Malathion改变了巨型波纹鲹肿瘤抑制基因tp53的靶基因转录以及癌症过程：DNA损伤应答，氧化应激和细胞凋亡的机制。
Malathion alters the transcription of target genes of the tumour suppressor tp53 and cancerous processes in Colossoma macropomum: Mechanisms of DNA damage response, oxidative stress and apoptosis.
发表日期：2023 Feb 14
作者：
Samara Silva de Souza, Jaqueline Custódio da Costa, Grazyelle Sebrenski da Silva, Vera Maria Fonseca de Almeida-Val
来源：
CHEMICO-BIOLOGICAL INTERACTIONS
摘要：
不同的农药类别，如杀菌剂、除草剂和杀虫剂，可以引起参与鱼类肿瘤发生事件的基因不同表达，包括肿瘤抑制基因tp53的表达。应激条件的程度和持续时间对定义哪种tp53依赖性通路被激活是决定性的。在这里，我们评估了黄金吴郎经过马拉硫磷接触后参与调节肿瘤抑制基因tp53通路和癌症过程的靶基因表达。我们的假设是马拉硫磷促进了基因响应，该响应在时间上是不同调节的，与凋亡通路相关的tp53靶基因是正调节的，而促进抗氧化响应的基因则被负调节。鱼类接触亚致死剂量的杀虫剂分别为6和48小时。使用肝脏样品分析了11个基因的实时PCR表达。总体而言，马拉硫磷随着时间的推移促进了tp53表达和与tp53有关基因的不同表达。接触导致损伤反应相关基因的激活，引起atm/atr基因的正表达。负调节的抗凋亡基因bcl2上调，而抗凋亡基因bcl2下调。在接触的前几个小时内，观察到mdm2和sesn1的表达增加，对抗氧化基因sod2和gpx1没有影响。我们还观察到hif-1α基因表达的增加，对ras原癌基因没有影响。这种应激状态的延伸加强了tp53的转录，减少了mdm2、sens1和bax的水平；然而，抑制了bcl2和bcl2/bax比率的水平，表明维持凋亡响应的代价是对抗氧化响应。 版权所有 © 2023 Elsevier B.V.
Different classes of pesticides such as fungicides, herbicides, and insecticides, can induce differential expression of genes that are involved in tumorigenesis events in fish, including the expression of tumor suppressor tp53. The degree and duration of the stressful condition is decisive in defining which tp53-dependent pathway will be activated. Herein we evaluate the target genes expression that participates in the regulation pathway of the tumor suppressor tp53 and in the cancerous processes in tambaqui after exposure to malathion. Our hypothesis is that malathion promotes a gene response that is differentially regulated over time, with positive regulation of tp53 target genes related to the apoptotic pathway and a negative regulation of genes that promote antioxidant responses. The fish were exposed to a sublethal concentration of the insecticide for 6 and 48 h. Liver samples were used to analyze the expression of 11 genes using real-time PCR. Overall, the malathion promoted over time increases in tp53 expression and differential expression of tp53 related genes. The exposure resulted in the activation of damage response related genes, caused a positive expression of atm/atr genes. The pro-apoptotic gene bax was up-regulated and the anti-apoptotic bcl2 was down-regulated. Increased expression of mdm2 and sesn1 in the first hours of exposure and no effect on the antioxidant genes sod2 and gpx1 were also observed. We also witnessed an increase in the expression of the hif-1α gene, with no effect on ras proto-oncogene. The extension of this stressful condition accentuated tp53 transcription, and minimized the levels of mdm2, sens1 and bax; however, it down regulated the levels of bcl2 and the bcl2/bax ratio, which indicates the maintenance of the apoptotic response to the detriment of an antioxidant response.Copyright © 2023 Elsevier B.V. All rights reserved.