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首页> 外文学位 >Antiestrogenicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin and non-ortho-substituted polychlorinated biphenyls.
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Antiestrogenicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin and non-ortho-substituted polychlorinated biphenyls.

机译：2,3,7,8-四氯二苯并-对-二恶英和非邻位取代的多氯联苯的抗雌激素性。

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摘要

Some mechanisms of toxicity of halogenated aromatic hydrocarbons (HAHs), including those of specific polychlorinated biphenyl (PCB) congeners, are mediated by the aromatic hydrocarbon receptor (AhR). 2,3,7,8-Tetrachlorodibenzo- p-dioxin (TCDD), a prototypical AhR agonist, elicits a wide range of biochemical and toxic responses, including antiestrogenic effects. TCDD is antiestrogenic both in vivo and in vitro, but the mechanisms of antiestrogenicity are not well understood. We studied antiestrogenic effects of PCBs and TCDD, using E2-responsive human breast-tumor cells in culture as systems to delineate the mechanism(s) of antiestrogenicity.; Exposure of ZR-75-1 cells to TCDD or the non-ortho-substituted PCBs, 3,4,4′,5-tetrachlorobiphenyl (PCB 81) and 3,3 ′,4,4′,5-pentachlorobiphenyl (PCB 126), blocked the 17β-estradiol (E2)-stimulated elevations in the levels of estrogen receptor-α (ER-α), progesterone receptor (PGR) and cathepsin D (CD) mRNAs, and elicited marked elevations in the levels of mRNAs encoding cytochromes P450 1A1 (CYP1A1), an E2 2-hydroxylase, and 1B1 (CYP1B1), an E2 4-hydroxylase. TCDD and non-ortho -substituted PCBs elicited elevated rates of E2 metabolism, but environmentally prevalent mono-ortho-substituted PCBs were much less effective. Long-term estrogen-deprived T47D cells exhibited diminished inducibility of E2 metabolism that was reversible by E2, suggesting a self-regulation of E2 metabolism.; Exposure of T47D cells to PCB 81, 3,3′,4,4 ′-tetrachlorobiphenyl (PCB 77), PCB 126, or 3,3′ ,4,4′,5,5′-hexachlorobiphenyl (PCB 169) inhibited E2-stimulated preconfluent proliferation. PCB 169, a potent inhibitor of CYP1A1 and CYP1B1, only slightly reduced the inhibitory effects of TCDD on cell proliferation, even in the presence of high E 2 concentrations.; E2 and estrone (E1) are interconverted in the liver. Cytochrome P4501A2 (CYP1A2), a liver enzyme, had the highest catalytic efficiency for E1 hydroxylation. Both human cDNA-expressed CYP1A1 and CYP1A2 catalyzed mainly 2-hydroxylation of E1 with minor 4-hydroxylation activities, while CYP1B1 catalyzed primarily E1 4- and 2-hydroxylation. CYP1A1 and 1B1, which favor E2 as substrate, may catalyze estrogen metabolism in extrahepatic, estrogen-responsive tissues in which E2 concentrations exceed those of E1. The stimulation of estrogen metabolism and the inhibition of cell proliferation may be important mechanistic components of the antiestrogenicity of TCDD and non-ortho-substituted PCBs.
机译：卤代芳烃（HAHs）的某些毒性机理，包括特定的多氯联苯（PCB）同源物的毒性，是由芳烃受体（AhR）介导的。典型的AhR激动剂2,3,7,8-四氯二苯并- p -二恶英（TCDD）引发了广泛的生化和毒性反应，包括抗雌激素作用。 TCDD在体内和体外都具有抗雌激素作用，但抗雌激素作用的机理尚不十分清楚。我们以培养物中E 2 反应的人乳腺肿瘤细胞为系统来研究PCBs和TCDD的抗雌激素作用，以描述抗雌激素作用的机制。 ZR-75-1细胞暴露于TCDD或非邻位取代的PCB，3,4,4 '，5-四氯联苯（PCB 81）和3， 3 '，4,4 '，5-五氯联苯（PCB 126）阻止了17β-雌二醇（E 2 ）刺激的升高雌激素受体-α（ER-α），孕激素受体（PGR）和组织蛋白酶D（CD）mRNA的水平，并引起编码细胞色素P450 1A1（CYP1A1），E 2 < / sub> 2-羟化酶和1B1（CYP1B1），一种E 2 4-羟化酶。 TCDD和非 取代的PCB引起E 2 代谢的速率增加，但是环境普遍的单 。长期被雌激素剥夺的T47D细胞表现出E 2 可逆的E 2 代谢诱导能力降低，表明E 2 的自我调节>代谢。 T47D细胞暴露于PCB 81、3,3 '，4,4 '-四氯联苯（PCB 77），PCB 126或3,3 '< / super>，4,4 '，5,5 '-六氯联苯（PCB 169）抑制E 2 刺激的汇合前增殖。 PCB 169是一种有效的CYP1A1和CYP1B1抑制剂，即使存在高E 2 浓度，也仅轻微降低TCDD对细胞增殖的抑制作用。 E 2 和雌酮（E 1 ）在肝脏中相互转化。细胞色素P4501A2（CYP1A2）是一种肝酶，对E 1 的羟基化反应具有最高的催化效率。人cDNA表达的CYP1A1和CYP1A2都主要催化E 1 的2-羟基化，而仅具有少量的4-羟基化活性，而CYP1B1主要催化E 1 的4-和2-羟基化。 CYP1A1和1B1有利于E 2 作为底物，可能在E 2 浓度超过E 1 < / sub>。刺激雌激素代谢和抑制细胞增殖可能是TCDD和非邻位取代PCB抗雌激素作用的重要机制。

著录项

  • 作者

    Oenga, Gideon Nyabuti.;

  • 作者单位

    State University of New York at Albany.;

  • 授予单位 State University of New York at Albany.;
  • 学科 Health Sciences Toxicology.
  • 学位 Ph.D.
  • 年度 2001
  • 页码 225 p.
  • 总页数 225
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 毒物学（毒理学）;
  • 关键词

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