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Systemic and Vascular Alterations in Rat models Exposed to Libby Amphibole
Citation:
KODAVANTI, U. P., W. Winnik, D. Andrews, M. SCHLADWEILER, J. Shannahan, R. Thomas, S. H. GAVETT, D. Carlin, J. Cyphert, AND O. Alzate. Systemic and Vascular Alterations in Rat models Exposed to Libby Amphibole. Presented at 2011 ASTM Johnson Conference , Burlington, VT, July 25 - 29, 2011.
Impact/Purpose:
This abstract examined the effects of Libby amphibole (LA) pulmonary exposure on the circulating biomarkers and thrombosis in several studies. The data show that while LA exposure is associated with latent decreases in platelets and coagulation, there are numerous biomarkers of chronic diseases that are increased shortly after exposure, The acute biomarker changes of LA exposure are largely reversed after a recovered at later time points.
Description:
Acute pulmonary injury and chronic diseases can impact systemic vasculature and extra pulmonary organ systems due to the hemodynamic properties of the pulmonary capillary network that allows mediators to release into the circulation. Exposure to Libby amphibole (LA) is associated with increased human cardiovascular mortality and autoimmune disease (Larson TC, et aI., J Occup Environ Med. 52(5):555-60, 2010; Noonan CW, et aI., Environ Health Perspect. 114(8):1243-7,2006). This toxicology project was aimed at understanding the systemic and vascular impact, including coagulation abnormalities of LA pulmonary exposure in healthy (Wistar Kyoto, WKY; and F344) and cardiovascular compromised (CVD) rat models (spontaneously hypertensive, SH; and SH heart failure, SHHF). An ancillary goal of this project was to identify novel epidemiologically-relevant biomarkers specific to LA exposure in rats using Meso Scale Discovery Technologies and proteomic profiling of plasma proteins. The mRNA biomarkers of oxidative stress, vascular thrombosis and contractile abnormalities in rat aortas were also examined. We have found that at 3 months after a single or multiple intratracheal LA exposure there is a decrease in blood coagulability that is associated with decreases in circulating blood platelets in WKY and F344 rats. Changes in circulating markers of blood coagulation and lymphocytes are associated with transcriptional upregulation of markers of oxidative stress, vasoconstriction and microvascular thrombosis in WKY rats. These effects are likely mediated by increased LOX-1 expression in thoracic aorta. F344 rats showed lower sensitivity to aortic changes. However, the normal decline in circulating lymphocytes with age was further exacerbated in F344 rats exposed to LA. Several markers of acute and chronic diseases were analyzed in serum samples of healthy and CVD rat models with varying exposure scenarios. These markers included mesothelin, alpha-2 macroglobulin, acid glycoprotein, lipocalin, adiponectin, osteopontin, insulin, leptin and HMGB-1. LA exposure in healthy rats caused marked and acute increases in several of these markers (alpha-2 macroglobulin, acid glycoprotein, lipocalin, osteopontin) but no change in mesothelin was noted in any strains or exposure conditions. These LA-induced changes were apparent only in healthy rats while SH and SHHF rats already demonstrated high levels at baseline consistent with their underlying disease. Proteomic profiling of WKY serum proteins was done at 1-day or 4 weeks after 4 weekly instillations of LA. No oxidative protein modifications (consistent with lack of aortic RAGE expression) were noted in LA-exposed rats, but marked LA exposure-related changes occurred in the levels of several serum protein biomarkers at 1-day time point. Quantitative Intact Proteomics revealed increases in circulating alpha-1macropglobulin, alpha-1-inhibitor 3, afamin, ceruloplasmin, T-kininogen 1, complement component 9, serine protease inhibitor A3K, Alpha-2-HS-glycoprotein, vitamin D binding protein, fetuin-B, factor Xheavy chain, and serum amyloid P, but surprisingly heptoglobin beta chain and apolipoprotein E levels were reduced. The levels of these proteins were largely reversed to control after 1 month recovery following the last instillation. These data collectively show that while latent coagulative and prothrombotic effects of LA on vasculature occur over a 3-month period, there are remarkable changes in circulating biomarkers of chronic diseases that occur very early following LA exposure, which might have lasting impact on systemic disease development since these biomarkers are increased in CVD models at baseline without LA exposure. (This abstract does not reflect US EPA policy).