Malignant peritoneal mesotheliomas of rats induced by multiwalled carbon nanotubes and amosite asbestos: transcriptome and epigenetic profiles

IF 7.2 1区医学 Q1 TOXICOLOGY

Particle and Fibre Toxicology Pub Date : 2024-01-31 DOI:10.1186/s12989-024-00565-x

Stella Marie Reamon-Buettner, Susanne Rittinghausen, Annika Klauke, Andreas Hiemisch, Christina Ziemann

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引用次数: 0

Abstract

Malignant mesothelioma is an aggressive cancer that often originates in the pleural and peritoneal mesothelium. Exposure to asbestos is a frequent cause. However, studies in rodents have shown that certain multiwalled carbon nanotubes (MWCNTs) can also induce malignant mesothelioma. The exact mechanisms are still unclear. To gain further insights into molecular pathways leading to carcinogenesis, we analyzed tumors in Wistar rats induced by intraperitoneal application of MWCNTs and amosite asbestos. Using transcriptomic and epigenetic approaches, we compared the tumors by inducer (MWCNTs or amosite asbestos) or by tumor type (sarcomatoid, epithelioid, or biphasic). Genome-wide transcriptome datasets, whether grouped by inducer or tumor type, showed a high number of significant differentially expressed genes (DEGs) relative to control peritoneal tissues. Bioinformatic evaluations using Ingenuity Pathway Analysis (IPA) revealed that while the transcriptome datasets shared commonalities, they also showed differences in DEGs, regulated canonical pathways, and affected molecular functions. In all datasets, among highly- scoring predicted canonical pathways were Phagosome Formation, IL8 Signaling, Integrin Signaling, RAC Signaling, and TREM1 Signaling. Top-scoring activated molecular functions included cell movement, invasion of cells, migration of cells, cell transformation, and metastasis. Notably, we found many genes associated with malignant mesothelioma in humans, which showed similar expression changes in the rat tumor transcriptome datasets. Furthermore, RT-qPCR revealed downregulation of Hrasls, Nr4a1, Fgfr4, and Ret or upregulation of Rnd3 and Gadd45b in all or most of the 36 tumors analyzed. Bisulfite sequencing of Hrasls, Nr4a1, Fgfr4, and Ret revealed heterogeneity in DNA methylation of promoter regions. However, higher methylation percentages were observed in some tumors compared to control tissues. Lastly, global 5mC DNA, m6A RNA and 5mC RNA methylation levels were also higher in tumors than in control tissues. Our findings may help better understand how exposure to MWCNTs can lead to carcinogenesis. This information is valuable for risk assessment and in the development of safe-by-design strategies.

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多壁碳纳米管和铁石棉诱导的大鼠恶性腹膜间皮瘤：转录组和表观遗传学特征

恶性间皮瘤是一种侵袭性癌症，通常起源于胸膜和腹膜间皮层。接触石棉是常见的诱因。然而，对啮齿类动物的研究表明，某些多壁碳纳米管（MWCNTs）也会诱发恶性间皮瘤。其确切机制尚不清楚。为了进一步了解导致癌变的分子途径，我们分析了腹腔注射 MWCNTs 和铁石棉诱导的 Wistar 大鼠肿瘤。利用转录组学和表观遗传学方法，我们比较了不同诱导剂（MWCNTs 或复合石棉）或不同肿瘤类型（肉瘤型、上皮样或双相型）的肿瘤。与对照腹膜组织相比，全基因组转录组数据集，无论是按诱导剂还是肿瘤类型分组，都显示出大量显著的差异表达基因（DEGs）。使用Ingenuity Pathway Analysis（IPA）进行的生物信息学评估显示，虽然转录组数据集具有共性，但它们在DEGs、受调控的规范通路和受影响的分子功能方面也存在差异。在所有数据集中，得分较高的预测经典通路包括吞噬体形成、IL8 信号传导、整合素信号传导、RAC 信号传导和 TREM1 信号传导。得分最高的激活分子功能包括细胞移动、细胞入侵、细胞迁移、细胞转化和转移。值得注意的是，我们发现了许多与人类恶性间皮瘤相关的基因，这些基因在大鼠肿瘤转录组数据集中也有类似的表达变化。此外，RT-qPCR 显示，在分析的全部或大部分 36 个肿瘤中，Hrasls、Nr4a1、Fgfr4 和 Ret 表达下调，Rnd3 和 Gadd45b 表达上调。对 Hrasls、Nr4a1、Fgfr4 和 Ret 的亚硫酸氢盐测序显示，启动子区域的 DNA 甲基化存在异质性。然而，与对照组织相比，在一些肿瘤中观察到了更高的甲基化百分比。最后，肿瘤中5mC DNA、m6A RNA和5mC RNA的整体甲基化水平也高于对照组织。我们的研究结果有助于更好地了解接触 MWCNT 如何导致致癌。这些信息对于风险评估和制定安全设计策略非常有价值。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Particle and Fibre Toxicology TOXICOLOGY-

CiteScore

15.90

自引率

4.00%

发文量

审稿时长

6 months

期刊介绍： Particle and Fibre Toxicology is an online journal that is open access and peer-reviewed. It covers a range of disciplines such as material science, biomaterials, and nanomedicine, focusing on the toxicological effects of particles and fibres. The journal serves as a platform for scientific debate and communication among toxicologists and scientists from different fields who work with particle and fibre materials. The main objective of the journal is to deepen our understanding of the physico-chemical properties of particles, their potential for human exposure, and the resulting biological effects. It also addresses regulatory issues related to particle exposure in workplaces and the general environment. Moreover, the journal recognizes that there are various situations where particles can pose a toxicological threat, such as the use of old materials in new applications or the introduction of new materials altogether. By encompassing all these disciplines, Particle and Fibre Toxicology provides a comprehensive source for research in this field.