Mutagenicity of acrylamide and glycidamide in human TP53 knock-in (Hupki) mouse embryo fibroblasts.
Mutagenicity of acrylamide and glycidamide in human TP53 knock-in (Hupki) mouse embryo fibroblasts.
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丙烯酰胺和糖二胺在人TP53敲入（Hupki）小鼠胚胎成纤维细胞中的诱变。
DOI：
10.1007/s00204-020-02878-0
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发表时间：
2020-12
影响因子：
6.1
通讯作者：
Arlt VM
中科院分区：
文献类型：
--
作者：
Hölzl-Armstrong L;Kucab JE;Moody S;Zwart EP;Loutkotová L;Duffy V;Luijten M;Gamboa da Costa G;Stratton MR;Phillips DH;Arlt VM
丙烯酰胺是一种疑似人类致癌物，是在高温烹饪富含淀粉的食物时形成的。它被细胞色素 P450 2E1 代谢为其反应性代谢产物缩水甘油酰胺，形成诱变前的 DNA 加合物。使用人 TP53 敲入 (Hupki) 小鼠胚胎成纤维细胞 (HUF) 永生化测定 (HIMA)，研究了肿瘤抑制基因 TP53 中丙烯酰胺和缩水甘油酰胺诱导的诱变。选定的永生化 HUF 克隆还进行了下一代测序，以确定整个基因组的突变。缩水甘油酰胺暴露后（1.1 mM，24 小时，n = 198）后的 TP53 突变频率为 9%，而用丙烯酰胺处理的培养物 [1.5 (n = 24) 或 3 mM (n = 6) 48 小时] 和未经处理的载体（水）对照 (n = 36) 处理的培养物中，TP53 突变频率为 0%。大多数缩水甘油酰胺诱导的突变发生在腺嘌呤上，其中 A > T/T > A 和 A > G/T > C 突变是最常见的类型。缩水甘油酰胺诱导的突变发生在特定的 TP53 密码子上，这些密码子也被发现在先前与丙烯酰胺暴露相关的人类肿瘤（即乳腺、卵巢、结直肠和肺）中发生突变。全基因组测序（WGS）检测到的突变进一步反映了TP53突变谱，并且在用缩水甘油酰胺处理的HUF克隆中发现了独特的WGS突变特征，其特征再次为A > G/T > C和A > T/T > A突变。 WGS 突变特征与先前在人类肿瘤（例如乳腺癌和卵巢）中发现的 COSMIC 突变特征 SBS3 和 25 相似，而腺嘌呤成分与主要在吸烟者肺癌中发现的 COSMIC SBS4 相似。相反，在丙烯酰胺处理的 HUF 克隆中，仅观察到与培养相关的背景 WGS 突变特征。总之，本研究的结果表明，缩水甘油酰胺可能参与乳腺癌、卵巢癌和肺癌的发生。本文的在线版本 (10.1007/s00204-020-02878-0) 包含补充材料，可供授权用户使用。
Acrylamide is a suspected human carcinogen formed during high-temperature cooking of starch-rich foods. It is metabolised by cytochrome P450 2E1 to its reactive metabolite glycidamide, which forms pre-mutagenic DNA adducts. Using the human TP53 knock-in (Hupki) mouse embryo fibroblasts (HUFs) immortalisation assay (HIMA), acrylamide- and glycidamide-induced mutagenesis was studied in the tumour suppressor gene TP53. Selected immortalised HUF clones were also subjected to next-generation sequencing to determine mutations across the whole genome. The TP53-mutant frequency after glycidamide exposure (1.1 mM for 24 h, n = 198) was 9% compared with 0% in cultures treated with acrylamide [1.5 (n = 24) or 3 mM (n = 6) for 48 h] and untreated vehicle (water) controls (n = 36). Most glycidamide-induced mutations occurred at adenines with A > T/T > A and A > G/T > C mutations being the most common types. Mutations induced by glycidamide occurred at specific TP53 codons that have also been found to be mutated in human tumours (i.e., breast, ovary, colorectal, and lung) previously associated with acrylamide exposure. The spectrum of TP53 mutations was further reflected by the mutations detected by whole-genome sequencing (WGS) and a distinct WGS mutational signature was found in HUF clones treated with glycidamide that was again characterised by A > G/T > C and A > T/T > A mutations. The WGS mutational signature showed similarities with COSMIC mutational signatures SBS3 and 25 previously found in human tumours (e.g., breast and ovary), while the adenine component was similar to COSMIC SBS4 found mostly in smokers’ lung cancer. In contrast, in acrylamide-treated HUF clones, only culture-related background WGS mutational signatures were observed. In summary, the results of the present study suggest that glycidamide may be involved in the development of breast, ovarian, and lung cancer. The online version of this article (10.1007/s00204-020-02878-0) contains supplementary material, which is available to authorized users.
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影响因子：
4.1
作者：
da Costa, GG;Churchwell, MI;Doerge, DR
通讯作者：
Doerge, DR
影响因子：
3.2
作者：
Jiang, Liping;Cao, Jun;Zhong, Laifu
通讯作者：
Zhong, Laifu
影响因子：
3.8
作者：
Hogervorst, Janneke G.;Schouten, Leo J.;van den Brandt, Piet A.
通讯作者：
van den Brandt, Piet A.
影响因子：
4.3
作者：
Beland, Frederick A.;Olson, Greg R.;Mendoza, Maria C. B.;Marques, M. Matilde;Doerge, Daniel R.
通讯作者：
Doerge, Daniel R.
影响因子：
2.8
作者：
Manjanatha, MG;Aidoo, A;Doerge, DR
通讯作者：
Doerge, DR