The androgen receptor （AR） plays a critical role in prostate cancer development and progression. This study aimed to use a computerized docking approach to examine the interactions between the human AR and phytooest...The androgen receptor （AR） plays a critical role in prostate cancer development and progression. This study aimed to use a computerized docking approach to examine the interactions between the human AR and phytooestrogens （genistein, daidzein, and flavone） and xeno-oestrogens （bisphenol A, 4-nonylphenol, dichlorodiphenyl trichloroethane [DDT], diethylstilbestrol [DES]）. The predicted three-dimensional structure of AR and androgens was established using X-ray diffraction. The binding of four xeno-oestrogens and three phyto-oestrogens to AR was analysed. The steroids estradiol and dihydrotestosterone （DHT） were used as positive controls and thyroxine as negative control. All the ligands shared the same binding site except for thyroxine. The endogenous hormones DHT and 17β-oestradiol showed the strongest binding with the lowest affinity energy （〈 -10 kcal mol-1）. All three phyto- oestrogens and two xeno-oestrogens （bisphenol A and DES） showed strong binding to AR. The affinities offlavone, genistein, and daidzein were between -8.8 and -8.5 kcal mol 1, while that of bisphenol A was -8.1 kcal mol-l and DES -8.3 kcal mol-1. Another two xeno-oestrogens, 4-nonylphenol and DDT, although they fit within the binding domain of AR, showed weak affinity （-6.4 and -6.7 kcal mol 1, respectively）. The phyto-oestrogens genistein, daidzein and flavone, and the xeno-oestrogens bisphenol A and DES can be regarded as androgenic effectors. The xenooestrogens DDT and 4-nonylphenol bind only weakly to AR.展开更多
<abstract>Ageing in man is associated with a decline in testosterone following changes in the hypothalamo-pituitary testicular axis. This may offset the physiologic equilibrium between oestrogen and androgen and...<abstract>Ageing in man is associated with a decline in testosterone following changes in the hypothalamo-pituitary testicular axis. This may offset the physiologic equilibrium between oestrogen and androgen and at some point when the ratio of free testosterone to oestradiol reaches a critical level, the oestrogenic gonadotropin suppressive effect predominates with decreased release of FSH and LH. Adding to this endocrinal complexity is the continued peripheral conversion to oestradiol through aromatisation. Although the androgen deficiency is not the sole cause for impotence in the elderly, there is a gradual decrease in nocturnal penile tumescence (NPT) and spontaneous morning erections with ageing. Despite the age related increase in oestrogen levels, the information on the pathophysiological role of the 'female hormone' in erectile dysfunction has been scanty. Together with our identification of oestrogen receptors within the penile cavernosum, we have delineated dysfunctional changes on male erection mediated by oestradiol. These findings parallel the recent concerns over environmental oestrogens on fertility declines in young men. Oestrogenic activity is also present in plants and thereby in human diet. These phytoestrogens are structurally and functionally similar to oestradiol and more potent than the environmental oestrogenic chemicals such as organochlorine and phenolic compounds. Thus in the light of growing concerns of possible compromising effects on sexuality by endogenous and environmental oestrogens, we are faced with the scientific need to delineate their role on the mechanism of male erectile pathway in health and disease for clinical correlates and prognostics.展开更多
We cloned the three androgen response elements（AREs, including AREI, AREII, and AREIII ） with a core transactivation TATA element of the prostate-specific antigen（PSA） promoter into pGL2 basic vector to create an ...We cloned the three androgen response elements（AREs, including AREI, AREII, and AREIII ） with a core transactivation TATA element of the prostate-specific antigen（PSA） promoter into pGL2 basic vector to create an artificial pGL2/AREs-TATA reporter system, which was applied to evaluating the effects of different xeno- oestrogens[bisphenol A（BPA）, 4-nonylphenol（4-NP）, dichlorodiphenyl trichloroethane（DDT） or diethylstilbestrol （DES）] on androgen receptor（AR） abnormal activation to regulate PSA expression and cell proliferation. In all the three AREs, AREIII-TATA displayed as a major element responsive to AR-mediated DHT stimulation of PSA promoter. Therefore, pGL2/AREIII-TATA reporter was adopted to analyze the activation capacity of AR activated by four different xeno-oestrogens. The activation of pGL2/AREIII-TATA reporter by each xeno-oestrogen was analyzed in two different cell lines, one was HEK293T（Human Embryonic Kidney 293T） cell line, and the other was AR stably expressed DU145 cell line, which was produced by infecting AR with pLenti-puro-AR into the prostate cancer DU145 cells and that were scanned with puromycin and tested by AR antibody. In both the two cell lines, BPA or DES significantly induced AR-mediated transcriptional activity of AREIII-TATA reporter, whereas DDT or 4-nonylphenol did not. Moreover, AR-mediated cell proliferation in response to each of four xeno-oestrogens was measured in MTT assays in both HEK293T cell or AR stably expressed DUI45 cell lines. BPA or DES, as an AR inducer, exhibited an enhanced effect in cell proliferation, rather than the effect of DDT or 4-NP, in both cell lines. Finally, we demonstrated that BPA or DES stimulated PSA expression and enhanced the recruitment of AR onto the PSA promoter, resulting in stronger binding to AREIII sites. Taken together, four xeno-oestrogens were identified to have different activities on AR. BPA and DES are demonstrated to be androgenic effectors in the regulation of PSA activation or cell proliferation.展开更多
基金This study was supported by Ministry of Science and Technology （No. 2010DFA31430）, the National Natural Science Foundation of China （No. 30871301, 30700827）, Ministry of Education of China （No. 108047）, Jilin Provincial Science ＆ Technology Department （No. 20070719, 20080731, 200905116）. We thank Mr Michael Hoyt, who critically read and revised our manuscript.
文摘The androgen receptor （AR） plays a critical role in prostate cancer development and progression. This study aimed to use a computerized docking approach to examine the interactions between the human AR and phytooestrogens （genistein, daidzein, and flavone） and xeno-oestrogens （bisphenol A, 4-nonylphenol, dichlorodiphenyl trichloroethane [DDT], diethylstilbestrol [DES]）. The predicted three-dimensional structure of AR and androgens was established using X-ray diffraction. The binding of four xeno-oestrogens and three phyto-oestrogens to AR was analysed. The steroids estradiol and dihydrotestosterone （DHT） were used as positive controls and thyroxine as negative control. All the ligands shared the same binding site except for thyroxine. The endogenous hormones DHT and 17β-oestradiol showed the strongest binding with the lowest affinity energy （〈 -10 kcal mol-1）. All three phyto- oestrogens and two xeno-oestrogens （bisphenol A and DES） showed strong binding to AR. The affinities offlavone, genistein, and daidzein were between -8.8 and -8.5 kcal mol 1, while that of bisphenol A was -8.1 kcal mol-l and DES -8.3 kcal mol-1. Another two xeno-oestrogens, 4-nonylphenol and DDT, although they fit within the binding domain of AR, showed weak affinity （-6.4 and -6.7 kcal mol 1, respectively）. The phyto-oestrogens genistein, daidzein and flavone, and the xeno-oestrogens bisphenol A and DES can be regarded as androgenic effectors. The xenooestrogens DDT and 4-nonylphenol bind only weakly to AR.
文摘<abstract>Ageing in man is associated with a decline in testosterone following changes in the hypothalamo-pituitary testicular axis. This may offset the physiologic equilibrium between oestrogen and androgen and at some point when the ratio of free testosterone to oestradiol reaches a critical level, the oestrogenic gonadotropin suppressive effect predominates with decreased release of FSH and LH. Adding to this endocrinal complexity is the continued peripheral conversion to oestradiol through aromatisation. Although the androgen deficiency is not the sole cause for impotence in the elderly, there is a gradual decrease in nocturnal penile tumescence (NPT) and spontaneous morning erections with ageing. Despite the age related increase in oestrogen levels, the information on the pathophysiological role of the 'female hormone' in erectile dysfunction has been scanty. Together with our identification of oestrogen receptors within the penile cavernosum, we have delineated dysfunctional changes on male erection mediated by oestradiol. These findings parallel the recent concerns over environmental oestrogens on fertility declines in young men. Oestrogenic activity is also present in plants and thereby in human diet. These phytoestrogens are structurally and functionally similar to oestradiol and more potent than the environmental oestrogenic chemicals such as organochlorine and phenolic compounds. Thus in the light of growing concerns of possible compromising effects on sexuality by endogenous and environmental oestrogens, we are faced with the scientific need to delineate their role on the mechanism of male erectile pathway in health and disease for clinical correlates and prognostics.
文摘We cloned the three androgen response elements（AREs, including AREI, AREII, and AREIII ） with a core transactivation TATA element of the prostate-specific antigen（PSA） promoter into pGL2 basic vector to create an artificial pGL2/AREs-TATA reporter system, which was applied to evaluating the effects of different xeno- oestrogens[bisphenol A（BPA）, 4-nonylphenol（4-NP）, dichlorodiphenyl trichloroethane（DDT） or diethylstilbestrol （DES）] on androgen receptor（AR） abnormal activation to regulate PSA expression and cell proliferation. In all the three AREs, AREIII-TATA displayed as a major element responsive to AR-mediated DHT stimulation of PSA promoter. Therefore, pGL2/AREIII-TATA reporter was adopted to analyze the activation capacity of AR activated by four different xeno-oestrogens. The activation of pGL2/AREIII-TATA reporter by each xeno-oestrogen was analyzed in two different cell lines, one was HEK293T（Human Embryonic Kidney 293T） cell line, and the other was AR stably expressed DU145 cell line, which was produced by infecting AR with pLenti-puro-AR into the prostate cancer DU145 cells and that were scanned with puromycin and tested by AR antibody. In both the two cell lines, BPA or DES significantly induced AR-mediated transcriptional activity of AREIII-TATA reporter, whereas DDT or 4-nonylphenol did not. Moreover, AR-mediated cell proliferation in response to each of four xeno-oestrogens was measured in MTT assays in both HEK293T cell or AR stably expressed DUI45 cell lines. BPA or DES, as an AR inducer, exhibited an enhanced effect in cell proliferation, rather than the effect of DDT or 4-NP, in both cell lines. Finally, we demonstrated that BPA or DES stimulated PSA expression and enhanced the recruitment of AR onto the PSA promoter, resulting in stronger binding to AREIII sites. Taken together, four xeno-oestrogens were identified to have different activities on AR. BPA and DES are demonstrated to be androgenic effectors in the regulation of PSA activation or cell proliferation.
