Transcriptomics analysis and hormonal changes of male and female neonatal rats treated chronically with a low dose of acrylamide in their drinking water.
Transcriptomics analysis and hormonal changes of male and female neonatal rats treated chronically with a low dose of acrylamide in their drinking water.
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DOI：
10.1016/j.toxrep.2016.03.009
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发表时间：
2016
影响因子：
--
通讯作者：
Denslow ND
中科院分区：
文献类型：
--
作者：
Collí-Dulá RC;Friedman MA;Hansen B;Denslow ND
已知丙烯酰胺可引起大鼠甲状腺滤泡细胞瘤。RccHan Wistar大鼠在子宫内暴露于致癌剂量丙烯酰胺（3 mg/Kg体重/天），从妊娠第6天到分娩，然后通过饮用水暴露到出生后第35天。为了确定甲状腺癌变的潜在机制，我们使用了转录组学方法。在晚上10点和上午10点或晚上10点分别收集雄性幼鼠和雌性幼鼠的甲状腺，以确定主动暴露于丙烯酰胺是否会影响可能与致癌有关的基因表达模式或途径。虽然所有接触丙烯酰胺的动物都表现出与致癌有关的预期目标途径的变化，如DNA修复、DNA复制、染色体分离等；在夜间活动期间主动饮用含有丙烯酰胺的水的动物，在氧化应激、解毒途径、代谢和检查点途径的激活等相关途径中，表现出更多的变化。此外，与对照组相比，丙烯酰胺处理大鼠的甲状腺激素，三碘甲状腺原氨酸（T3）和甲状腺素（T4）在夜间升高，但在静止动物中没有升高。数据清楚地表明，一天中采集样本的时间对于确定暴露改变的分子途径至关重要。这些结果表明，丙烯酰胺处理的大鼠甲状腺癌变可能由多种不同的机制引起，如激素变化和氧化应激，而不仅仅是直接的遗传毒性，正如迄今为止所假设的那样。
Acrylamide is known to produce follicular cell tumors of the thyroid in rats. RccHan Wistar rats were exposed in utero to a carcinogenic dose of acrylamide (3 mg/Kg bw/day) from gestation day 6 to delivery and then through their drinking water to postnatal day 35. In order to identify potential mechanisms of carcinogenesis in the thyroid glands, we used a transcriptomics approach. Thyroid glands were collected from male pups at 10 PM and female pups at 10 AM or 10 PM in order to establish whether active exposure to acrylamide influenced gene expression patterns or pathways that could be related to carcinogenesis. While all animals exposed to acrylamide showed changes in expected target pathways related to carcinogenesis such as DNA repair, DNA replication, chromosome segregation, among others; animals that were sacrificed while actively drinking acrylamide-laced water during their active period at night showed increased changes in pathways related to oxidative stress, detoxification pathways, metabolism, and activation of checkpoint pathways, among others. In addition, thyroid hormones, triiodothyronine (T3) and thyroxine (T4), were increased in acrylamide-treated rats sampled at night, but not in quiescent animals when compared to controls. The data clearly indicate that time of day for sample collection is critical to identifying molecular pathways that are altered by the exposures. These results suggest that carcinogenesis in the thyroids of acrylamide treated rats may ensue from several different mechanisms such as hormonal changes and oxidative stress and not only from direct genotoxicity, as has been assumed to date.