Male and female mice show significant differences in hepatic transcriptomic response to 2,3,7,8-tetrachlorodibenzo-p-dioxin.
Male and female mice show significant differences in hepatic transcriptomic response to 2,3,7,8-tetrachlorodibenzo-p-dioxin.
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DOI：
10.1186/s12864-015-1840-6
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发表时间：
2015-08-20
期刊：
影响因子：
4.4
通讯作者：
Boutros PC
中科院分区：
文献类型：
--
作者：
Lee J;Prokopec SD;Watson JD;Sun RX;Pohjanvirta R;Boutros PC
2，3，7，8-四氯二苯并对二恶英（TCDD）是二恶英同系物中毒性最强的一种，能够在许多动物模型中引起广泛的毒性作用。以往的研究表明，男性和女性的同一物种可以显示不同的敏感性表型TCDD毒性。虽然现在已经清楚，大多数TCDD诱导的毒性结果是由芳香烃受体（AHR）介导的，性别之间的TCDD暴露的差异反应的机制仍然在很大程度上是未知的。为了研究雄性和雌性小鼠的敏感性差异，我们分析了成年雄性和雌性C57 BL/6 Kuo小鼠暴露于不同剂量的TCDD（125、250、500或1000 μg/kg）后4天的肝脏转录组学反应。我们的研究揭示了几个关键发现。1)在检查的所有剂量下，两种性别之间的肝脏转录组存在显著差异。2)TCDD对雄性大鼠肝脏转录组的影响大于雌性大鼠。3)无论性别如何，“AHR核心”基因的改变在幅度上是一致的。4)一个基因子集表现出性别依赖性TCDD诱导的转录变化，包括Fmo 3和Nr 1 i3，这是显着诱导雄性小鼠的肝脏。此外，进行了荟萃分析，以对比暴露于等毒性剂量的TCDD后各种生物体和组织的转录组学特征。在TCDD敏感或TCDD耐药模型之间的差异中观察到最小的重叠。对TCDD暴露的性别依赖性敏感性与一组性别特异性TCDD反应基因相关。此外，芳烃和性激素受体之间的复杂相互作用可能会影响两性之间敏感性表型的可观察差异。进一步的工作是必要的，以更好地了解这些基因的作用，改变了TCDD在性别依赖的方式，以及它们与性激素和受体的变化。本文的在线版本（doi：10.1186/s12864-015-1840-6）包含补充材料，可供授权用户使用。
2,3,7,8–tetrachlorodibenzo-p-dixion (TCDD) is the most potent of the dioxin congeners, capable of causing a wide range of toxic effects across numerous animal models. Previous studies have demonstrated that males and females of the same species can display divergent sensitivity phenotypes to TCDD toxicities. Although it is now clear that most TCDD-induced toxic outcomes are mediated by the aryl hydrocarbon receptor (AHR), the mechanism of differential responses to TCDD exposure between sexes remains largely unknown. To investigate the differential sensitivities in male and female mice, we profiled the hepatic transcriptomic responses 4 days following exposure to various amounts of TCDD (125, 250, 500 or 1000 μg/kg) in adult male and female C57BL/6Kuo mice. Several key findings were revealed by our study. 1) Hepatic transcriptomes varied significantly between the sexes at all doses examined. 2) The liver transcriptome of males was more dysregulated by TCDD than that of females. 3) The alteration of “AHR-core” genes was consistent in magnitude, regardless of sex. 4) A subset of genes demonstrated sex-dependent TCDD-induced transcriptional changes, including Fmo3 and Nr1i3, which were significantly induced in livers of male mice only. In addition, a meta-analysis was performed to contrast transcriptomic profiles of various organisms and tissues following exposure to equitoxic doses of TCDD. Minimal overlap was observed in the differences between TCDD-sensitive or TCDD-resistant models. Sex-dependent sensitivities to TCDD exposure are associated with a set of sex-specific TCDD-responsive genes. In addition, complex interactions between the aryl hydrocarbon and sex hormone receptors may affect the observable differences in sensitivity phenotypes between the sexes. Further work is necessary to better understand the roles of those genes altered by TCDD in a sex-dependent manner, and their association with changes to sex hormones and receptors. The online version of this article (doi:10.1186/s12864-015-1840-6) contains supplementary material, which is available to authorized users.