Chronic health sequelae of dioxin exposure

About This Grant

Significance to VA: Type 2 diabetes (T2D) is a chronic, adult-onset metabolic disease with no cure to date. Alarmingly 1 in 4 (25%) Veterans are diabetic, significantly higher percent compared to civilians. Diabetes is the leading cause of renal and cardiovascular diseases, blindness, and amputations in Veterans. The annual mortality rate of Veterans with diabetes is nearly twice the rate compared to Veterans without diabetes (VA Fact Sheet 2019). The predominant risk factors for T2D advent in Veterans are military exposures and PTSD. Relevance to VA Military Exposures Research Program Mission: Vietnam War (VW) Veterans were exposed to Agent Orange (AO). Evaluating the effects of military exposures, it is established that tetra- chloro-dibenzo-p-dioxin (TCDD), contained in AO caused T2D pathology. T2D is a presumptive condition in VW Veterans. In the recent Global War on Terrorism (GWOT) conflicts, 85% of military personnel were exposed to open burn pits which emitted large amounts of TCDD. Measuring TCDD levels in the blood involves a long, cumbersome procedure requiring specific equipment and highly trained personnel, thereby deterring routine evaluation of TCDD exposures. Further, little is known about the chronic metabolic outcomes, specifically T2D, in GWOT Veterans. There is an immediate and dire need to identify Veterans with increased susceptibility to advent of T2D due to service-related TCDD exposures, independent of their genetic makeup, aging, or obesity. The proposal fills this gap with our overarching goal to establish a rapid, blood genetic test to identify Veterans vulnerable to chronic health sequelae of T2D, years after TCDD exposures. Innovation and Impact: We have established that low GAS5 levels are causal to T2D (US Patent Nos. 10,724,097; 11,214,835, 11,278,521. All with VA-asserted rights). The data demonstrates that GAS5, a noncoding regulatory RNA, is the genetic target of TCDD in humans, which unknown thus far. The project will establish GAS5 as a surrogate biomarker of TCDD-exposure related advent of T2D in Veterans. Importantly, to integrate into clinic, we developed a rapid blood droplet test for reproducible, consistent measurements of GAS5 levels requiring minimal technical expertise. Successful completion of the proposal will establish GAS5 as a surrogate biomarker of TCDD-exposure related advent of T2D in Veterans. This determination will significantly reduce the advent of T2D as the most preventable cause of death in US Veterans. Specific Aims: Our compelling data shows TCDD decreases GAS5. We hypothesize that low GAS5 levels in the blood correlate with past military associated TCDD exposures and the advent of T2D in Veterans. Specific Aim 1: Longitudinal study evaluating the correlation of blood GAS5 with TCDD levels in Veterans. Specific Aim 2: Determine the TCDD-regulated molecular mechanisms affecting GAS5 in human adipocytes. Methodology: For SA1, we will leverage our existing JAHVA Research Biospecimen Repository and obtain de-identified blood samples (IRB determination: Not Human Subject Research). The levels of TCDD, GAS5 will be measured and correlated to T2D by a sample-blinded biostatistician. For SA2, we will use human adipose stem cells differentiated to adipocytes. We will elucidate the underlying molecular and cellular mechanisms to understand TCDD-regulation of GAS5 levels, thereby providing unequivocable support complementary to SA1. NPC86, a therapeutic which increases GAS5, will be used as a molecular tool. Path to Translation/Implementation: We have developed a minimally invasive, minimal technical expertise requirement and ease-of-use, rapid (2-hour turn around) blood droplet test to measure GAS5 levels that can be easily incorporated into clinic. The results can be evaluated along with the Veterans’ TCDD exposure history to implement a personalized, time-sensitive treatment plan to prevent the advent of T2D.