Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD, USA.
Division of Toxicology and Human Health Sciences, Agency for Toxic Substances and Disease Registry, Atlanta, GA, USA.
J Toxicol Environ Health A. 2020 Apr 2;83(7):269-278. doi: 10.1080/15287394.2020.1749919. Epub 2020 Apr 14.
Previously an increased risk for monoclonal gammopathy of undetermined significance (MGUS), a precursor of multiple myeloma (MM), was reported among Vietnam veterans exposed to Agent Orange and its contaminant 2,3,7,8-tetrachlorodibenzo--dioxin (TCDD). Dysregulated expression of certain microRNAs (miRNAs) was demonstrated in MGUS and MM. Given the important role of miRNAs in cellular homeostasis, the aim of this study was to determine if there was an association between serum levels of selected miRNAs and TCDD in 47 MGUS cases identified in our previous investigation using serum specimens and exposure data archived by the Air Force Health Study (AFHS). A total of 13 miRNA levels (let-7a, let-7i, miR-16, miR-20a, miR-21, miR-34a, miR-106b, miR-146a, miR-181a, miR-192, miR-205, miR-335, and miR-361) was measured in serum stored during the 2002 AFHS follow-up and the relationship to lipid-adjusted serum TCDD levels in 1987 was determined. miR-34a showed the strongest relationship with TCDD; after age-adjustment, this positive association was more pronounced. In contrast, the other 12 miRNAs displayed absolute values of age adjusted coefficient estimates below 1.16 and non-significant -values. The observed strong positive association between high body burdens of TCDD and miR-34a, a tumor suppressor regulated by p53, in this MGUS population warrants clarification of the TCDD-miR-34a relationship and its role in the pathogenesis of MGUS and risk for MM.
先前有研究报道，接触过橙剂及其污染物 2,3,7,8-四氯二苯并对二恶英（TCDD）的越战老兵，其发生意义未明的单克隆丙种球蛋白病（MGUS）——多发性骨髓瘤（MM）的一种前期病症——的风险增加。在 MGUS 和 MM 中已经证明某些 microRNAs（miRNAs）的表达失调。鉴于 miRNAs 在细胞内稳态中的重要作用，本研究旨在确定在我们之前的研究中，使用血清标本和空军健康研究（AFHS）存档的暴露数据，在 47 例 MGUS 病例中，是否存在选定的 miRNA 与 TCDD 之间的血清水平关联。在 2002 年 AFHS 随访期间储存的血清中测量了总共 13 种 miRNA 水平（let-7a、let-7i、miR-16、miR-20a、miR-21、miR-34a、miR-106b、miR-146a、miR-181a、miR-192、miR-205、miR-335 和 miR-361），并确定了它们与 1987 年脂质调整后的血清 TCDD 水平的关系。miR-34a 与 TCDD 呈最强相关性；在年龄调整后，这种正相关更为明显。相比之下，其他 12 种 miRNA 的年龄调整系数估计值绝对值低于 1.16，且无显著-值。在这种 MGUS 人群中，TCDD 高负荷与 miR-34a（一种受 p53 调控的肿瘤抑制因子）之间的强正相关，需要进一步阐明 TCDD-miR-34a 之间的关系及其在 MGUS 发病机制和 MM 风险中的作用。
