Molecular targets that link dioxin exposure to toxicity phenotypes.
Molecular targets that link dioxin exposure to toxicity phenotypes.
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DOI：
10.1016/j.jsbmb.2010.12.005
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发表时间：
2011-10
影响因子：
4.1
通讯作者：
Tohyama, Chiharu
中科院分区：
文献类型：
--
作者：
Yoshioka, Wataru;Peterson, Richard E.;Tohyama, Chiharu
许多毒理学研究阐明了与接触各种化学品有关的健康影响，但很少有人确定导致特定毒性终点的分子靶点。我们对二恶英的毒性的了解也不例外，二恶英是一组能够在与环境相关的暴露水平上造成毒性的化学品。与我们在环境中接触到的大多数化学物质相比，二恶英是独一无二的，因为它们激活了一种高亲和力的受体，即芳香烃受体(AhR)，该受体在30多年前被发现。近年来，几行实验证据为打开包含二恶英作用分子机制的“黑匣子”提供了线索。毒物学家开始确定将AhR信号与组织特异性毒性表型联系起来的分子靶标，从而出现了这些线索。二恶英毒性的终点是在发育或组织再生过程中观察到的下游分子靶点，包括小鼠胚胎和幼鼠的前列腺发育受损和肾积水，斑马鱼胚胎的中脑血流减少和颌骨畸形，以及幼体和成年斑马鱼的鳍再生受损。在确定二恶英引起的成年小鼠肝毒性的分子靶点方面也取得了重大进展。AHR下游通路的错误调节，如通过环氧合酶-2将花生四烯酸转化为前列腺素类化合物，改变Wnt/β-catenin信号下调Sox9，以及炎性细胞因子受体的信号转导，都与二恶英毒性的组织特异性终点有关。这些发现不仅可能开始阐明二恶英作用的分子靶点，还可能揭示与发育和疾病相关的新的分子事件。
Many toxicology studies have elucidated health effects associated with exposure to various chemicals, but few have identified the molecular targets that cause specific endpoints of toxicity. Our understanding of the toxicity of dioxins, a group of chemicals capable of causing toxicity at environmentally relevant levels of exposure, is no exception. Dioxins are unique compared to most chemicals that we are exposed to in the environment because they activate a high affinity receptor, aryl hydrocarbon receptor (AhR), that was identified more than three decades ago. In recent years, several lines of experimental evidence have provided clues for opening the “black box” that contains the molecular mechanisms of dioxin action. These clues have emerged by toxicologists beginning to identify the molecular targets that link AhR signaling to tissue-specific toxicity phenotypes. Endpoints of dioxin toxicity for which downstream molecular targets have begun to be elucidated are observed in developmental or tissue regeneration processes, and include impaired prostate development and hydronephrosis in mouse fetuses and pups, reduced midbrain blood flow and jaw malformation in zebrafish embryos, and impaired fin regeneration in larval and adult zebrafish. Significant progress in identifying molecular targets for dioxin-induced hepatotoxicity in adult mice also has occurred. Misregulation of AhR downstream pathways, such as conversion of arachidonic acid to prostanoids via cyclooxygenase-2, and altered Wnt/β-catenin signaling downregulating Sox9, and signaling by receptors for inflammatory cytokines have been implicated in tissue-specific endpoints of dioxin toxicity. These findings may not only begin to clarify the molecular targets of dioxin action but shed light on new molecular events associated with development and disease.
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DOI：
10.1093/toxsci/kfn149
发表时间：
2008-11
期刊：
Toxicological sciences : an official journal of the Society of Toxicology
影响因子：
--
作者：
Bunger MK;Glover E;Moran SM;Walisser JA;Lahvis GP;Hsu EL;Bradfield CA
通讯作者：
Bradfield CA
影响因子：
--
作者：
Duan, RQ;Porter, W;Safe, S
通讯作者：
Safe, S
影响因子：
4.8
作者：
Lorenz, JN;Baird, NR;Shull, GE
通讯作者：
Shull, GE
影响因子：
3.8
作者：
Nishimura, Noriko;Matsumura, Fumio;Tohyama, Chiharu
通讯作者：
Tohyama, Chiharu
影响因子：
3
作者：
Chevalier, Robert L.;Thornhill, Barbara A.;Kiley, Susan C.
通讯作者：
Kiley, Susan C.