielen, Michel W. F.; Hoogenboom, Ron L. A. P.
Fonte: Springer-Verlag Publicador: Springer-Verlag
Tipo: Artigo de Revista Científica
Português
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Public concern about the presence of natural and anthropogenic compounds which affect human health by modulating normal endocrine functions is continuously growing. Fast and simple high-throughput screening methods for the detection of hormone activities are thus indispensable. During the last two decades, a panel of different in vitro assays has been developed, mainly for compounds with an estrogenic mode of action. Here we describe the development of an androgen transcription activation assay that is easy to use in routine screening. Recombinant yeast cells were constructed that express the human androgen receptor and yeast enhanced green fluorescent protein (yEGFP), the latter in response to androgens. Compared with other reporters, the yEGFP reporter protein is very convenient because it is directly measurable in intact living cells, i.e., cell wall disruption and the addition of a substrate are not needed. When yeast was exposed to 17β-testosterone, the concentration where half-maximal activation is reached (EC50) was 50 nM. The relative androgenic potencies, defined as the ratio between the EC50 of 17β-testosterone and the EC50 of the compound, of 5α-dihydrotestosterone, methyltrienolone, and 17β-boldenone are 2.3, 1.4, and 0.15 respectively. The results presented in this paper demonstrate that this new yeast androgen bioassay is fast...

‣ Triclocarban Enhances Testosterone Action: A New Type of Endocrine Disruptor?

Chen, Jiangang; Ahn, Ki Chang; Gee, Nancy A.; Ahmed, Mohamed I.; Duleba, Antoni J.; Zhao, Ling; Gee, Shirley J.; Hammock, Bruce D.; Lasley, Bill L.
Fonte: The Endocrine Society Publicador: The Endocrine Society
Tipo: Artigo de Revista Científica
Português
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17.48117%
Many xenobiotics have been associated with endocrine effects in a wide range of biological systems. These associations are usually between small nonsteroid molecules and steroid receptor signaling systems. In this report, triclocarban (TCC; 3,4,4′-trichlorocarbanilide), a common ingredient in personal care products that is used as an antimicrobial agent was evaluated and found to represent a new category of endocrine-disrupting substance. A cell-based androgen receptor-mediated bioassay was used to demonstrate that TCC and other urea compounds with a similar structure, which have little or no endocrine activity when tested alone, act to enhance testosterone (T)-induced androgen receptor-mediated transcriptional activity in vitro. This amplification effect of TCC was also apparent in vivo when 0.25% TCC was added to the diet of castrated male rats that were supported by exogenous testosterone treatment for 10 d. All male sex accessory organs increased significantly in size after the T+TCC treatment, compared with T or TCC treatments alone. The data presented here suggest that the bioactivity of endogenous hormones may be amplified by exposure to commercial personal care products containing sufficient levels of TCC.

‣ Bovine liver slices combined with an androgen transcriptional activation assay: an in-vitro model to study the metabolism and bioactivity of steroids

Wang, S.; Rijk, J. C. W.; Riethoff-Poortman, J. H.; Van Kuijk, S.; Peijnenburg, A. A. C. M.; Bovee, T. F. H.
Fonte: Springer-Verlag Publicador: Springer-Verlag
Tipo: Artigo de Revista Científica
Português
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Previously we described the properties of a rapid and robust yeast androgen bioassay for detection of androgenic anabolic compounds, validated it, and showed its added value for several practical applications. However, biotransformation of potent steroids into inactive metabolites, or vice versa, is not included in this screening assay. Within this context, animal-friendly in-vitro cellular systems resembling species-specific metabolism can be of value. We therefore investigated the metabolic capacity of precision-cut slices of bovine liver using 17β-testosterone (T) as a model compound, because this is an established standard compound for assessing the metabolic capacity of such cellular systems. However, this is the first time that slice metabolism has been combined with bioactivity measurements. Moreover, this study also involves bioactivation of inactive prohormones, for example dehydroepiandrosterone (DHEA) and esters of T, and although medium extracts are normally analyzed by HPLC, here the metabolites formed were identified with more certainty by ultra-performance liquid chromatography time-of-flight mass spectrometry (UPLC–TOFMS) with accurate mass measurement. Metabolism of T resulted mainly in the formation of the less potent phase I metabolites 4-androstene-3...

‣ Identification strategy for unknown pollutants using high-resolution mass spectrometry: Androgen-disrupting compounds identified through effect-directed analysis

Weiss, Jana M.; Simon, Eszter; Stroomberg, Gerard J.; de Boer, Ronald; de Boer, Jacob; van der Linden, Sander C.; Leonards, Pim E. G.; Lamoree, Marja H.
Fonte: Springer-Verlag Publicador: Springer-Verlag
Tipo: Artigo de Revista Científica
Português
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27.48117%
Effect-directed analysis has been applied to a river sediment sample of concern to identify the compounds responsible for the observed effects in an in vitro (anti-)androgenicity assay. For identification after non-target analysis performed on a high-resolution LTQ-Orbitrap, we developed a de novo identification strategy including physico-chemical parameters derived from the effect-directed analysis approach. With this identification strategy, we were able to handle the immense amount of data produced by non-target accurate mass analysis. The effect-directed analysis approach, together with the identification strategy, led to the successful identification of eight androgen-disrupting compounds belonging to very diverse compound classes: an oxygenated polyaromatic hydrocarbon, organophosphates, musks, and steroids. This is one of the first studies in the field of environmental analysis dealing with the difficult task of handling the large amount of data produced from non-target analysis. The combination of bioassay activity assessment, accurate mass measurement, and the identification and confirmation strategy is a promising approach for future identification of environmental key toxicants that are not included as priority pollutants in monitoring programs.

‣ Recombinant cell bioassays for the detection of (gluco)corticosteroids and endocrine-disrupting potencies of several environmental PCB contaminants

Bovee, Toine F. H.; Helsdingen, Richard J. R.; Hamers, Astrid R. M.; Brouwer, Bram A.; Nielen, Michel W. F.
Fonte: Springer-Verlag Publicador: Springer-Verlag
Tipo: Artigo de Revista Científica
Português
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Sensitive and robust bioassays for glucocorticoids are very useful for the pharmaceutical industry, environmental scientists and veterinary control. Here, a recombinant yeast cell was constructed that expresses the human glucocorticoid receptor alpha and a green fluorescent reporter protein in response to glucocorticoids. Both the receptor construct and the reporter construct were stably integrated into the yeast genome. The correct and specific functioning of this yeast glucocorticoid bioassay was studied by exposures to cortisol and other related compounds and critically compared to a GR-CALUX bioassay based on a human bone cell. Although less sensitive, the new yeast glucocorticoid bioassay showed sensitivity towards all (gluco)corticoids tested, with the following order in relative potencies: budesonide >> corticosterone > dexamethasone > cortisol = betamethasone > prednisolone > aldosterone. Hormone representatives for other hormone nuclear receptors, like 17β-estradiol for the oestrogen receptor, 5α-dihydrotestosterone for the androgen receptor and progesterone for the progesterone receptor, showed no clear agonistic responses, whilst some polychlorinated biphenyls were clearly able to interfere with the GR activity.

‣ The EPI Bioassay identifies natural compounds with estrogenic activity that are potent inhibitors of androgenic pathways in human prostate stromal and epithelial cells

Vollmer, Günter; Helle, Janina; Amri, Hakima; Liu, Xunxian; Arnold, Julia T.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Português
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The reactive stromal phenotype is an important factor for prostate cancer progression and may be a new target for treatment and prevention. A new high efficiency preclinical protocol, the EPI bioassay, reflects the interaction of endocrine, paracrine and immune, (EPI) factors on induced androgen metabolism in human prostate reactive stroma. The bioassay is based on co-culturing human primary prostate stromal cells and LAPC-4 prostatic adenocarcinoma cells in a downscaled format of 96-well-plates for testing multiple doses of multiple target compounds. Metabolism of dehydroepiandrosterone (DHEA) with or without TGFβ1–induced stimulation (D+T) of the reactive stroma phenotype was assessed by increased testosterone in the media and PSA production of the epithelial prostate cancer cells. By using the non-metabolizable androgen R1881, effects from direct androgen action were distinguished from stromal androgen production from DHEA. Stromal cell androgenic bioactivity was confirmed using conditioned media from D+T-treated stromal cell monocultures in an androgen-inducible AR screening assay. We further showed that both agonists to estrogen receptor (ER), DPN (ERβ) and PPT (ERα), as well as estrogenic natural compounds including soy isoflavones attenuated D+T-induced PSA production. Studies with the pure ER agonists showed that activating either ERα or ERβ could inhibit both D+T-mediated and R1881-mediated PSA production with the D+T effect being more pronounced. In conclusion...

‣ In Vitro Androgen Bioassays as a Detection Method for Designer Androgens

Cooper, Elliot R.; McGrath, Kristine C. Y.; Heather, Alison K.
Fonte: Molecular Diversity Preservation International (MDPI) Publicador: Molecular Diversity Preservation International (MDPI)
Tipo: Artigo de Revista Científica
Publicado em 06/02/2013 Português
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Androgens are the class of sex steroids responsible for male sexual characteristics, including increased muscle mass and decreased fat mass. Illicit use of androgen doping can be an attractive option for those looking to enhance sporting performance and/or physical appearance. The use of in vitro bioassays to detect androgens, especially designer or proandrogens, is becoming increasingly important in combating androgen doping associated with nutritional supplements. The nutritional sports supplement market has grown rapidly throughout the past decade. Many of these supplements contain androgens, designer androgens or proandrogens. Many designer or proandrogens cannot be detected by the standard highly-sensitive screening methods such as gas chromatography-mass spectrometry because their chemical structure is unknown. However, in vitro androgen bioassays can detect designer and proandrogens as these assays are not reliant on knowing the chemical structure but instead are based on androgen receptor activation. For these reasons, it may be advantageous to use routine androgen bioassay screening of nutraceutical samples to help curb the increasing problem of androgen doping.

‣ Differential Response to Abiraterone Acetate and Di-n-butyl Phthalate in an Androgen-Sensitive Human Fetal Testis Xenograft Bioassay

Spade, Daniel J.; Hall, Susan J.; Saffarini, Camelia M.; Huse, Susan M.; McDonnell, Elizabeth V.; Boekelheide, Kim
Fonte: Oxford University Press Publicador: Oxford University Press
Tipo: Artigo de Revista Científica
Português
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In utero exposure to antiandrogenic xenobiotics such as di-n-butyl phthalate (DBP) has been linked to congenital defects of the male reproductive tract, including cryptorchidism and hypospadias, as well as later life effects such as testicular cancer and decreased sperm counts. Experimental evidence indicates that DBP has in utero antiandrogenic effects in the rat. However, it is unclear whether DBP has similar effects on androgen biosynthesis in human fetal testis. To address this issue, we developed a xenograft bioassay with multiple androgen-sensitive physiological endpoints, similar to the rodent Hershberger assay. Adult male athymic nude mice were castrated, and human fetal testis was xenografted into the renal subcapsular space. Hosts were treated with human chorionic gonadotropin for 4 weeks to stimulate testosterone production. During weeks 3 and 4, hosts were exposed to DBP or abiraterone acetate, a CYP17A1 inhibitor. Although abiraterone acetate (14 d, 75mg/kg/d po) dramatically reduced testosterone and the weights of androgen-sensitive host organs, DBP (14 d, 500mg/kg/d po) had no effect on androgenic endpoints. DBP did produce a near-significant trend toward increased multinucleated germ cells in the xenografts. Gene expression analysis showed that abiraterone decreased expression of genes related to transcription and cell differentiation while increasing expression of genes involved in epigenetic control of gene expression. DBP induced expression of oxidative stress response genes and altered expression of actin cytoskeleton genes.

‣ Endogenous serum testosterone in man: ageing, the metabolic syndrome, functional decline and the role of supplementation

Haren, Matthew Timothy
Fonte: Universidade de Adelaide Publicador: Universidade de Adelaide
Tipo: Tese de Doutorado Formato: 1084594 bytes; 370104 bytes; 2890463 bytes; 1020791 bytes; 193907 bytes; application/pdf; application/pdf; application/pdf; application/pdf; application/pdf
Publicado em //2005 Português
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This thesis investigates the age - related decline in the various available measures and estimates of serum testosterone levels in men. Testosterone circulates predominantly bound with high affinity to sex - hormone binging globulin ( SHBG ) in plasma ( ~ 60 % ) and with lower affinity to albumin ( < 40 % ) ; approximately 1 - 2 % circulates unbound in plasma. It is the albumin - bound and free fractions ( termed " bioavailable testosterone " ) that are most likely to have biological effects on target tissues. This thesis reports the establishment, validation and derivation of normal ranges for an ammonium sulphate precipitation method for the measurement of bioavailable testosterone in serum. This method is in use by a number of laboratories at present including the laboratory of Professor John Morley at St Louis University with whom we collaborated. Testosterone has been shown, both cross - sectionally and longitudinally, to decline progressively beginning around the age of thirty. Total testosterone declines at approximately 0.4 % per year while bioavailable and free testosterone decline at approximately 1.2 % per year. The mechanisms that may be responsible for this include age - related changes to the hypothalamic - pituitary - testicular axis...

‣ Androgens and androgen receptor signalling in men.

Need, Eleanor Frances
Fonte: Universidade de Adelaide Publicador: Universidade de Adelaide
Tipo: Tese de Doutorado
Publicado em //2008 Português
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59.01115%
Androgens are critical for the development and maintenance of adult male characteristics such as muscle mass and sexual function. Consequently, the established decline with age of serum testosterone (T) in males has major health implications. While the androgen receptor (AR) is the major mediator of genomic androgen action and is required for the development of the male phenotype, reproductive organs and the maintenance of male secondary sexual characteristics, it is the entrance of androgens into the cell that mediates the activation of the AR and the subsequent modulation of expression of androgen regulated genes. Testosterone, biologically the most important androgen in male serum, circulates either free, loosely bound to albumin or tightly bound to sex hormone binding globulin (SHBG). Each of these forms of serum T have different abilities to enter cells, and which proportion of serum T is capable of entering cells and initiating the androgen signalling cascade, thereby leading to the activation of the AR has not been precisely defined. The AR amino terminal domain (NTD) is responsible for the majority of the ability of the AR to activate genes but the relative roles of the two activation functions in the AR NTD (activation functions 1 and 5; AF1 and 5) have not been precisely defined while the role of the AF2 surface which forms in the ligand binding domain upon agonist binding is responsible for interactions with key coregulators and also with the NTD in the amino-carboxyl (N/C) interaction. Our laboratory has recently identified a region within AF5 between amino acids 500-535 to which somatic mutations in castrate resistant prostate tumour samples collocate. Due to the lack of functional information on the AF5 region and the NTD in general...

‣ Identification strategy for unknown pollutants using high-resolution mass spectrometry: Androgen-disrupting compounds identified through effect-directed analysis

WEISS JANA; SIMON Eszter; STROOMBERG Gerard J; DE BOER Ronald; DE BOER Jacob; VAN DER LINDEN Sander; LEONARDS Pim Eg; LAMOREE Marja
Fonte: SPRINGER HEIDELBERG Publicador: SPRINGER HEIDELBERG
Tipo: Articles in Journals Formato: Online
Português
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27.679885%
The aim of this study was to develop and employ a de novo identification strategy to handle the immense amount of data produced by non-target LC-accurate mass analysis. The identification strategy is based on the implementation of SIEVE, an automated software for label-free comparative analyses to determine a change of expression between control and sample. The software has been adopted for protein and peptide analysis in 2-grouped controlled studies and this is to our knowledge the first time the software has been applied to the field of identifying unknown pollutants in the environment. The effect-directed analysis approach together with the de novo identification strategy was used to identify androgen disrupting compounds in sediment from a European river basin. Earlier, GC/MS results of this sediment were presented and here we complement that study with the identification results after LTQ-Orbitrap analysis. Our comprehensive strategy led to the successful identification of eight androgen disrupting compounds belonging to very diverse compound classes: an oxygenated polyaromatic hydrocarbon, organophosphates, musks and steroids. None of these compounds are currently represented on the priority pollutants list that is used as monitoring guidance in the EU Water Framework Directive. This is one of the first studies in the field of environmental analysis dealing with the difficult task of handling the large amount of data produced from non-target analysis. The combination of bioassay activity assessment...

‣ Serum testosterone bioassay evaluation in a large male cohort

Need, E.; O'Loughlin, P.; Armstrong, D.; Haren, M.; Martin, S.; Tilley, W.; Wittert, G.; Buchanan, G.
Fonte: Blackwell Science Ltd Publicador: Blackwell Science Ltd
Tipo: Artigo de Revista Científica
Publicado em //2010 Português
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28.235898%
Objective:  To assess if a cell-based readout of androgen action in serum demonstrates a closer association with recognized classical parameters of androgen action in men than current measures of serum testosterone (T). Design:  To develop, validate and utilize a mammalian cell-based assay to measure specifically bioactive T and determine if this measure is a physiologically relevant fraction of serum T. Measurements and participants:  We have developed a specific serum T bioassay using human prostate cancer cells. A rapid 5-min exposure to 100% serum followed by serum withdrawal confers specificity of the assay to serum T and provides sufficient sensitivity to measure T in male serum samples. Matrix effects were experimentally discounted as a confounding issue. A total of 960 male serum samples from the Florey Adelaide Male Ageing Study (FAMAS) with previous comprehensive cohort data and serum measurements were utilized. Results:  Bioassay T measurement in the 960 FAMAS serum samples returned a median of 10·7 nmol/l (1·7–45·4), and was most closely related to immunoassayed total T, but not immunoassayed bioavailable T or calculated free T. Immunoassayed total T demonstrated a positive association with isometric grip-strength (R2 = 0·127...

‣ Detection and metabolic investigations of a novel designer steroid: 3-chloro-17α-methyl-5α-androstan-17β-ol

Cawley, Adam T.; Blakey, Karen; Waller, Christopher C.; McLeod, Malcolm D.; Boyd, Sue; Heather, Alison; McGrath, Kristine C.; Handelsman, David J.; Willis, Anthony C.
Fonte: Wiley Publicador: Wiley
Tipo: Artigo de Revista Científica Formato: 12 pages
Português
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In 2012, seized capsules containing white powder were analyzed to show the presence of unknown steroid-related compounds. Subsequent gas chromatography–mass spectrometry (GC-MS) and nuclear magnetic resonance (NMR) investigations identified a mixture of 3α- and 3β- isomers of the novel compound; 3-chloro-17α-methyl-α-androstan-17β-ol. Synthesis of authentic reference materials followed by comparison of NMR, GC-MS and gas chromatography-tandem mass spectrometry (GC-MS/MS) data confirmed the finding of a new ‘designer’ steroid. Furthermore, in vitro androgen bioassays showed potent activity highlighting the potential for doping using this steroid. Due to the potential toxicity of the halogenated steroid, in vitro metabolic investigations of 3α-chloro-17α-methyl-α-androstan-17β-ol using equine and human S9 liver fractions were performed. For equine, GC-MS/MS analysis identified the diagnostic 3α-chloro-17α-methyl-5α-androstane-16α,17β-diol metabolite. For human, the 17α-methyl-α-androstane-3α,17β-diol metabolite was found. Results from these studies were used to verify the ability of GC-MS/MS precursor-ion scanning techniques to support untargeted detection strategies for designer steroids in anti-doping analyses.; Synthesis and in vitro metabolic investigations of 3α/β-chloro-17α-methyl-5α-androstan -17β-ol was suppo rted by the Austr a-lian Research Council Linkage Grant (LP120200444) Strat egies for the detection of designer ster oids in ra cehorses.

‣ The Impact of Exogenic Testosterone and Nortestosterone-Decanoate Toxicological Evaluation Using a Rat Model

Cristina, Romeo Teodor; Hanganu, Flavia; Dumitrescu, Eugenia; Muselin, Florin; Butnariu, Monica; Constantin, Adriana; Chiurciu, Viorica
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em 10/10/2014 Português
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17.48117%
The impact of exogenic testosterone (T): 1.5 and 3.0 mg/kg.bw) and 19-nortestosterone 17-decanoate (ND): 1.5 and 7.5 mg/kg.bw) in castrated male rats was evaluated based on: (a) weight increase of the androgen target tissues, respecting the Hershberger methodology; (b) the 17α and β-testosterone, 17 α and β-estradiol and 17 α and β-nortestosterone levels using the GC-MS/MS technique; and (c) observation of the serum free thyroxine levels (T4). Results revealed that T and ND significantly increased the weight of androgen target tissues as follows: ND was more influential on seminal vesicles, levator ani-bulbocavernosus muscle (LABC) and Cowper's glands and T (at a dose of 3.0 mg/kg.bw) influenced the weight of the ventral prostate and glans penis. Serum samples analyzed for steroid hormone levels showed the presence of 17β-testosterone, 17β-estradiol and 17β-nor-testosterone, in castrated male rats injected with testosterone and nortestosterone, but no significant differences were found between thyroid responses and thyroid hormone levels. The results of this research proved the disrupting activity of T and ND when administered in high doses and the useful application of the Hershberger bioassay in the case of ND.

‣ Low immune responses in high androgen responder C57BR/cdj males.

Cohn, D A
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /01/1986 Português
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27.94484%
Previous studies have shown that male mice of strains with high target organ responsiveness to androgen, the C57L/J and RF/J, have lower plasma immunoglobulin levels and weaker antibody responses to protein and polysaccharide antigens than mice of low androgen responder (LAR) strains, the A/J and 129/J. In the current report, the relationship between high androgen responsiveness and low immune performance has been investigated in another strain, the C57BR/cdj. Compared to LAR A/J males, C57BR/cdj males had significantly higher target organ responses to androgen as measured by both seminal vesicle bioassay and haematocrit. High androgen responder (HAR C57BR/cdj males were lower than A/J's in PFC responses to sheep red blood cells (SRBC), lipopolysaccharide (LPS) induced spleen cell proliferation and polyclonal B cell activation. HAR C57BR/cdj males were not significantly different from C57BR/cdj females or A/J mice in proliferative responses to concanavalin A (Con A) or phytohaemagglutinin (PHA). These results are compatible with our previous findings in other HAR strains and suggest that the consistently low in vivo immune responses of HAR males may be due to B cell weakness or T suppressor dysregulation.

‣ Structure-activity relationships of synthetic progestins in a yeast-based in vitro androgen bioassay

McRobb, Lucinda; Handelsman, David J; Kazlauskas, Rymantas; Wilkinson, Shane M; McLeod, Malcolm; Heather, Alison K
Fonte: Pergamon Press Publicador: Pergamon Press
Tipo: Artigo de Revista Científica
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The recent identification of tetrahydrogestrinone (THG), a non-marketed designer androgen used for sports doping but previously undetectable by established mass spectrometry-based urine drug screens, and its production by a facile chemical modification of