Biochemical and molecular changes at the cellular level in response to exposure to environmental estrogen-like chemicals.
Biochemical and molecular changes at the cellular level in response to exposure to environmental estrogen-like chemicals.
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DOI：
10.1080/009841097160573
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发表时间：
1997
期刊：
影响因子：
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通讯作者：
D. Roy;M. Palangat;Chiao-Wen Chen;R. D. Thomas;J. Colerangle;Alfonzo Atkinson;Zhi-Jie Yan
中科院分区：
文献类型：
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作者：
D. Roy;M. Palangat;Chiao-Wen Chen;R. D. Thomas;J. Colerangle;Alfonzo Atkinson;Zhi-Jie Yan
与非雌激素外源性物质相比，类雌激素化学物质是独特的，因为除了它们的化学特性外，这些化合物的雌激素特性使它们能够像性激素一样发挥作用。无论弱还是强，化学物质的雌激素反应如果不克服，都会给系统增加额外的雌激素负担。众所周知，在高剂量下，天然雌激素和环境雌激素样化学物质会产生不利影响。额外或升高浓度的雌激素的来源可以是内源性的或外源性的。人类和动物接触环境中类雌激素化学物质的可能性很高。只有有限数量的雌激素样化合物，如己烯雌酚 (DES)、双酚 A、壬基酚、多氯联苯 (PCB) 和二氯二苯基三氯乙烷 (DDT)，被用于评估细胞水平的生化和分子变化。其中，DES是研究最广泛的类雌激素化学物质，因此本文主要关注与DES相关的观察。除了雌激素作用外，环境中的雌激素样化学物质还会产生多种类型的遗传和/或非遗传影响。叙利亚仓鼠接触二苯乙烯雌激素（DES）会导致致癌靶器官（肾脏）的细胞核发生多种变化：（1）DES的核氧化还原反应产物修饰转录调节蛋白和DNA； (2)转录受到抑制； (3) 核蛋白酪氨酸磷酸化发生改变，包括RNA聚合酶II、p53和核胰岛素样生长因子1受体； (4)DNA修复基因DNA聚合酶β转录物减少和突变。 Noble 大鼠暴露于 DES 也会导致乳腺发生一些变化：增殖活性急剧改变；乳腺上皮细胞的细胞周期受到干扰；端粒长度变短；似乎其他一些雌激素化合物，如双酚 A 和壬基酚，也可能遵循与 DES 类似的作用模式，因为我们最近表明这些化合物改变细胞周期动力学，产生端粒关联，并产生染色体畸变。与DES一样，双酚A在代谢活化后能够与DNA结合。然而，应该注意的是，特定的或多类型的命中将取决于环境雌激素样化学物质的性质。目前阶段尚不清楚个别攻击导致特定变化的作用。这些对细胞核的多种攻击的后果可能是（1）核毒性/细胞死亡； (2)修复所有命中，然后发挥正常细胞作用； (3) 承受大部分打击并充当不稳定细胞。最后一种细胞的增殖预计会产生转化细胞。
Estrogen-like chemicals are unique compared to nonestrogenic xenobiotics, because in addition to their chemical properties, the estrogenic property of these compounds allows them to act like sex hormones. Whether weak or strong, the estrogenic response of a chemical, if not overcome, will add extra estrogenic burden to the system. At elevated doses, natural estrogens and environmental estrogen-like chemicals are known to produce adverse effects. The source of extra or elevated concentration of estrogen could be either endogenous or exogenous. The potential of exposure for humans and animals to environmental estrogen-like chemicals is high. Only a limited number of estrogen-like compounds, such as diethylstilbestrol (DES), bisphenol A, nonylphenol, polychlorinated biphenyls (PCBs), and dichlorodiphenyltrichloroethane (DDT), have been used to assess the biochemical and molecular changes at the cellular level. Among them, DES is the most extensively studied estrogen-like chemical, and therefore this article is focused mainly on DES-related observations. In addition to estrogenic effects, environmental estrogen-like chemicals produce multiple and multitype genetic and/or nongenetic hits. Exposure of Syrian hamsters to stilbene estrogen (DES) produces several changes in the nuclei of target organ for carcinogenesis (kidney): (1) Products of nuclear redox reactions of DES modify transcription regulating proteins and DNA; (2) transcription is inhibited; (3) tyrosine phosphorylation of nuclear proteins, including RNA polymerase II, p53, and nuclear insulin-like growth factor-1 receptor, is altered; and (4) DNA repair gene DNA polymerase beta transcripts are decreased and mutated. Exposure of Noble rats to DES also produces several changes in the mammary gland: proliferative activity is drastically altered; the cell cycle of mammary epithelial cells is perturbed; telomeric length is attenuated; etc. It appears that some other estrogenic compounds, such as bisphenol A and nonylphenol, may also follow a similar pattern of effects to DES, because we have recently shown that these compounds alter cell cycle kinetics, produce telomeric associations, and produce chromosomal aberrations. Like DES, bisphenol A after metabolic activation is capable of binding to DNA. However, it should be noted that a particular or multitype hit(s) will depend upon the nature of the environmental estrogen-like chemical. The role of individual attack leading to a particular change is not clear at this stage. Consequences of these multitypes of attack on the nuclei of cells could be (1) nuclear toxicity/cell death; (2) repair of all the hits and then acting as normal cells; or (3) sustaining most of the hits and acting as unstable cells. Proliferation of the last type of cell is expected to result in transformed cells.