Department of Genetic Toxicology, The Key Laboratory of Modern Toxicology of Ministry of Education, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, China.
Department of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing 211166, Jiangsu, China.
Environ Sci Technol. 2023 Feb 21;57(7):2864-2876. doi: 10.1021/acs.est.2c07389. Epub 2023 Feb 6.
Element contamination, including that from heavy metals, is associated with gastrointestinal tumorigenesis, but the effects and mechanisms of crucial element exposure associated with colorectal cancer remain unclear. We profiled 56 elements by ICP-MS and used logistic regression, LASSO, BKMR, and GAM to identify colorectal cancer-relevant elements. A series of biochemical experiments were performed to demonstrate the cytotoxicity and the mechanisms of malignant transformation after metal exposure. Using an elementomics approach, we first found that the metal thallium (Tl) was positively correlated with many toxic metals and was associated with a significantly increased risk of colorectal cancer. Acute exposure to Tl induced cytotoxicity and cell death by accelerating the generation of reactive oxygen species and DNA damage. Chronic exposure to Tl led to the inhibition of cell death and thereby induced the malignant transformation of normal colon cells and xenograft tumor formation in nude mice. Furthermore, we describe the first identification of a significant metal quantitative trait locus for the novel colorectal cancer susceptibility locus rs1511625 near . Mechanistically, Tl increased the level of aberrant -methyladenosine (mA) modification of via the //- axis to promote colorectal tumorigenesis. This study provides a basis for the development of public health strategies for reducing metal exposure among populations at high risk for colorectal cancer.
元素污染，包括重金属，与胃肠道肿瘤发生有关，但与结直肠癌相关的关键元素暴露的影响和机制仍不清楚。我们通过 ICP-MS 对 56 种元素进行了分析，并使用逻辑回归、LASSO、BKMR 和 GAM 来识别与结直肠癌相关的元素。进行了一系列生化实验，以证明金属暴露后细胞毒性和恶性转化的机制。通过元素组学方法，我们首先发现金属铊（Tl）与许多有毒金属呈正相关，与结直肠癌的风险显著增加有关。Tl 的急性暴露通过加速活性氧和 DNA 损伤的产生，诱导细胞毒性和细胞死亡。慢性暴露于 Tl 导致细胞死亡抑制，从而诱导正常结肠细胞的恶性转化，并在裸鼠中形成异种移植肿瘤。此外，我们描述了第一个鉴定的与 rs1511625 附近的新型结直肠癌易感位点相关的显著金属数量性状位点。从机制上讲，Tl 通过 //-轴增加了异常 -甲基腺苷（mA）修饰的水平，从而促进了结直肠肿瘤的发生。这项研究为制定针对结直肠癌高危人群减少金属暴露的公共卫生策略提供了依据。
