Phookphan Preeyaphan, Navasumrit Panida, Waraprasit Somchamai, Promvijit Jeerawan, Chaisatra Krittinee, Ngaotepprutaram Thitirat, Ruchirawat Mathuros
Laboratory of Environmental Toxicology, Chulabhorn Research Institute, Laksi, Bangkok, Thailand; Post-graduate Program in Environmental Toxicology, Chulabhorn Graduate Institute, Laksi, Bangkok, Thailand; Center of Excellence on Environmental Health, Toxicology (EHT), Office of the Higher Education Commission, Ministry of Education, Thailand.
Laboratory of Environmental Toxicology, Chulabhorn Research Institute, Laksi, Bangkok, Thailand.
Toxicol Appl Pharmacol. 2017 Feb 1;316:36-47. doi: 10.1016/j.taap.2016.12.015. Epub 2016 Dec 23.
Early-life exposure to arsenic increases risk of developing a variety of non-malignant and malignant diseases. Arsenic-induced carcinogenesis may be mediated through epigenetic mechanisms and pathways leading to inflammation. Our previous study reported that prenatal arsenic exposure leads to increased mRNA expression of several genes related to inflammation, including COX2, EGR1, and SOCS3. This study aimed to investigate the effects of arsenic exposure on promoter DNA methylation and mRNA expression of these inflammatory genes (COX2, EGR1, and SOCS3), as well as the generation of 8-nitroguanine, which is a mutagenic DNA lesion involved in inflammation-related carcinogenesis. Prenatally arsenic-exposed newborns had promoter hypomethylation of COX2, EGR1, and SOCS3 in cord blood lymphocytes (p<0.01). A follow-up study in these prenatally arsenic-exposed children showed a significant hypomethylation of these genes in salivary DNA (p<0.01). In vitro experiments confirmed that arsenite treatment at short-term high doses (10-100μM) and long-term low doses (0.5-1μM) in human lymphoblasts (RPMI 1788) caused promoter hypomethylation of these genes, which was in concordance with an increase in their mRNA expression. Additionally, the level of urinary 8-nitroguanine was significantly higher (p<0.01) in exposed newborns and children, by 1.4- and 1.8-fold, respectively. Arsenic accumulation in toenails was negatively correlated with hypomethylation of these genes and positively correlated with levels of 8-nitroguanine. These results indicated that early-life exposure to arsenic causes hypomethylation of COX2, EGR1, and SOCS3, increases mRNA expression of these genes, and increases 8-nitroguanine formation. These effects may be linked to mechanisms of arsenic-induced inflammation and cancer development later in life.
生命早期接触砷会增加患多种非恶性和恶性疾病的风险。砷诱导的致癌作用可能通过表观遗传机制和导致炎症的途径介导。我们之前的研究报告称，产前接触砷会导致与炎症相关的多个基因（包括COX2、EGR1和SOCS3）的mRNA表达增加。本研究旨在调查砷暴露对这些炎症基因（COX2、EGR1和SOCS3）的启动子DNA甲基化和mRNA表达的影响，以及8-硝基鸟嘌呤的生成，8-硝基鸟嘌呤是一种参与炎症相关致癌作用的诱变DNA损伤。产前接触砷的新生儿脐带血淋巴细胞中COX2、EGR1和SOCS3的启动子低甲基化（p<0.01）。对这些产前接触砷的儿童的后续研究表明，唾液DNA中这些基因存在显著的低甲基化（p<0.01）。体外实验证实，在人淋巴母细胞（RPMI 1788）中短期高剂量（10 - 100μM）和长期低剂量（0.5 - 1μM）的亚砷酸盐处理会导致这些基因的启动子低甲基化，这与它们的mRNA表达增加一致。此外，暴露的新生儿和儿童尿中8-硝基鸟嘌呤水平分别显著升高（p<0.01），为1.4倍和1.8倍。指甲中的砷积累与这些基因的低甲基化呈负相关，与8-硝基鸟嘌呤水平呈正相关。这些结果表明，生命早期接触砷会导致COX2、EGR1和SOCS3低甲基化，增加这些基因的mRNA表达，并增加8-硝基鸟嘌呤的形成。这些影响可能与砷诱导的炎症和生命后期癌症发展的机制有关。
