Estrogenic effects of organochlorine pesticides on uterine leiomyoma cells in vitro
Estrogenic effects of organochlorine pesticides on uterine leiomyoma cells in vitro
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DOI：
10.1093/toxsci/54.2.355
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发表时间：
2000-04-01
影响因子：
3.8
通讯作者：
Walker, CL
中科院分区：
文献类型：
--
作者：
Hodges, LC;Bergerson, JS;Walker, CL
子宫平滑肌瘤虽然是良性的，但在育龄妇女中发生率高，发病率高，是一个严重的健康问题。平滑肌瘤发生在子宫肌层，对卵巢激素敏感，使其成为内分泌干扰物的潜在靶点。在这里，我们利用来自大鼠子宫平滑肌瘤的细胞系，以确定是否有一个面板的7种有机氯农药在子宫肌层细胞使用细胞和分子在体外测定具有潜在的激动剂活性。所研究的有机氯农药先前已被表征为在其他子宫反应组织中具有激动剂活性，但尚未在子宫肌层细胞中研究其影响。在Eker大鼠平滑肌瘤衍生细胞中，HPTE、酮和硫丹的α异构体刺激增殖，抗雌激素ICI 182，780抑制了这种效应。此外，这些化合物通过ER在转录报告基因测定中刺激卵黄蛋白原雌激素反应元件的转录，并诱导内源性雌激素反应基因孕酮受体（PR）的表达。这与甲氧滴滴涕、狄氏剂、毒杀芬和β硫丹的激动剂特性形成对比。这些化合物，不能刺激子宫平滑肌瘤细胞的增殖，在雌激素敏感的报告基因测定中在转录水平上在这些细胞中确实表现出激动活性，并且它们也能够上调PR信息。这些数据表明，有机氯农药作为雌激素受体激动剂在Eker大鼠子宫肌层细胞，他们表明，需要进一步调查的潜在组织特异性激动剂活性，这些农药和它们的作用，在子宫平滑肌瘤的发病机制。
Although benign, uterine leiomyomas occur with high frequency and significant morbidity in reproductive-age women, and they present a significant health problem. Leiomyomas develop in the uterine myometrium and are sensitive to ovarian hormones, making them potential target sites for endocrine disrupters. Here we utilize cell lines derived from rat uterine leiomyomas to determine if a panel of 7 organochlorine pesticides have potential agonist activity in myometrial cells using cellular and molecular in vitro assays. The organochlorine pesticides investigated have been previously characterized as having agonist activity in other hormonally responsive tissues, but their effects have not been studied in uterine myometrial cells. In Eker rat leiomyoma-derived cells, HPTE, kepone, and the alpha isomer of endosulfan stimulated proliferation, an effect dampened by the antiestrogen ICI 182,780. In addition, these compounds stimulated transcription of the vitellogenin estrogen-response element via the ER in a transcriptional reporter gene assay and induced the expression of an endogenous estrogen-responsive gene, the progesterone receptor (PR). This contrasted with the agonist profile of methoxychlor, dieldrin, toxaphene, and endosulfan-beta. These compounds, unable to stimulate proliferation of uterine leiomyoma cells, did exhibit agonistic activity in these cells at the transcriptional level in the estrogen-sensitive reporter gene assay, and they were also able to upregulate PR message. These data demonstrate that organochlorine pesticides act as estrogen receptor agonists in Eker rat uterine myometrial cells, and they indicate a need for further investigation of the potential tissue-specific agonist activity of these pesticides and their role in the pathogenesis of uterine leiomyoma.