Tobacco smoking is a major public health threat and is associated with cardiovascular disease (CVD)-related morbidity and mortality. Being the single most preventable risk factor for CVD, a trend towards tobacco harm reduction started years ago. Thus, while tobacco usage has declined, that of Electronic Delivery Systems (ENDs) experienced widespread popularity, especially among pregnant women and women of childbearing age. This is alarming as pregnant women view them as safe(r) compared to cigarettes; which we now know not to be evidence-based. Thus, it is paramount to establish the health impact/CV safety of prenatal exposure to ENDs. This was addressed by employing a well-established ENDs inhalation system and performing whole-body exposures of 150 puffs/day on C57/BL6 mice, under prenatal/
in uteroexperimental settings throughout the gestational period. Our results show that platelets from the offspring of prenatally ENDs-exposed mice are hyperactive with enhanced: aggregation, dense and granule secretion, activation of the IIb3 integrin, clot retraction and phosphatidylserine expression, when compared to clean air exposed platelets, which suggests a prothrombotic state. Moreover, we observed that ENDs-exposed platelets are resistant to the inhibitory effects of prostacyclin, and that they exhibit increased activation of Akt and ERK. Furthermore, and consistent with these findings, ENDs were also found to shorten the thrombosis occlusion and bleeding times, relative to controls. Interestingly, we also observed alternations in the platelet miRNome, transcriptome and enrichment of platelet activation pathways, as follows: 1) miR-221 is differentially expressed, unlike mirR-146b; 2) Itg3, Src, and Rap2b transcripts are upregulated; and 3) oxidative phosphorylation, and platelet activation pathways are enriched. Taken together, our data demonstrate for the first time that prenatal exposure to ENDs modulates platelet reactivity and increase the risk of thrombogenesis, in part via impacting the platelet epigenetics and genetics. Thus, the negative health consequences of ENDs should not be underestimated, and warrant further investigation. These findings should also guide policy development for regulating exposure to ENDs.