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Jerry R Reel - One of the best experts on this subject based on the ideXlab platform.
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the potent Synthetic Androgens dimethandrolone 7α 11β dimethyl 19 nortestosterone and 11β methyl 19 nortestosterone do not require 5α reduction to exert their maximal androgenic effects
The Journal of Steroid Biochemistry and Molecular Biology, 2010Co-Authors: Barbara J Attardi, Sheri Ann Hild, Sailaja Koduri, Bruce Till, Trung Pham, Laurent Pessaint, Jean A Engbring, David Gropp, Anne Semon, Jerry R ReelAbstract:Dimethandrolone (DMA: 7α,11β-dimethyl-19-nortestosterone) and 11β-methyl-19-nortestosterone (MNT) are potent Androgens in development for hormonal therapy in men. As 5α-reduced Androgens, such as 5α-dihydrotestosterone (DHT), may raise the risk of benign prostate hyperplasia, accelerate the development of prostate carcinoma, and increase male pattern baldness and acne, we investigated the role of 5α-reduction in the androgenic activity of DMA and MNT. The authentic 5α-reduced metabolites, 5α-dihydroDMA (5α-DHDMA) and 5α-dihydroMNT (5α-DHMNT), were prepared by chemical synthesis and compared in vitro and in vivo to the parent compounds. Both 5α-reduced Androgens bound with high affinity to the rat androgen receptor (AR) and were potent inducers of transactivation of 3XHRE-LUC in CV-1 cells cotransfected with a human AR expression plasmid. To examine in vivo androgenic (stimulation of ventral prostate [VP] and seminal vesicle [SV] weights) and anabolic (stimulation of levator ani [LA] muscle weights) activity, 22-day-old castrate male rats were treated sc for 7 days with various doses of DMA, 5α-DHDMA, or testosterone (T) or MNT, 5α-DHMNT, or T and necropsied on day 8. 5α-DHDMA was at least threefold more potent than T in stimulating growth of the VP but only 30-40% as potent as DMA. 5α-DHMNT was four- to eightfold more potent than T, whereas MNT was approximately equipotent to T. To assess the possible role of 5α-reduction in VP and SV growth, castrate immature rats were treated with maximally effective doses of T, DHT, DMA, MNT, or the related 19-norandrogen, 7α-methyl-19-nortestosterone (MENT), or vehicle, with or without dutasteride (DUT), an inhibitor of 5α-reductases types 1 and 2. In rats treated with T+DUT, serum T was significantly higher (P<0.05) than in rats treated with T alone, and serum DHT was decreased (P<0.001) to levels observed in castrate vehicle-treated rats. DUT significantly reduced both VP and SV weights in T-treated rats, whereas there was no significant effect of DUT on weights of these accessory sex glands in rats treated with DMA, MNT, DHT, or MENT. These results indicate that inhibition of 5α-reductase activity in vivo does not affect the androgenic potency of DMA, MNT, or MENT.
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effects of Synthetic Androgens on liver function using the rabbit as a model
Journal of Andrology, 2010Co-Authors: Sheri Ann Hild, Barbara J Attardi, Sailaja Koduri, Bruce Till, Jerry R ReelAbstract:ABSTRACT: The objective of this study was to determine whether the rabbit was a suitable model to test new Synthetic Androgens for potential liver toxicity within a short dosing interval. Adult male rabbits were dosed orally daily on days 0–13 with 17α-methyltestosterone (MT) as a positive control and testosterone (T) as a negative control to validate this model. Synthetic Androgens tested were: 7α-methyl-19-nortestosterone (MENT), dimethandrolone-undecanoate (DMAU), and 11β-methyl-19-nortestosterone-17β-dodecylcarbonate (11β-MNTDC). Serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma glutamyl transpeptidase (GGT), and sorbitol dehydrogenase (SDH), as well as clearance of intravenous injected bromsulfonphthalein (BSP) from serum on days 0, 7, and 14, were determined. As expected, T (10 mg/kg/d) did not adversely affect BSP retention or serum liver enzymes. MT (10 mg/kg/d) increased BSP retention, and AST, ALT, GGT, and SDH levels, indicating that this model could detect Androgens known to be hepatotoxic. DMAU and MENT (10 mg/kg/d) increased BSP retention and all 4 serum liver enzymes as well, but the effects were less than those observed with MT at the same dose. All parameters returned to baseline 2 weeks after cessation of dosing. 11β-MNTDC at 10 mg/kg/d did not have an effect on BSP retention or liver enzymes, but a slight increase in serum GGT levels was observed in rabbits treated with 25 mg/kg/d. For the Androgens that exhibited liver toxicity at 10 mg/kg/d (MT, DMAU, and MENT), a no-observed-effect level of 1 mg/kg/d was established. Overall ranking of the Synthetic Androgens from most to least hepatotoxic on the basis of percent BSP retention was: MT & DMAU > MENT > 11β-MNTDC. Hence, the rabbit appears to be a promising model for detection of potential liver toxicity by Synthetic Androgens using BSP clearance and serum liver enzyme levels as early indicators of injury.
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steroid hormonal regulation of growth prostate specific antigen secretion and transcription mediated by the mutated androgen receptor in cwr22rv1 human prostate carcinoma cells
Molecular and Cellular Endocrinology, 2004Co-Authors: Barbara J Attardi, Sheri Ann Hild, Janet Burgenson, Jerry R ReelAbstract:Abstract CWR22Rv1 (22Rv1) is an androgen-responsive human prostate carcinoma cell line derived from a primary prostate tumor that expresses mutant (H874Y) androgen receptors (AR) and secretes low levels of prostate specific antigen (PSA). In this study, we examined the effects of various Androgens and other steroid hormones on proliferation of 22Rv1 cells, PSA secretion, and transactivation. Incubation of 22Rv1 cells with various concentrations of testosterone resulted in a dose-dependent 50–80% increase in growth over 72 h. PSA release and transactivation of PRE 2 -tk-LUC in 22Rv1 cells were stimulated by low concentrations of natural and Synthetic Androgens (EC 50 s = 10 −10 to 10 −9 M) and a broad range of other classes of steroid hormones, albeit with lower potency. Uniform positive immunocytochemical staining was observed in 22Rv1 cell nuclei with mouse monoclonal antibodies to human AR. Competitive binding assays indicated that the mutant AR in 22Rv1 cytosol is more promiscuous than a wild-type AR (ARLBD: rat AR ligand binding domain). Testosterone (10 −8 M)-induced PSA release and transactivation were blocked by both antiAndrogens and antiprogestins with IC 50 s of 10 −7 to 10 −6 M. At high concentration (10 −6 M), these antagonists showed partial agonist activity in terms of PSA secretion but not transactivation. In conclusion, the mutant AR in 22Rv1 cells binds and responds to low levels of Androgens and a wide spectrum of other natural and Synthetic steroid hormones, mechanisms proposed to contribute to tumor progression following androgen ablation.
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steroid hormonal regulation of growth prostate specific antigen secretion and transcription mediated by the mutated androgen receptor in cwr22rv1 human prostate carcinoma cells
Molecular and Cellular Endocrinology, 2004Co-Authors: Barbara J Attardi, Sheri Ann Hild, Janet Burgenson, Jerry R ReelAbstract:Abstract CWR22Rv1 (22Rv1) is an androgen-responsive human prostate carcinoma cell line derived from a primary prostate tumor that expresses mutant (H874Y) androgen receptors (AR) and secretes low levels of prostate specific antigen (PSA). In this study, we examined the effects of various Androgens and other steroid hormones on proliferation of 22Rv1 cells, PSA secretion, and transactivation. Incubation of 22Rv1 cells with various concentrations of testosterone resulted in a dose-dependent 50–80% increase in growth over 72 h. PSA release and transactivation of PRE 2 -tk-LUC in 22Rv1 cells were stimulated by low concentrations of natural and Synthetic Androgens (EC 50 s = 10 −10 to 10 −9 M) and a broad range of other classes of steroid hormones, albeit with lower potency. Uniform positive immunocytochemical staining was observed in 22Rv1 cell nuclei with mouse monoclonal antibodies to human AR. Competitive binding assays indicated that the mutant AR in 22Rv1 cytosol is more promiscuous than a wild-type AR (ARLBD: rat AR ligand binding domain). Testosterone (10 −8 M)-induced PSA release and transactivation were blocked by both antiAndrogens and antiprogestins with IC 50 s of 10 −7 to 10 −6 M. At high concentration (10 −6 M), these antagonists showed partial agonist activity in terms of PSA secretion but not transactivation. In conclusion, the mutant AR in 22Rv1 cells binds and responds to low levels of Androgens and a wide spectrum of other natural and Synthetic steroid hormones, mechanisms proposed to contribute to tumor progression following androgen ablation.
Barbara J Attardi - One of the best experts on this subject based on the ideXlab platform.
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the potent Synthetic Androgens dimethandrolone 7α 11β dimethyl 19 nortestosterone and 11β methyl 19 nortestosterone do not require 5α reduction to exert their maximal androgenic effects
The Journal of Steroid Biochemistry and Molecular Biology, 2010Co-Authors: Barbara J Attardi, Sheri Ann Hild, Sailaja Koduri, Bruce Till, Trung Pham, Laurent Pessaint, Jean A Engbring, David Gropp, Anne Semon, Jerry R ReelAbstract:Dimethandrolone (DMA: 7α,11β-dimethyl-19-nortestosterone) and 11β-methyl-19-nortestosterone (MNT) are potent Androgens in development for hormonal therapy in men. As 5α-reduced Androgens, such as 5α-dihydrotestosterone (DHT), may raise the risk of benign prostate hyperplasia, accelerate the development of prostate carcinoma, and increase male pattern baldness and acne, we investigated the role of 5α-reduction in the androgenic activity of DMA and MNT. The authentic 5α-reduced metabolites, 5α-dihydroDMA (5α-DHDMA) and 5α-dihydroMNT (5α-DHMNT), were prepared by chemical synthesis and compared in vitro and in vivo to the parent compounds. Both 5α-reduced Androgens bound with high affinity to the rat androgen receptor (AR) and were potent inducers of transactivation of 3XHRE-LUC in CV-1 cells cotransfected with a human AR expression plasmid. To examine in vivo androgenic (stimulation of ventral prostate [VP] and seminal vesicle [SV] weights) and anabolic (stimulation of levator ani [LA] muscle weights) activity, 22-day-old castrate male rats were treated sc for 7 days with various doses of DMA, 5α-DHDMA, or testosterone (T) or MNT, 5α-DHMNT, or T and necropsied on day 8. 5α-DHDMA was at least threefold more potent than T in stimulating growth of the VP but only 30-40% as potent as DMA. 5α-DHMNT was four- to eightfold more potent than T, whereas MNT was approximately equipotent to T. To assess the possible role of 5α-reduction in VP and SV growth, castrate immature rats were treated with maximally effective doses of T, DHT, DMA, MNT, or the related 19-norandrogen, 7α-methyl-19-nortestosterone (MENT), or vehicle, with or without dutasteride (DUT), an inhibitor of 5α-reductases types 1 and 2. In rats treated with T+DUT, serum T was significantly higher (P<0.05) than in rats treated with T alone, and serum DHT was decreased (P<0.001) to levels observed in castrate vehicle-treated rats. DUT significantly reduced both VP and SV weights in T-treated rats, whereas there was no significant effect of DUT on weights of these accessory sex glands in rats treated with DMA, MNT, DHT, or MENT. These results indicate that inhibition of 5α-reductase activity in vivo does not affect the androgenic potency of DMA, MNT, or MENT.
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effects of Synthetic Androgens on liver function using the rabbit as a model
Journal of Andrology, 2010Co-Authors: Sheri Ann Hild, Barbara J Attardi, Sailaja Koduri, Bruce Till, Jerry R ReelAbstract:ABSTRACT: The objective of this study was to determine whether the rabbit was a suitable model to test new Synthetic Androgens for potential liver toxicity within a short dosing interval. Adult male rabbits were dosed orally daily on days 0–13 with 17α-methyltestosterone (MT) as a positive control and testosterone (T) as a negative control to validate this model. Synthetic Androgens tested were: 7α-methyl-19-nortestosterone (MENT), dimethandrolone-undecanoate (DMAU), and 11β-methyl-19-nortestosterone-17β-dodecylcarbonate (11β-MNTDC). Serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma glutamyl transpeptidase (GGT), and sorbitol dehydrogenase (SDH), as well as clearance of intravenous injected bromsulfonphthalein (BSP) from serum on days 0, 7, and 14, were determined. As expected, T (10 mg/kg/d) did not adversely affect BSP retention or serum liver enzymes. MT (10 mg/kg/d) increased BSP retention, and AST, ALT, GGT, and SDH levels, indicating that this model could detect Androgens known to be hepatotoxic. DMAU and MENT (10 mg/kg/d) increased BSP retention and all 4 serum liver enzymes as well, but the effects were less than those observed with MT at the same dose. All parameters returned to baseline 2 weeks after cessation of dosing. 11β-MNTDC at 10 mg/kg/d did not have an effect on BSP retention or liver enzymes, but a slight increase in serum GGT levels was observed in rabbits treated with 25 mg/kg/d. For the Androgens that exhibited liver toxicity at 10 mg/kg/d (MT, DMAU, and MENT), a no-observed-effect level of 1 mg/kg/d was established. Overall ranking of the Synthetic Androgens from most to least hepatotoxic on the basis of percent BSP retention was: MT & DMAU > MENT > 11β-MNTDC. Hence, the rabbit appears to be a promising model for detection of potential liver toxicity by Synthetic Androgens using BSP clearance and serum liver enzyme levels as early indicators of injury.
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steroid hormonal regulation of growth prostate specific antigen secretion and transcription mediated by the mutated androgen receptor in cwr22rv1 human prostate carcinoma cells
Molecular and Cellular Endocrinology, 2004Co-Authors: Barbara J Attardi, Sheri Ann Hild, Janet Burgenson, Jerry R ReelAbstract:Abstract CWR22Rv1 (22Rv1) is an androgen-responsive human prostate carcinoma cell line derived from a primary prostate tumor that expresses mutant (H874Y) androgen receptors (AR) and secretes low levels of prostate specific antigen (PSA). In this study, we examined the effects of various Androgens and other steroid hormones on proliferation of 22Rv1 cells, PSA secretion, and transactivation. Incubation of 22Rv1 cells with various concentrations of testosterone resulted in a dose-dependent 50–80% increase in growth over 72 h. PSA release and transactivation of PRE 2 -tk-LUC in 22Rv1 cells were stimulated by low concentrations of natural and Synthetic Androgens (EC 50 s = 10 −10 to 10 −9 M) and a broad range of other classes of steroid hormones, albeit with lower potency. Uniform positive immunocytochemical staining was observed in 22Rv1 cell nuclei with mouse monoclonal antibodies to human AR. Competitive binding assays indicated that the mutant AR in 22Rv1 cytosol is more promiscuous than a wild-type AR (ARLBD: rat AR ligand binding domain). Testosterone (10 −8 M)-induced PSA release and transactivation were blocked by both antiAndrogens and antiprogestins with IC 50 s of 10 −7 to 10 −6 M. At high concentration (10 −6 M), these antagonists showed partial agonist activity in terms of PSA secretion but not transactivation. In conclusion, the mutant AR in 22Rv1 cells binds and responds to low levels of Androgens and a wide spectrum of other natural and Synthetic steroid hormones, mechanisms proposed to contribute to tumor progression following androgen ablation.
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steroid hormonal regulation of growth prostate specific antigen secretion and transcription mediated by the mutated androgen receptor in cwr22rv1 human prostate carcinoma cells
Molecular and Cellular Endocrinology, 2004Co-Authors: Barbara J Attardi, Sheri Ann Hild, Janet Burgenson, Jerry R ReelAbstract:Abstract CWR22Rv1 (22Rv1) is an androgen-responsive human prostate carcinoma cell line derived from a primary prostate tumor that expresses mutant (H874Y) androgen receptors (AR) and secretes low levels of prostate specific antigen (PSA). In this study, we examined the effects of various Androgens and other steroid hormones on proliferation of 22Rv1 cells, PSA secretion, and transactivation. Incubation of 22Rv1 cells with various concentrations of testosterone resulted in a dose-dependent 50–80% increase in growth over 72 h. PSA release and transactivation of PRE 2 -tk-LUC in 22Rv1 cells were stimulated by low concentrations of natural and Synthetic Androgens (EC 50 s = 10 −10 to 10 −9 M) and a broad range of other classes of steroid hormones, albeit with lower potency. Uniform positive immunocytochemical staining was observed in 22Rv1 cell nuclei with mouse monoclonal antibodies to human AR. Competitive binding assays indicated that the mutant AR in 22Rv1 cytosol is more promiscuous than a wild-type AR (ARLBD: rat AR ligand binding domain). Testosterone (10 −8 M)-induced PSA release and transactivation were blocked by both antiAndrogens and antiprogestins with IC 50 s of 10 −7 to 10 −6 M. At high concentration (10 −6 M), these antagonists showed partial agonist activity in terms of PSA secretion but not transactivation. In conclusion, the mutant AR in 22Rv1 cells binds and responds to low levels of Androgens and a wide spectrum of other natural and Synthetic steroid hormones, mechanisms proposed to contribute to tumor progression following androgen ablation.
Sheri Ann Hild - One of the best experts on this subject based on the ideXlab platform.
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the potent Synthetic Androgens dimethandrolone 7α 11β dimethyl 19 nortestosterone and 11β methyl 19 nortestosterone do not require 5α reduction to exert their maximal androgenic effects
The Journal of Steroid Biochemistry and Molecular Biology, 2010Co-Authors: Barbara J Attardi, Sheri Ann Hild, Sailaja Koduri, Bruce Till, Trung Pham, Laurent Pessaint, Jean A Engbring, David Gropp, Anne Semon, Jerry R ReelAbstract:Dimethandrolone (DMA: 7α,11β-dimethyl-19-nortestosterone) and 11β-methyl-19-nortestosterone (MNT) are potent Androgens in development for hormonal therapy in men. As 5α-reduced Androgens, such as 5α-dihydrotestosterone (DHT), may raise the risk of benign prostate hyperplasia, accelerate the development of prostate carcinoma, and increase male pattern baldness and acne, we investigated the role of 5α-reduction in the androgenic activity of DMA and MNT. The authentic 5α-reduced metabolites, 5α-dihydroDMA (5α-DHDMA) and 5α-dihydroMNT (5α-DHMNT), were prepared by chemical synthesis and compared in vitro and in vivo to the parent compounds. Both 5α-reduced Androgens bound with high affinity to the rat androgen receptor (AR) and were potent inducers of transactivation of 3XHRE-LUC in CV-1 cells cotransfected with a human AR expression plasmid. To examine in vivo androgenic (stimulation of ventral prostate [VP] and seminal vesicle [SV] weights) and anabolic (stimulation of levator ani [LA] muscle weights) activity, 22-day-old castrate male rats were treated sc for 7 days with various doses of DMA, 5α-DHDMA, or testosterone (T) or MNT, 5α-DHMNT, or T and necropsied on day 8. 5α-DHDMA was at least threefold more potent than T in stimulating growth of the VP but only 30-40% as potent as DMA. 5α-DHMNT was four- to eightfold more potent than T, whereas MNT was approximately equipotent to T. To assess the possible role of 5α-reduction in VP and SV growth, castrate immature rats were treated with maximally effective doses of T, DHT, DMA, MNT, or the related 19-norandrogen, 7α-methyl-19-nortestosterone (MENT), or vehicle, with or without dutasteride (DUT), an inhibitor of 5α-reductases types 1 and 2. In rats treated with T+DUT, serum T was significantly higher (P<0.05) than in rats treated with T alone, and serum DHT was decreased (P<0.001) to levels observed in castrate vehicle-treated rats. DUT significantly reduced both VP and SV weights in T-treated rats, whereas there was no significant effect of DUT on weights of these accessory sex glands in rats treated with DMA, MNT, DHT, or MENT. These results indicate that inhibition of 5α-reductase activity in vivo does not affect the androgenic potency of DMA, MNT, or MENT.
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effects of Synthetic Androgens on liver function using the rabbit as a model
Journal of Andrology, 2010Co-Authors: Sheri Ann Hild, Barbara J Attardi, Sailaja Koduri, Bruce Till, Jerry R ReelAbstract:ABSTRACT: The objective of this study was to determine whether the rabbit was a suitable model to test new Synthetic Androgens for potential liver toxicity within a short dosing interval. Adult male rabbits were dosed orally daily on days 0–13 with 17α-methyltestosterone (MT) as a positive control and testosterone (T) as a negative control to validate this model. Synthetic Androgens tested were: 7α-methyl-19-nortestosterone (MENT), dimethandrolone-undecanoate (DMAU), and 11β-methyl-19-nortestosterone-17β-dodecylcarbonate (11β-MNTDC). Serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma glutamyl transpeptidase (GGT), and sorbitol dehydrogenase (SDH), as well as clearance of intravenous injected bromsulfonphthalein (BSP) from serum on days 0, 7, and 14, were determined. As expected, T (10 mg/kg/d) did not adversely affect BSP retention or serum liver enzymes. MT (10 mg/kg/d) increased BSP retention, and AST, ALT, GGT, and SDH levels, indicating that this model could detect Androgens known to be hepatotoxic. DMAU and MENT (10 mg/kg/d) increased BSP retention and all 4 serum liver enzymes as well, but the effects were less than those observed with MT at the same dose. All parameters returned to baseline 2 weeks after cessation of dosing. 11β-MNTDC at 10 mg/kg/d did not have an effect on BSP retention or liver enzymes, but a slight increase in serum GGT levels was observed in rabbits treated with 25 mg/kg/d. For the Androgens that exhibited liver toxicity at 10 mg/kg/d (MT, DMAU, and MENT), a no-observed-effect level of 1 mg/kg/d was established. Overall ranking of the Synthetic Androgens from most to least hepatotoxic on the basis of percent BSP retention was: MT & DMAU > MENT > 11β-MNTDC. Hence, the rabbit appears to be a promising model for detection of potential liver toxicity by Synthetic Androgens using BSP clearance and serum liver enzyme levels as early indicators of injury.
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steroid hormonal regulation of growth prostate specific antigen secretion and transcription mediated by the mutated androgen receptor in cwr22rv1 human prostate carcinoma cells
Molecular and Cellular Endocrinology, 2004Co-Authors: Barbara J Attardi, Sheri Ann Hild, Janet Burgenson, Jerry R ReelAbstract:Abstract CWR22Rv1 (22Rv1) is an androgen-responsive human prostate carcinoma cell line derived from a primary prostate tumor that expresses mutant (H874Y) androgen receptors (AR) and secretes low levels of prostate specific antigen (PSA). In this study, we examined the effects of various Androgens and other steroid hormones on proliferation of 22Rv1 cells, PSA secretion, and transactivation. Incubation of 22Rv1 cells with various concentrations of testosterone resulted in a dose-dependent 50–80% increase in growth over 72 h. PSA release and transactivation of PRE 2 -tk-LUC in 22Rv1 cells were stimulated by low concentrations of natural and Synthetic Androgens (EC 50 s = 10 −10 to 10 −9 M) and a broad range of other classes of steroid hormones, albeit with lower potency. Uniform positive immunocytochemical staining was observed in 22Rv1 cell nuclei with mouse monoclonal antibodies to human AR. Competitive binding assays indicated that the mutant AR in 22Rv1 cytosol is more promiscuous than a wild-type AR (ARLBD: rat AR ligand binding domain). Testosterone (10 −8 M)-induced PSA release and transactivation were blocked by both antiAndrogens and antiprogestins with IC 50 s of 10 −7 to 10 −6 M. At high concentration (10 −6 M), these antagonists showed partial agonist activity in terms of PSA secretion but not transactivation. In conclusion, the mutant AR in 22Rv1 cells binds and responds to low levels of Androgens and a wide spectrum of other natural and Synthetic steroid hormones, mechanisms proposed to contribute to tumor progression following androgen ablation.
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steroid hormonal regulation of growth prostate specific antigen secretion and transcription mediated by the mutated androgen receptor in cwr22rv1 human prostate carcinoma cells
Molecular and Cellular Endocrinology, 2004Co-Authors: Barbara J Attardi, Sheri Ann Hild, Janet Burgenson, Jerry R ReelAbstract:Abstract CWR22Rv1 (22Rv1) is an androgen-responsive human prostate carcinoma cell line derived from a primary prostate tumor that expresses mutant (H874Y) androgen receptors (AR) and secretes low levels of prostate specific antigen (PSA). In this study, we examined the effects of various Androgens and other steroid hormones on proliferation of 22Rv1 cells, PSA secretion, and transactivation. Incubation of 22Rv1 cells with various concentrations of testosterone resulted in a dose-dependent 50–80% increase in growth over 72 h. PSA release and transactivation of PRE 2 -tk-LUC in 22Rv1 cells were stimulated by low concentrations of natural and Synthetic Androgens (EC 50 s = 10 −10 to 10 −9 M) and a broad range of other classes of steroid hormones, albeit with lower potency. Uniform positive immunocytochemical staining was observed in 22Rv1 cell nuclei with mouse monoclonal antibodies to human AR. Competitive binding assays indicated that the mutant AR in 22Rv1 cytosol is more promiscuous than a wild-type AR (ARLBD: rat AR ligand binding domain). Testosterone (10 −8 M)-induced PSA release and transactivation were blocked by both antiAndrogens and antiprogestins with IC 50 s of 10 −7 to 10 −6 M. At high concentration (10 −6 M), these antagonists showed partial agonist activity in terms of PSA secretion but not transactivation. In conclusion, the mutant AR in 22Rv1 cells binds and responds to low levels of Androgens and a wide spectrum of other natural and Synthetic steroid hormones, mechanisms proposed to contribute to tumor progression following androgen ablation.
Chad T. Jafvert - One of the best experts on this subject based on the ideXlab platform.
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Hormone loads exported by a tile-drained agroecosystem receiving animal wastes
Hydrological Processes, 2013Co-Authors: Heather E. Gall, Stephen A. Sassman, Byron Jenkinson, Chad T. JafvertAbstract:Little is known regarding hormone export from tile-drained agricultural fields despite the widespread presence of tile drains in the Midwestern United States. By intensively measuring water flow rates and hormone concentrations in four subsurface tile drains and three receiving ditches at a working Midwest farm, hormone fluxes and loads from the tile-drained fields were quantified. Before and during the 17-month study period (January 2009 – May 2010), the associated farm fields received various animal waste applications (beef, dairy, poultry, sheep, and swine). Hormones monitored included the estrogens17β- and 17α-estradiol, estrone, and estriol; the natural Androgens testosterone, and androstenedione; and the Synthetic Androgens 17β- and 17α-trenbolone, and trendione. Hormone loads measured in the ditches for three drainage areas during the entire 17-month study period were in ranges of 16–58 mg/ha for total estrogens, 6.8–19 mg/ha for natural Androgens, and 4.2–44 mg/ha for Synthetic Androgens. Because higher hormone concentrations generally occurred during discrete periods of increased flow, high flow rates often were associated with a disproportionately high hormone flux. For example, 80% of total estrogens and natural Androgens exported into the ditches occurred during only 9–26% of the study period, coinciding with the most significant storm events. In addition, hormone fluxes were highest during storm events that occurred shortly after animal waste applications. Therefore, to effectively reduce hormone loads exported to downstream aquatic ecosystems in the absence of any application reduction, the short periods during which high-flow events occur must be targeted. Copyright © 2012 John Wiley & Sons, Ltd.
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hormone discharges from a midwest tile drained agroecosystem receiving animal wastes
Environmental Science & Technology, 2011Co-Authors: Heather E. Gall, Linda S. Lee, Stephen A. Sassman, Chad T. JafvertAbstract:Manure is increasingly being viewed as a threat to aquatic ecosystems due to the introduction of natural and Synthetic hormones from land application to agricultural fields. In the Midwestern United States, where most agricultural fields are tile-drained, there is little known about hormone release from fields receiving animal wastes. To this end, seven sampling stations (four in subsurface tile drains and three in the receiving ditch network) were installed at a Midwest farm where various types of animal wastes (beef, dairy, and poultry lagoon effluent, dairy solids, and subsurface injection of swine manure) are applied to agricultural fields. Water flow was continuously monitored and samples were collected for hormone analysis during storm events and baseline flow for a 15 month study period. The compounds analyzed included the natural hormones 17α- and 17β-estradiol, estrone, estriol, testosterone, and androstenedione and the Synthetic Androgens 17α- and 17β-trenbolone and trendione. Hormones were detected in at least 64% of the samples collected at each station, with estrone being detected the most frequently and estriol the least. Testosterone and androstendione were detected more frequently than Synthetic Androgens, which were detected in fewer than 15% of samples. Hormone concentrations in subsurface tile drains increased during effluent irrigation and storm events. Hormones also appeared to persist over the winter, with increased concentrations coinciding with early thaws and snowmelt from fields amended with manure solids. The highest concentration of Synthetic Androgens (168 ng/L) observed coincided with a snowmelt. The highest concentrations of hormones in the ditch waters (87 ng/L for total estrogens and 52 ng/L for natural Androgens) were observed in June, which coincides with the early life stage development period of many aquatic species in the Midwest.
Carl J Barrett - One of the best experts on this subject based on the ideXlab platform.
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and progesterone on cell transformation and mutagenesis in Syrian hamster embryo cells
2016Co-Authors: Takeki Tsutsui, Akiko Komine, James Huff, Carl J BarrettAbstract:'To whom correspondence should be addressed Testosterone, testosterone propionate, npMrenbolone and progesterone, which represent the main endogenous and Synthetic Androgens and a progestin, were evaluated for possible cell transformation and. genetic effects in Syrian hamster embryo (SHE) cells. Cell growth was reduced by treatment with the steroids at 10-30 fig/ml in a dose-related manner. Testosterone and testosterone propionate were less toxic than the other two steroids. Testosterone, testos-terone propionate and progesterone induced morphological transformation of SHE cells with similar transformation frequencies. The most potent effects were observed with testosterone propionate, which induced cell transformation at 1-30 ng/ml in a dose-related manner. Testosterone and progesterone transformed cells only at the highest dose (30 ug/ml). 17p-Trenbolone did not induce a statistically significant level of cell transformations at any dose tested (up to 30 (ig/ml). The transformation frequencies induced by testosterone, testosterone propionate and progesterone were less than one-half that induced by benzo[a]pyrene at 1 |ig/ml. None of these steroids induced significant increases in frequencies of chromosome aberrations or aneuploidy. Gene mutations were not observed for testosterone at the HPRT or Na+/K+ ATPase locus. Because these steroids are also associated with carcinogenic activity in vivo, these in vitro findings provide a model and new insights into the study of the mechanisms of androgen- and progestin-induced cell transformation
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effects of testosterone testosterone propionate 17β trenbolone and progesterone on cell transformation and mutagenesis in syrian hamster embryo cells
Carcinogenesis, 1995Co-Authors: Takeki Tsutsui, Akiko Komine, James Huff, Carl J BarrettAbstract:Testosterone, testosterone propionate, 17β-trenbolone and progesterone, which represent the main endogenous and Synthetic Androgens and a progestin, were evaluated for possible cell transformation and genetic effects in Syrian hamster embryo (SHE) cells. Cell growth was reduced by treatment with the steroids at 10-30 μg/ml in a dose-related manner. Testosterone and testosterone propionate were less toxic than the other two steroids. Testosterone, testosterone propionate and progesterone induced morphological transformation of SHE cells with similar transformation frequencies. The most potent effects were observed with testosterone propionate, which induced cell transformation at 1-30 μg/ml in a dose-related manner. Testosterone and progesterone transformed cells only at the highest dose (30 μg/ml). 17β-Trentiolone did not induce a statistically significant level of cell transformations at any dose tested (up to 30 μg/ml). The transformation frequencies induced by testosterone, testosterone propionate and progesterone were less than one-half that induced by benzo[a]pyrene at 1 μg/ml. None of these steroids induced significant increases in frequencies of chromosome aberrations or aneuploidy. Gene mutations were not observed for testosterone at the HPRT or Na + /K + ATPase locus. Because these steroids are also associated with carcinogenic activity in vivo, these in vitro findings provide a model and new insights into the study of the mechanisms of androgen- and progestininduced cell transformation
