Aryl-hydrocarbon receptor-dependent pathway and toxic effects of TCDD in humans: a population-based study in Seveso, Italy
Aryl-hydrocarbon receptor-dependent pathway and toxic effects of TCDD in humans: a population-based study in Seveso, Italy
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DOI：
10.1016/j.toxlet.2003.12.062
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发表时间：
2004-04-01
影响因子：
3.5
通讯作者：
Landi, MT
中科院分区：
文献类型：
--
作者：
Baccarelli, A;Pesatori, AC;Landi, MT
在意大利塞维索事故发生约20年后，我们进行了一项基于人群的研究，以评估2，3，7，8-四氯二苯并对二恶英（TCDD）暴露对人体二恶英反应的免疫和机械生物标志物的影响。已知TCDD的毒性作用由芳香烃受体（AhR）介导。我们从最高暴露区随机选择了62名研究对象，从周围的非污染区随机选择了59名研究对象。这些受试者目前的血脂调整血浆TCDD浓度范围为3.5至90 ng/kg（或ppt），与血浆IgG浓度呈负相关（r = -0.35，P = 0.0002）。在淋巴细胞中测量AhR依赖性途径中的基因表达，包括AhR、芳香烃受体核转运蛋白（ARNT）、CYP 1A 1和CYP 1B 1转录物，以及CYP 1A 1相关的7-乙氧基试卤灵-O-脱乙基酶（EROD）活性。未培养淋巴细胞AhR mRNA水平与血浆TCDD水平呈负相关（P = 0.03）。当有丝分裂原诱导的淋巴细胞与10 nM TCDD培养时，所有AhR依赖基因均被诱导1.2至13倍。在这些细胞中，血浆TCDD与EROD活性降低有关。AhR通路内的标记物相互关联。我们的研究结果表明，在塞维索事故后暴露于TCDD的受试者存在长期影响。(C)2004爱思唯尔爱尔兰有限公司保留所有权利。
Approximately 20 years after the Seveso, Italy accident, we conducted a population-based study to evaluate the impact of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure upon immune and mechanistically based biomarkers of dioxin response in humans. TCDD toxic effects are known to be mediated by the aryl-hydrocarbon receptor (AhR). We randomly selected 62 study subjects from the highest exposed zones and 59 from the surrounding non-contaminated area. Current lipid-adjusted plasma TCDD concentrations in these subjects ranged from 3.5 to 90 ng/kg (or ppt) and were negatively associated with plasma IgG concentrations (r = -0.35; P = 0.0002). The expression of genes in the AhR-dependent pathway, including AhR, aryl-hydrocarbon receptor nuclear translocator (ARNT), CYP1A1, and CYP1B1 transcripts, and the CYP1A1-associated 7-ethoxyresorufin-O-deethylase (EROD) activity was measured in lymphocytes. AhR mRNA levels in uncultured lymphocytes were negatively associated with plasma TCDD (P = 0.03). When mitogen-induced lymphocytes were cultured with 10 nM TCDD, all AhR-dependent genes were induced 1.2- to 13-fold. In these cells, plasma TCDD was associated with decreased EROD activity. Markers within the AhR pathway were correlated with one another.Our findings suggest the presence of long-term effects in the subjects exposed to TCDD after the Seveso accident. (C) 2004 Elsevier Ireland Ltd. All rights reserved.