Boonma Tiwapan, Navasumrit Panida, Parnlob Varabhorn, Waraprasit Somchamai, Ruchirawat Mathuros
Laboratory of Environmental Toxicology, Chulabhorn Research Institute, Bangkok, 10210, Thailand; Chulabhorn Graduate Institute, Bangkok, 10210, Thailand; Center of Excellence on Environmental Health and Toxicology (EHT), OPS, MHESI, Thailand.
Laboratory of Environmental Toxicology, Chulabhorn Research Institute, Bangkok, 10210, Thailand.
Chem Biol Interact. 2022 Jul 1;361:109965. doi: 10.1016/j.cbi.2022.109965. Epub 2022 Apr 28.
Growing evidence suggests that arsenic exposure increases the risk of developing a variety of inflammation-associated chronic diseases and cancers. Our previous study revealed that increased transcript levels of inflammatory genes (i.e. COX2, EGR1, and SOCS3) coupled with hypomethylation of the promoter regions of these genes was associated with increased DNA damage in arsenic-exposed newborns through their early childhood. This study further investigated the ability of the methyl group donors, S-adenosyl methionine (SAM) and folic acid, to prevent promoter hypomethylation that results in decreased mRNA expression of inflammatory genes (COX2, EGR1, and SOCS3), and a reduction in arsenic-induced oxidative and nitrative DNA damage in human lymphoblast cells. Pretreatment with SAM (100 nM, 2 days) increased promoter methylation, reduced the mRNA levels of these inflammatory genes, and decreased both 8-hydroxydeoxyguanosine (8-OHdG) and 8-nitroguanine levels by 50% (p < 0.01) in arsenic-treated cells. In addition, pretreatment with folic acid (10 μM, 7 days), a micronutrient, led to a significant increase in promoter methylation associated with the reduction in mRNA levels of these inflammatory genes and decreased levels of 8-OHdG and 8-nitroguanine by 80% and 90% (p < 0.01), respectively, compared with arsenic treatment alone. Moreover, pretreatments with these methyl group donors increased mRNA expression of an antioxidant defense regulator (Nrf2) and DNA repair genes (hOGG1, XRCC1, and PARP1). This study shows for the first time that SAM or folic acid supplementation can prevent arsenic-induced oxidative and nitrative DNA damage. This suggests the potential use of SAM or folic acid for prevention of arsenic toxicity in human populations.
越来越多的证据表明，接触砷会增加患各种炎症相关慢性病和癌症的风险。我们之前的研究表明，炎症基因（即COX2、EGR1和SOCS3）转录水平的增加，以及这些基因启动子区域的低甲基化，与砷暴露新生儿从幼儿期开始DNA损伤增加有关。本研究进一步探讨了甲基供体S-腺苷甲硫氨酸（SAM）和叶酸预防启动子低甲基化的能力，启动子低甲基化会导致炎症基因（COX2、EGR1和SOCS3）的mRNA表达降低，并减少人淋巴母细胞中砷诱导的氧化和硝化DNA损伤。用SAM（100 nM，2天）预处理可增加启动子甲基化，降低这些炎症基因的mRNA水平，并使砷处理细胞中的8-羟基脱氧鸟苷（8-OHdG）和8-硝基鸟嘌呤水平均降低50%（p<0.01）。此外，用微量营养素叶酸（10 μM，7天）预处理导致启动子甲基化显著增加，同时这些炎症基因的mRNA水平降低，与单独砷处理相比，8-OHdG和8-硝基鸟嘌呤水平分别降低80%和90%（p<0.01）。此外，用这些甲基供体预处理可增加抗氧化防御调节因子（Nrf2）和DNA修复基因（hOGG1、XRCC1和PARP1）的mRNA表达。本研究首次表明，补充SAM或叶酸可以预防砷诱导的氧化和硝化DNA损伤。这表明SAM或叶酸在预防人群砷中毒方面具有潜在用途。
