Transcriptional profiling of male F344 rats suggests the involvement of calcium signaling in the mode of action of acrylamide-induced thyroid cancer
Transcriptional profiling of male F344 rats suggests the involvement of calcium signaling in the mode of action of acrylamide-induced thyroid cancer
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DOI：
10.1016/j.fct.2017.06.019
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发表时间：
2017-09-01
影响因子：
4.3
通讯作者：
Yauk, Carole L.
中科院分区：
文献类型：
--
作者：
Chepelev, Nikolai L.;Gagne, Remi;Yauk, Carole L.
丙烯酰胺（AA）暴露在2年的癌症生物测定导致甲状腺，但不是肝，腺瘤和腺癌的大鼠。假设的作用模式（MOA）包括遗传毒性/致突变性或甲状腺激素失调。为了检查这两种或任何替代MOA的可接受性，对AA暴露大鼠的甲状腺和肝脏进行RNA测序，同时测量遗传毒性在雄性Fischer 344/DuCrl大鼠暴露于0.0、0.5、1.5、3.0、6.0或12.0 mg AA/kg bw-天，持续5、15或31天。两种组织中差异表达的基因为激素和遗传毒性MOA提供了边际支持，这与阴性/可疑遗传毒性试验和甲状腺激素水平的边际变化一致。相反，对甲状腺中的钙信号传导/细胞骨架基因有明显影响。钙信号传导途径RNA测序数据的基准剂量建模表明，起始点（POD）为0.68 mg/kg bw-天，这与甲状腺2年癌症生物测定数据得出的POD 0.82 mg/kg bw-天一致。总体而言，本研究表明AA诱导的雄性大鼠甲状腺致癌性的一种新MOA，其中心是钙信号的扰动。皇冠版权所有（C）2017由Elsevier Ltd.发布
Acrylamide (AA) exposure in 2-year cancer bioassays leads to thyroid, but not liver, adenomas and adenocarcinomas in rats. Hypothesized modes of action (MOAs) include genotoxicity/mutagenicity, or thyroid hormone dysregulation. To examine the plausibility of these two or any alternative MOAs, RNA-sequencing was performed on the thyroids and livers of AA-exposed rats, in parallel with measurement of genotoxicity (blood micronucleus and Pig-a mutant frequency) and serum thyroid hormone levels, following the exposure of male Fischer 344/DuCrl rats to 0.0, 0.5,1.5, 3.0, 6.0, or 12.0 mg AA/kg bw-day in drinking water for 5, 15, or 31 days. Differentially expressed genes in both tissues provided marginal support for hormonal and genotoxic MOAs, which was consistent with negative/equivocal genotoxicity assay and marginal changes in thyroid hormone levels. Instead, there was a pronounced effect on calcium signaling/cytoskeletal genes in the thyroid. Benchmark dose modeling of RNA-sequencing data for the calcium signaling pathway suggests a point of departure (POD) of 0.68 mg/kg bw-day, which is consistent with a POD of 0.82 mg/kg bw-day derived from the thyroid 2-year cancer bioassay data. Overall, this study suggests a novel MOA for AA-induced thyroid carcinogenicity in male rats centered around perturbation of calcium signaling. Crown Copyright (C) 2017 Published by Elsevier Ltd.