In Utero Third-Hand Smoke Impact on Platelet Function and Thrombogenesis

虽然子宫内暴露于一手烟（FHS）和二手烟（SHS） 血栓性疾病的发病机制已有充分记录，新“发现”的第三手药物的贡献 这种疾病过程中的形式（THS）仍然未知。这部分源于：(1) 最初缺乏知识 THS 的存在； (2) 对其“真正的”负面健康后果缺乏认识； (3) 缺乏THS暴露 模仿现实世界场景的动物模型； (4) 缺乏关于这种对血小板影响的研究 生物学。本申请提出了解决基本、机械、表观遗传和 新“实现”的吸烟形式对健康的不利影响的临床相关转化方面， THS，在子宫内以及在血栓性疾病和血小板生物学以及性别的背景下。研究还 提议以类似的方式研究 THS 对血小板和相关的影响的毒物 疾病。鉴于 THS 的危险性，这些研究具有至关重要的意义。 被低估/未被重视，尽管有证据表明它比二手烟的毒性更大，尤其是对弱势群体 儿童和少数民族（例如西班牙裔美国人）等人群。我们提案的目标是： 目标 1. 研究子宫内 THS 暴露对血小板依赖性疾病的影响。在子宫内时 研究发现接触众所周知的 FHS 和 SHS 会导致心肌梗塞的发生， 子宫内接触 THS 是否也与血栓性疾病风险增加相关，尚待确定 确定。为了解决这个问题，我们将确定子宫内 THS 暴露对正常胎儿的影响 止血、血小板计数以及凝血因子和其他血栓形成介质，在剂量和时间上 依赖时尚。后续研究将检验子宫内 THS 是否参与发育 血栓性疾病。 目标 2. 研究子宫内 THS 暴露调节血小板功能的机制。我们的 最近发表的研究结果首次表明，成人 THS 暴露可调节生理止血， 并通过增强血小板活化增加血栓形成的风险。然而，是否在子宫内 THS 是 与类似的作用相关，如果是这样，那么它调节血小板功能的机制仍有待进一步研究。 调查了。因此，本节提出的实验的总体目标是确定重要性， 子宫内 THS 暴露对各种血小板功能反应影响的毒物和机制， 血小板表观遗传学，其对其他血细胞（例如白细胞）和血栓形成“标记物”的影响，及其 主要暴露途径。 总的来说，这些实验将为我们理解 子宫内 THS 暴露对血小板活化和心血管人类健康的影响，其 表观遗传学，以及 THS 发挥作用的机制和毒物。

While the involvement of in utero exposure to first-hand smoke (FHS) and second-hand smoke (SHS) in the pathogenesis of thrombotic diseases is well documented, the contribution of the newly “discovered” third-hand form (THS) in such disease processes remains unknown. This derives, in part, from: (1) initial lack of knowedlge of THS existence; (2) lack of appreciation for its “real” negative health consequences; (3) lack of a THS-exosure animal model that mimics real-world scenarios; and (4) lack of studies regarding such consequences on platelet biology. The present application proposes experiments that address fundamental, mechanistic, epigenetic and clinically-relevant translational aspects of the adverse-health effects of the newly “realized” form of smoking, THS, in utero and in the context of thrombotic disease and platelet biology, and gender. Studies are also proposed to investigate, in a similar fashion, the toxicants that underlie THS effects on platelets and associated diseases. These studies are of paramount significance given that the dangers of THS are underestimated/unappreciated, despite evidence that it is more toxic than SHS, especially in vulnerable populations such as children and minorities (e.g., Hispanic Americans). The Aims of our proposal are: Aim 1. Investigate the impact of in utero THS-exposure on platelet-dependent diseases. While in utero exposure to the well-known FHS and SHS was found to contribute to the genesis of myocardial infarctions, whether in utero exposure to THS is also associated with an increased risk of thrombotic disorders, is yet to be determined. To address this issue, we will determine the ramifications of in utero THS exposure on normal hemostasis, platelet counts, as well as on clotting factors and other thrombosis mediators, in a dose-, and time- dependent fashion. Subsequent studies will examine whether in utero THS participates in the development of thrombotic disorders. Aim 2. Investigate the mechanism by which in utero THS-exposure modulates platelet function. Our recently published findings show, for the first time, that adult THS exposure modulates physiological hemostasis, and increases the risk of thrombogenesis, via enhancing platelet activation. However, whether in utero THS is associated with similar effects, and if so, the mechanism by which it modulates platelet function remain to be investigated. Thus, the overall goal of the experiments proposed in this section is to determine the significance, toxicants and mechanism of the impact of in utero THS-exposure on various platelet functional responses, platelet epigenetics, its effect on other blood cells (e.g., leukocytes) and thrombosis “markers”, as well as its major route of exposure. Collectively, these experiments will make significant contributions to our understanding of the consequences of in utero THS exposure on platelet activation and cardiovascular human health, its epigenetics, and the mechanism and toxicants by which THS exerts its effects.