Developmental exposure to 2,3,7,8 tetrachlorodibenzo-p-dioxin attenuates later-life Notch1-mediated T cell development and leukemogenesis
Developmental exposure to 2,3,7,8 tetrachlorodibenzo-p-dioxin attenuates later-life Notch1-mediated T cell development and leukemogenesis
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DOI：
10.1016/j.taap.2014.12.017
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发表时间：
2015-03-01
影响因子：
3.8
通讯作者：
Laiosa, Michael D.
中科院分区：
文献类型：
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作者：
Ahrenhoerster, Lori S.;Leuthner, Tess C.;Laiosa, Michael D.
超过一半的T细胞急性淋巴细胞白血病（T-ALL）患者在Notch基因中存在激活突变。此外，污染物2，3，7，8-四氯二苯并-对-二恶英（TCDD）是已知的致癌物，其通过芳烃受体（AHR）介导其毒性，并且先前已经观察到激活的AHR和Notch信号通路之间的串扰。鉴于Notch信号在胸腺细胞发育和T-ALL疾病进展中的重要性，我们假设活化的AHR在Notch 1诱导的胸腺瘤体内模型中增强疾病的发生和进展。在表达组成型活性Notch 1转基因（Notch（ICN-TG））的小鼠中，利用成年和发育暴露于TCDD的范例对这一假设进行了测试。成年Notch（ICN-TG）小鼠暴露于单次高剂量的TCDD后，我们观察到CD 8胸腺细胞生成效率显著增加。接下来，我们将孕鼠暴露于3 μ g/kg的TCDD在整个妊娠期和哺乳期，以阐明发育AHR激活对以后T细胞发育和Notch 1诱导的T-ALL样胸腺瘤易感性的影响。我们发现暴露于溶剂的Notch（ICN-TG）后代的外周血T细胞池严重偏向于CD 4谱系，而暴露于TCDD的Notch（ICN-TG）后代偏向于CD 8谱系。此外，虽然暴露于溶剂的NotchICN-TG小鼠表现出脾肿大增加和13/T细胞比率指示疾病，但发育中暴露于TCDD的小鼠在很大程度上免受疾病的影响。这些研究支持了一个模型，其中发育AHR激活减弱了晚年Notch 1依赖性对胸腺细胞发育和疾病进展的影响。(C)2015 Elsevier Inc. All rights reserved.
Over half of T cell acute lymphoblastic leukemia (T-ALL) patients have activating mutations in the Notch gene. Moreover, the contaminant 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD) is a known carcinogen that mediates its toxicity through the aryl hydrocarbon receptor (AHR), and crosstalk between activated AHR and Notch signaling pathways has previously been observed. Given the importance of Notch signaling in thymocyte development and T-ALL disease progression, we hypothesized that the activated AHR potentiates disease initiation and progression in an in vivo model of Notch1-induced thymoma. This hypothesis was tested utilizing adult and developmental exposure paradigms to TCDD in mice expressing a constitutively active Notch1 transgene (Notch(ICN-TG)). Following exposure of adult Notch(ICN-TG) mice to a single high dose of TCDD, we observed a significant increase in the efficiency of CD8 thymocyte generation. We next exposed pregnant mice to 3 mu g/kg of TCDD throughout gestation and lactation to elucidate effects of developmental AHR activation on later-life T cell development and T-ALL-like thymoma susceptibility induced by Notch1. We found that the vehicle-exposed Notch(ICN-TG) offspring have a peripheral T cell pool heavily biased toward the CD4 lineage, while TCDD-exposed Notch(ICN-TG) offspring were biased toward the CD8 lineage. Furthermore, while the vehicle-exposed NotchICN-TG mice showed increased splenomegaly and 13 to T cell ratios indicative of disease, mice developmentally exposed to TCDD were largely protected from disease. These studies support a model where developmental AHR activation attenuates later-life Notch1-dependent impacts on thymocyte development and disease progression. (C) 2015 Elsevier Inc. All rights reserved.