The Effects of Prenatal Thirdhand E-cigarette Exposure on Platelets

点击翻译按钮获取中文摘要

While smoking has been on the decline, e-cigarette usage has been on the rise; especially in vulnerable populations. Furthermore, even though the contribution of in utero third-hand smoke (THS) and e-cigarettes to the pathogenesis of thrombotic diseases have recently been documented, the involvement of in utero third-hand e-cigarettes (IUTHEC) in such disease processes remains unknown. Consequently, the present application outlines studies that address fundamental, mechanistic, and clinically-relevant translational aspects of the adverse-health effects of IUTHEC, in the context of thrombotic disease and platelet biology, and in a device-, e- liquid-, and sex-specific manner. These studies are of paramount significance given the “perceived safety” of e- cigarettes, and will be conducted using a novel/new IUTHEC exposure model. The Aims of this proposal are: Aim 1. Investigate the impact of IUTHEC exposure on platelet-dependent disease states. While there is compelling evidence that e-cigarettes and in utero THS do exert negative health effects, the impact of IUTHEC on platelet-dependent diseases is still unknown. To address this issue, the consequences of IUTHEC exposure on normal hemostasis and platelet counts will be determined. Subsequent studies will examine whether IUTHEC participates in the development of thrombosis-based disease. Finally, the effects of IUTHEC on plasma “markers” of thrombosis will also be determined. Notably, experiments will be designed in a manner that addresses the role of the device, and e-liquid in mediating the “platelet”-dependent negative effects of IUTHEC. Furthermore, the preliminary data does show, for the first time, that IUTHEC, in utero THS and e-cigarettes increase the risk of thrombotic cardiovascular disease. Aim 2. Investigate the mechanism by which IUTHEC exposure modulates platelet function. Even though published data indicate that in utero THS and e-cigarettes modulate platelet activation, whether IUTHEC produces similar effects (i.e., the mechanism by which it modulates platelet function) remains to be investigated. Thus, the overall goal of the mechanistic experiments proposed in this section is to determine the impact of IUTHEC exposure on the various platelet functional responses (e.g., GPIIb-IIIa activation), thromboxane A2 levels, biochemical “markers” of platelet activation, as well as assess the contribution of other blood cells (e.g., neutrophils) and alterations in the platelet epigenetics to the IUTHEC phenotype. Collectively, these experiments will make significant contributions to the understanding of the consequences of IUTHEC/e-cigarettes on platelet activation and cardiovascular human health, and the mechanism by/through which it exerts these effects, in a device-, e-liquid-, and sex-specific manner.