Serum microRNA profiles among dioxin exposed veterans with monoclonal gammopathy of undetermined significance

ABSTRACT

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-p-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 p-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.

KEYWORDS:

• 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD)
• microRNA
• miR-34a
• monoclonal gammopathy of undetermined significance (MGUS)
• dioxin

Acknowledgments

The authors would like to acknowledge the contribution of the Medical Follow-up Agency of the Institute of Medicine, which prepared the AFHS data used throughout this article. This study was supported by the Intramural Program at the Agency for Toxic Substances and Disease Registry, the Intramural Program at the National Cancer Institute and the Clinical Center of the National Institutes of Health, and the Air Force Health Study Assets Research Program at the Institute of Medicine through an award to the CDC Foundation. Dr. Landgren was supported by the Memorial Sloan Kettering Core Grant (P30 CA008748). Dr. Michalek was supported by the UT Health Mays Cancer Center Core Grant (P30 CA054174). No relevant conflict of interest exists for any of the authors. All authors contributed to the manuscript writing. KC, OL, GM, JM, YS, RV, and WW contributed to the study design. EB, KC, LS, and WW oversaw and performed laboratory testing. KC, YS, and WW oversaw the overall conduct of data collection. BC, NK, JM, YS, and CW performed final data analysis. YS and WW had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the Agency for Toxic Substances and Disease Registry, Centers for Disease Control and Prevention, National Institutes of Health, and Food and Drug Administration.

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Funding

This work was supported by the Agency for Toxic Substances and Disease Registry; Memorial Sloan-Kettering Cancer Center [P30 CA008748]; NIH Clinical Center; National Cancer Institute; the Air Force Health Study Assets Research Program at the Institute of Medicine through an award to the CDC Foundation; University of Texas Health Science Center at San Antonio [P30 CA054174].