Novel Approaches for Gestational E-Cigarette Vaping-Induced Neuronal Adaptations

About This Grant

PROJECT SUMMARY Electronic cigarette (e-cig) use during pregnancy has become a major health concern in recent years and is perpetuated by the perception that e-cigs are less harmful than traditional combustible cigarettes. Recent estimates show 7% of women use e-cigs in pregnancy, and 45% view them as less harmful and may help them quit or reduce combustible cigarettes in pregnancy. An extensive knowledge gap persists regarding their health impact when aerosolized, especially during pregnancy. Using our well-established pregnant rat model, we obtained preliminary data utilizing a state-of-the-art e-cig system with a commercial e-cig unit and atomizer that offered a translational inhalation delivery and generated vapor profiles directly comparable to human vaping. Our preliminary data demonstrated that a cardinal outcome of e-cig use was a significant fetal and neonatal growth deficit. Concomitant with growth restriction, our exciting preliminary data provides direct evidence that e-cig vaping significantly alters developmental brain hippocampal mTOR system. As a critical node, mTOR regulates essential brain metabolic activities, including protein synthesis and autophagy. Interestingly, our new preliminary data indicate that these mTORC1 and mTORC2 signaling adaptations were accompanied by altered fetal hippocampal dendritic morphology and hippocampal-dependent long term memory deficits. We subsequently generated critical preliminary data that demonstrated that optimizing mTORC1/C2 activity via in vivo administration of the 3rd gen mTORC1/C2 blocker (RapaLink-1) concomitant with e-cig aerosol exposure reversed specific e-cig-induced fetal developmental phenotypes. Thus, we hypothesize that the mTOR system plays a central role in e-cig induced alterations in fetal brain hippocampal adaptations. To test this hypothesis, we will (1) seek to answer fundamental questions about the impact of e-cig aerosol exposure on hippocampal mTORC1/C2 system using novel mechanistic in vivo studies, (2) assess the role of mTOR in e-cig-induced fetal brain hippocampal developmental adaptations using morphometric, stereological and behavioral approaches, and (3) identify e-cig-induced protein signal propagation pathways leading to activation of mTOR and signal propagation downstream of mTORC1/C2 utilizing mass spectrometry- based phosphoproteomics followed by stochastic optimization and reinforcement learning algorithms. We will then compare and interpret the signature pathways impacted by e-cig vaping with and without mTOR blocker using machine learning models. Upon successful completion of these aims, we will have comprehensively characterized the mTOR signaling cascade as it transduces cues from e-cig vaping into molecular action, enabling the identification of potential strategies to mitigate e-cig-induced neurodevelopmental deficits in the hippocampus. The proposed studies develop a strong etiological framework and directly address a “major research area” of developmental impacts under Theme One of NIEHS Strategic Plan 2018-2023, titled “Advancing Environmental Health Sciences”.