Thursday, November 21, 2024
11/21/2024
Each puff of an e-cigarette generates micromolar amounts dihydroxyacetone (DHA) from the combustion of propylene glycol and glycerol. Up to 40-55% of e-liquid content is converted to DHA in each puff from an e- cigarette, making DHA a high-volume component found in all e-cigarette vapors, which the vaper inhales with each puff of the e-cigarette. DHA is approved for external use as a sunless tanning agent, but serious concerns have been raised about inhalation exposures through spray tanning and now e-cigarette use. We have shown that DHA is genotoxic, cytotoxic, and induces mitochondrial dysfunction in skin and kidney cells, but the effects of inhalation exposures to DHA are currently unknown. The long-term goal of the proposal is the identification and validation of markers for cellular and metabolic stress induced by DHA exposure that can be examined in tissues from vapers to understand the consequences of repeated inhalation exposures to DHA. The objective of this proposal is to address the gap in existing studies, which have only focused on skin models, by examining the exposure effects of DHA at both acute and chronic doses in pulmonary and cardiovascular cells. Our central hypothesis is that exposure to DHA alters metabolic pathways, promotes oxidative stress, disrupts Ca2+ homeostasis, and leads to mitochondrial dysfunction. The rationale for this work is that DHA exposures to the lung and cardiovascular system allow direct absorption of DHA into cells. DHA-induced changes in metabolism and mitochondrial function would compromise overall cellular function, leading to disease. Three specific aims will test the central hypothesis: 1) DHA incorporation into metabolic pathways alters glycolysis and induces glycosylation protein damage; 2) DHA exposure alters NAD(P)H pools inducing oxidative stress, and 3) DHA exposure alters cytosolic Ca2+ levels and disrupts mitochondrial function. The first aim will test the sub-hypothesis that DHA alters metabolic pathways by tracing DHA metabolism using isotopologues of DHA and identifying metabolite disequilibrium. The second aim will test the sub-hypothesis that an excess of DHA changes cofactor pools and induces oxidative stress. The third aim will test the sub-hypothesis that DHA alters Ca2+ signaling to induce mitochondrial dysfunction, in addition to causing metabolic stress and oxidation-reduction imbalance. The study is innovative because it extends beyond the genotoxic and cytotoxic characterization of DHA to measure DHA’s ability to reprogram pulmonary and cardiovascular cells metabolically. The research is significant because e-cigarette users are chronically exposed to DHA, which will directly impact pulmonary and cardiovascular cell homeostasis and cause severe declines in cellular function or even induce cell death. This work will establish essential markers for DHA exposure to allow future epidemiological work to associate DHA exposure to disease.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
