己烯雌酚及代谢物在鲤体内的组织分布及药物代谢动力学

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Embryotoxicity induced by diethylstilbestrol in vitro1

The embryotoxic potential of diethylstilbestrol (DES) was examined in a whole embryo culture system containing a P-450–dependent bioactivating system. Sprague-Dawley rat embryos were explanted on day 10 and cultured for 24 hours. Concentration-dependent effects of DES on embryonic growth parameters, viability, and embryotoxicity were observed. Concentrations of DES greater than 0.26 mM (final concentration) produced 100% embryolethality, while those below 0.15 mM were without significant effects. At a final concentration of 0.19 mM, DES produced only a slight increase in embryolethality. The same concentration elicited a marked increase in observed embryotoxicity, including prosencephalic hypoplasia, incomplete axial rotation, and open neural tubes. In addition, reductions in embryonic length, somite number, and protein and DNA content were observed. An exogenous P-450–dependent hepatic biotransforming (catechol-generating) system failed to alter either the incidence of observed toxic effects or measured growth parameters. Likewise, exposure of cultured embryos to 20% carbon monoxide (CO) failed to reduce DES-induced embryotoxicity, indicating a lack of participation of an endogenous P-450-dependent embryonic bioactivating system. Arachidonic acid (0.20 mM) and/or indomethacin (0.50 mM) also had no observable effect on DES-induced embryotoxicity, suggesting that prostaglandin synthase was not involved in the embryotoxic activity of DES, as has been proposed to explain its carcinogenic effect. The antioxidants N-acetylcysteine (1.14 mM) and α-tocopherol (0.08 mM) failed to protect against DES-induced embryotoxicity, while the antiestrogen tamoxifen (up to 0.85 mM) actually enhanced this effect of DES in culture. The DES analogs Z,Z-dienestrol (DIES, 0.10 mM) and hexestrol (HES, 0.48 mM) were both embryotoxic in vitro. The presence of an exogenous P-450-dependent hepatic biotransforming system appeared to protect against HES-induced embryolethality but had little effect upon DIES-induced embryotoxicity. The results were consistent with a direct effect of DES independent of either estrogenicity or exogenously generated metabolites.     

Relations between fatty acids and oestrogen binding properties of pure rat alpha1-foetoprotein

A delipidation procedures based on treatment with charcoal at pH 3 has been applied to highly purified rat alpha₁-foetoprotein preparations. The oestrogen binding properties of the delipidated proteins have been studied with an equilibrium dialysis technique, and compared with the properties of the untreated foetal protein, as well as those of preparations reconstituted from the defatted α₁-foetoprotein and the removed lipids. An important increase has been evidenced for the binding levels of oestrone, oestradiol-17β and diethyl-stilboestrol by the delipidated α₁-foetoprotein. A reversal of this effect has been obtained by incubating the delipidated protein either with the lipids extracted from the purified α₁-foetoprotein or with a potent competitor of the rat α₁-foetoprotein-oestrogen interaction, designated as ‘L’, previously demonstrated and isolated from whole rat sera, and tentatively characterized as a mixture of fatty acids. Scatchard analysis of the oestrone and oestradiol-17β binding parameters show that the enhanced fixation of the hormones after defatting is primarily due to a two-fold increase of the apparent number of binding sites/ mol α₁-foetoprotein. The results are interpreted in terms of the probable, at least partial, identity between the lipids closely associated with the pure α₁-foetoprotein and the fatty acid mixture ‘L’ isolated from whole sera. The possible biological role of a complex interplay between oestrophilic α₁-foetoproteins, phenolsteroids and fatty acids in the control of eostrogen levels during development is discussed brieftly.     

己烯雌酚特异性抗体的制备及鉴定

利用4-溴丁酸乙酯对小分子半抗原己烯雌酚(DES)进行活化,引入羧基活性基团,应用活泼酯法将其与牛血清白蛋白(BSA)偶联,合成DES-CP-BSA完全抗原,免疫新西兰长耳白兔,制备特异性抗体.结果显示:成功制备了DES完全抗原,且由此获得了特异性的DES抗体,效价达1.28×105,与己烷雌酚、双烯雌酚的交叉反应分别...     

Comparison of the efficiences of enzymatic and chemical hydrolysis of (nortestosterone and diethylstilboestrol) glucuronides in bovine urine

Residues of 19-nortestosterone (19-NT) and diethylstilboestrol (DES) are excreted in bovine urine, mainly conjugated to glucuronic acid. Prior to quantification, urine must be deconjugated, which is commonly performed by enzymatic or chemical hydrolysis. The efficiencies of two enzymatic and two chemical deconjugation methods were studied. The range of efficiencies obtained for DES were 51.8% (β-glucuronidase, incubation at 37°C overnight) and 2.7% (methanolic HCl), respectively. Similarly, efficiencies for NT ranged from 43.1% (β-glucuronidase, incubation at 55°C for 2 h) to 12.7% (methanolic HCl). The results highlight that within control laboratories significant underestimation of drug residue content in samples may occur, due to poor deconjugation.     

Diethylstilbestrol increases the density of prolactin cells in male mouse pituitary by inducing proliferation of prolactin cells and transdifferentiation of gonadotropic cells

Diethylstilbestrol (DES) has been implicated in mammalian abnormalities. We examined the effects of DES on follicle-stimulating hormone (FSH), luteinizing hormone (LH), and prolactin (PRL) cells in the pituitaries of male mice treated with various doses of DES for 20 days. DES reduced the density of FSH and LH cells in a dose-dependent manner, but increased that of PRL cells. When the expression of estrogen receptor (ER) α and β was assessed, an induction of ERβ by DES was found predominantly in PRL cells. However, since these effects were abolished in ERα knockout mice, DES appears to act primarily through ERα. When the expression of Ki-67 and Pit-1 in PRL cells was examined at various time-points after DES treatment, some PRL cells became Ki-67 positive at 10–15 days, and Pit-1-positive cells were increased at 5–15 days. Furthermore, some FSH and LH cells became Pit-1 positive, and co-localized with PRL at 5–10 days. Our results indicate that DES increases PRL cells by inducing proliferation of PRL cells and transdifferentiation of FSH/LH cells to PRL cells.     

Electrochemical behaviors of diethylstilbestrol and its application in pharmacokinetics

The electrochemical behaviors of diethylstilbestrol (DES) at a glassy carbon electrode were investigated by cyclic voltammetry, linear sweep voltammetry, and differential pulse voltammetry (DPV). Based on these, a sensitive and selective DPV method was developed for determination of DES. The linear response range of DES is 1.0 x 10(-4)-2.0 x 10(-6) mol/L and the detection limit was 8.0 x 10(-8) mol/L. The developed method has been used for the pharmacokinetics of DES in rabbit blood plasma.     

稀有鮈鲫生命早期的己烯雌酚暴露对生长发育与繁殖的影响

研究了己烯雌酚(DES)对稀有鲫(Gobiocypris rarus)生命早期暴露的影响。经10μg/L和100μg/L己烯雌酚暴露26d后,稀有鲫死亡率升高,生长发育迟缓,鱼体内卵黄蛋白原(VTG)的诱导明显。经过一段时间清水养殖后,暴露组中雌鱼比例增加,雌雄鱼生长较对照组有显著变化。雌鱼性腺发育及产卵量与对照组相比虽无显著差异,但暴露组成鱼所繁育后代与对照组相比受精率、孵化率显著下降,死亡率、畸形率明显上升。这些结果说明己烯雌酚生命早期暴露影响稀有鲫的生长发育及生殖,稀有鲫生命早期暴露实验可以用于评价水生态系统中内分泌干扰物的生态影响。     

米曲霉M-4降解己烯雌酚的条件优化

【目的】以米曲霉(Aspergillus oryzae)M-4对己烯雌酚(Diethylstilbestrol,DES)的降解率为响应值,对其降解条件进行优化。【方法】采用Plackett-Burman法对培养基组分和降解条件筛选显著性影响因素,并通过Box-Bohnken设计试验优化降解条件。【结果】最优培养基配方为:蛋白胨1.3%,CaCl_2 0.045%,葡萄糖0.5%,K_2HPO_4 0.15%,KH_2PO_4 0.05%,NaCl 0.05%,Tween 80 0.2%,DES质量浓度44 mg/L;最优培养条件为:初始p H 7.5,种龄72 h,转速140 r/min,培养温度28°C,培养时间72 h。【结论】在最优条件下菌株M-4对DES降解率为83.89%,比优化前(60.98%)提高1.38倍,差异极显著(P0.01)。     

What is an endocrine disruptor?

Endocrine disrupting chemicals (EDCs) and potential EDCs are mostly man-made found in various materials. By interfering with the body's endocrine system, endocrine disruptors produce adverse developmental, reproductive, neurological, and immune effects in humans, abnormal growth patterns and neurodevelopmental delays in children. Thus, diethylstilbestrol (DES) a non-steroidal estrogen, which is regarded as a proof of concept, induces clear cell carcinoma among young women. EDCS may be found in plastic bottles and metal food cans (BPA), medical devices (phthalates), detergents, flame retardants (polybrominated diphenyl ethers), food (BPA), toys (phthalates), cosmetics and drugs (parabens), and pesticides (alkyl phenols such as nonylphenol). The deleterious effects of endocrine disruptors constitute a real public health issue. However concerning the mechanisms of action of EDCs, many questions remain unanswered and need further investigations.