Routledge E J, Parker J, Odum J, Ashby J, Sumpter J P
Department of Biology & Biochemistry, Brunel University, Uxbridge, Middlesex, United Kingdom.
Toxicol Appl Pharmacol. 1998 Nov;153(1):12-9. doi: 10.1006/taap.1998.8544.
The inadvertent estrogenicity of certain synthetic chemicals, and their subsequent effects on the endocrine system of humans and wildlife, is of concern. In this paper we report findings from in vitro and in vivo (uterotrophic) studies which confirm that a range of alkyl hydroxy benzoate preservatives (parabens) are weakly estrogenic. In a receptor-binding assay, butylparaben was able to compete with 3H-estradiol for binding to the rat estrogen receptor with an affinity approximately 5 orders of magnitude lower than that of diethylstilboestrol, and between 1 and 2 orders of magnitude less than nonylphenol. In an in vitro yeast-based estrogen assay, the four most widely used parabens (namely methyl-, ethyl-, propyl-, and butylparaben) were all found to be weakly estrogenic with the most potent (butylparaben) being 10,000-fold less potent than 17 beta-estradiol. The estrogenic activity of parabens was inhibited by 4-hydroxy tamoxifen in vitro, illustrating the requirement of these chemicals to interact with the estrogen receptor in order to activate the yeast. When administered orally to immature rats, the parabens were inactive. However, subcutaneous administration of butylparaben produced a positive uterotrophic response in vivo, although it was approximately 100,000 times less potent than 17 beta-estradiol. Given their use in a wide range of commercially available topical preparations, it is suggested that the safety in use of these chemicals should be reassessed, with particular attention being paid to estimation of the actual levels of systemic exposure of humans exposed to these chemicals. The acquisition of such data is a prerequisite to the derivation of reliable estimates of the possible human risk of exposure to parabens.
某些合成化学物质意外具有的雌激素活性及其对人类和野生动物内分泌系统的后续影响令人担忧。在本文中，我们报告了体外和体内（子宫增重）研究的结果，这些研究证实了一系列烷基羟基苯甲酸酯防腐剂（对羟基苯甲酸酯）具有弱雌激素活性。在一项受体结合试验中，对羟基苯甲酸丁酯能够与3H-雌二醇竞争结合大鼠雌激素受体，其亲和力比己烯雌酚低约5个数量级，比壬基酚低1至2个数量级。在一项基于酵母的体外雌激素试验中，发现四种使用最广泛的对羟基苯甲酸酯（即对羟基苯甲酸甲酯、乙酯、丙酯和丁酯）均具有弱雌激素活性，其中活性最强的（对羟基苯甲酸丁酯）比17β-雌二醇的活性低10000倍。对羟基苯甲酸酯的雌激素活性在体外被4-羟基他莫昔芬抑制，这表明这些化学物质需要与雌激素受体相互作用才能激活酵母。当给未成熟大鼠口服时，对羟基苯甲酸酯没有活性。然而，对羟基苯甲酸丁酯皮下给药在体内产生了阳性子宫增重反应，尽管其效力比17β-雌二醇低约100000倍。鉴于它们在各种市售外用制剂中的使用，建议重新评估这些化学物质的使用安全性，尤其要注意估计接触这些化学物质的人类的实际全身暴露水平。获取此类数据是可靠估计人类接触对羟基苯甲酸酯可能风险的前提条件。
