Maternal use of electronic cigarettes and impact on offspring: a double-hit model.

Endothelial dysfunction is a predictor for cardiovascular disease. Preclinical data suggest longstanding cardiovascular and cerebrovascular dysfunction occurs in offspring with perinatal electronic cigarette (Ecig) exposure. Furthermore, direct use of Ecigs increases reactive oxygen species and impairs cerebrovascular function, but the combined effect of direct use in offspring with a history of perinatal exposure (i.e. double-hit condition) is not known. We tested the hypothesis that offspring with double-hit Ecig exposure will lead to greater cerebrovascular and neurocognitive dysfunction compared with in utero exposure only. Male and female offspring were obtained from time-mated Sprague Dawley female rats exposed to air ( = 5 dams) or Ecig exposed ( = 5 dams) and studied at either 3 or 6 mo after birth. Ecig exposure for double-hit offspring began at 1-mo before the timepoints and lasted 4 wk (5 days/wk with 90-min exposure/day). We found double-hit offspring (Ecig:Ecig = exposure dam:offspring) sustained further blunted middle cerebral artery (MCA) reactivity, increased severity of neuronal damage, and increased interactions of astrocytes and endothelial cells compared with offspring with maternal (Ecig:Air) or direct (Air:Ecig) exposure only. Circulating extracellular vesicles (EVs) were increased, whereas sirtuin 1 (SIRT1) was decreased, in all Ecig-exposed groups compared with controls (Air:Air), with Ecig:Ecig group showing the greatest respective change for each. Electron paramagnetic resonance (EPR) spectroscopy revealed oxidative stress was the highest in the plasma of Ecig:Ecig group ( < 0.05) than the other groups. These data show that a double-hit exposure in adolescent or adult offspring results in a greater decline in cerebrovascular function, biomarkers of neuronal dysfunction, and increased circulation of EVs compared with a single-hit exposure. These data add to the growing body of literature demonstrating that electronic cigarette (Ecig) use during pregnancy (even without nicotine) is not safe, and primes offspring to have worse cardiovascular health outcomes in early and adult life. A key finding from this work is that a second insult from direct vaping in offspring with prior in utero exposure induces greater vascular dysfunction, increased oxidative stress, and shows evidence of neuronal dysfunction compared with either direct- or maternal-only exposure.