环境雌激素研究进展

评述第45卷第21期 2000年11月

环境雌激素研究进展

杜克久徐晓白*

(中国科学院生态环境研究中心, 北京 100085. * 联系人, Email: [email protected])

摘要环境雌激素通过雌激素受体以及其他的细胞核受体或通过细胞中的信号传递系统, 如离子

通道

现代农业对农药的过分依赖都对环境造成

了极大的污染. 越来越多的证据表明, 存在于环境中一些人工合成的化学物质具有体内雌激素的生物效应,

它们可干扰鸟类

内分泌干扰剂

(endocrine disrupters)

4]等. 这些物质在环境中的暴露对人类生殖健康负

面影响的证据也越来越多.

近年来的隐睾症

阴阳人

精液密度以及精子数量的报道存在争议, 但过去50年中某些地区确实存在男性

精液数量明显下降之趋势[613], 所以有人将它们比喻为威胁人类存亡的定时炸弹[14]. 鉴于它们深远的负面效应, 类雌激素环境污染物的研究已经受到各国尤其是欧美以及日本等工业发达国家相当高度的重视[14

1996年16年间, 对全国39

个市县的万名健康男性的精液量

骨骼以及

大脑的发育息息相关. 目前就雌激素作用机制比较公认的是受体介导理论. 雌激素分子作为一种配体(ligand)和雌激素受体(ER-α)结合, 导致原结合于受体上的热休克蛋白-90(hsp90)从受体上解离下来; 结合了配体的雌激素受体发生构象改变并同型二聚体化(homodimerize), 这种同型二聚体复合物和DNA上雌激素反应元件(EREs)具有高度亲和能力(雌激素反应元件为位于

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出各种生理效应. 最近又发现雌激素分子还可以和另一雌激素受体亚型(ER-β)结合, 并通过DNA上的AP1反应原件以和ER-α相反的介导模式影响ER介导的基因转录活性, 如17β-雌二醇和ER-α结合通过DNA上的AP1反应元件激活并提高报告基因的转录, 然而和ER-β结合则抑制转录[18

-DDE, 利谷隆(linuron), vinclozolin以及某些PAHs 可和雄激素受体结合, 在体内

和体外抑制其活性并具有抗雄激素的生理效应. 近来的一些证据表明其他的细胞核受体对环境化学物质也是敏感的, 如糖皮质醇激素受体和甲状腺激素受体等[27].

除受体模式外, 环境雌激素通过直接调节细胞信号途径产生应答的证据也很多, 如高浓度的

p,p

¼ºÏ´Æ·Ó(DES)

等物质对微管

Ca2+

浓度以及钙调蛋白

２　０００种新的化学物质. 这些化学物质都可能对环境以及人类健康构成极大的危害. 在环境污染物中有许多物质具有雌激素活性, 世界范围内对有关数据的统计目前尚无准确定论,大约有

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2.1

农药类物质

使用农药是现代农业提高作物产量的重要手段之一, 但它确实是一把双刃剑. 由于长期和大量地使用, 尤其是农药发展早期人们对它们在自然界中迁移转化规律以及在生物体中的代谢途径

难降解的农药如大多数的

有机氯农药进入环境, 并通过生物富集和食物链造成了在动植物体内, 甚至在人体内的积累,出现了严重的农药残留问题. 这类农药对环境的污染, 特别是目前大量证据显示它们当中有些具有雌激素活性并可能影响实验动物

乙基

对硫磷以及马拉硫磷等少数几种外大部分是有机氯农药. 值得着重指出的是这部分农药公认的脂溶

在Wister cats中导致胚胎毒性[53]

和p,p

3个数量级,我们认为这极有可能在三氯杀螨醇和其中所含杂质(如一些

表1 具有雌激素活性证据的农药

名称

DDT及代谢产物*引发的主要生物效应促子宫活性, 影响E2与ER和hPR结合, 胞间通讯以及钙离子浓度

等细胞内其他信号传递系统文献[30

56]

抗雄激素Vinclozolin

*其他类农药: 六氯苯, 五氯酚, 三氯苯氧乙酸, 二氯苯氧乙酸, 莠去津, 系马津, 乙基对硫磷, 西

维因, 氯丹*, 艾氏剂*, 异狄氏剂*, 七氯*, 马拉硫磷, 灭多虫, 除草醚

*表示POP类化合物[5][14]

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DDT)之间存在协同作用. 三氯杀螨醇的这种细胞增殖效应也得到了小鼠促子宫效应实验结果的支持, 因此我们认为将三氯杀螨醇列入环境雌激素怀疑名单中是非常有必要的[55, 56].

图1 p,p

2.2

添加剂

添加剂可以通过多种途径和人类直接接触并可能进入人体, 和我们关系密切的主要有食品添加剂多氯联苯(PCBs)类

二口恶英是人类生产活动产生的副产品, 对其生成

影响过氧化酶活性

以及EGF受体和c-fos原致癌基因mRNA水平. 并抑制E2诱

导的MCF-7细胞的增殖以及160 ku蛋白的分泌[59]. 最近研究显示TCDD可使大鼠胚胎细胞的染色体缺失[63].

多氯联苯(PCBs)是由209种同类物组成的一组氯代芳烃化合物, 具有潜在的致癌生物效应. 世界各国真正对PCBs进行大量研究始于60年代末, 即在1968年日本发生了举世震惊的“米糠油中毒事件”后人们才对其造成的环境污染的严重性给予高度的重视. PCBs作为一种典型的持久性有机污染物(POP), 由于其污染的广泛性

对受体结合

子宫效应等方面[32, 63特异蛋白和酶活性的诱导以及小鼠促

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1254的生物活性高. MCF-7细胞增殖实验中国产PCB3和PCB5在大约30

pmol

ëàÊóÒÔ¼°´óÊóµÄÑÐ

¾¿·¢ÏÖÇ¦µÄ×÷ÓÃ¿ÉÓÉ¸¸Ìå×ªÒÆ¶ø¶ÔÏÂÒ»´úÔì³ÉËðº¦, 这包括新生儿的体重以及存活率的降低[74]. Telisman等[75]

总结了铅

精子

活动能力下降以及出现大量的异常精子等现象. 最近的流行病学调查也表明铅的中等职业接

触可以导致男性工人生育率下降

镉

细胞第二信使系统等而发生作

用[14, 74].

2.5 多环芳烃类物质(PAHs)

多环芳烃同样是典型的有机污染物. 这类人类活动的副产品主要产生于有机物的不完全燃烧过程, 在石油产品以及木材处理过程中的化学混合物中都含有这类物质. 许多证据显示一些PAHs可诱发啮齿类动物乳腺肿瘤的发生. 其作用机制被认为是: PAHs代谢成具有活性的中间代谢物以后, 可以和DNA共价结合, 从而发挥它们的致癌作用[79, 80]. 另有证据显示PAHs可通过影响钙离子体内平衡, 调节人乳腺上皮细胞的增殖, 进而可能引发肿瘤的形成[81

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2.6

植物来源的雌激素植物来源的雌激素是存在于植物体内的天然激素物质, 适量植物来源的雌激素对人类是有益的, 如东方人比西方人低的乳腺癌发病和饮食结构有关, 主要区别在于东方人高豆制品摄取. 但在发现羊食用了豆科植物草木樨出现不育现象后, 人们才醒悟该类物质应该还存在副效应. 研究发现它们超过一定量以后, 也会像化学合成物质一样产生干扰内分泌的作用. 如存在于植物体内的类黄酮物质可导致动物的不育; 虽然5, 6, 7-三羟基黄酮(baicalein)

橙皮素(hesperetin)

benzo- flavone)三羟基黄酮(apigenin) 槲皮苷(quercetin)以及染料木因(gest- ein)都有抗细胞增殖能力, 但其中只有染料木因和雌激素受体结合. 7, 8-苯唑黄酮(7,8-

酶以及还原酶的活性[27]. 烷基酚化

学物质(alkylphenolic chemicals)中的辛基酚(octylphenol)[58]和壬基酚(p-nonyl-phenol NP)[98]2246

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培养基中使用的酸碱指示剂酚红(phenol red)[99, 100], 以及一些非离子型表面活性剂[101]也都有弱雌激素活性的报道.

3 总结和展望

20世纪初由于人类科学水平的局限性, 包括农药在内的大量化学品的盲目使用对环境造成了严重污染. 它们所产生的后果之一

们面前. 带着众多的疑惑和恐惧,

医疗

环境雌激素问题在人类进入21世纪之际突现在我造船

男性和女性都被卷入了这场骚动. 从以上罗列的研究结果也不难看出, 目前在对雌激素作用机制尚不清楚的情况下对环境污染物雌激素生物活性的研究还处于探索性研究阶段,我们仅仅根据有限的实验数据来推测哪些环境污染物可能具有雌激素活性, 而且尚无足够的在人体中负面效应的证据. 所以雌激素以及类雌激素环境污染物作用机制的深入研究, 对了解和确定一种环境污染物的雌激素性质十分必要.

随着分子生物学实验方法的渗透

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