Nicotine influence on cerebrovascular and neurocognitive function with <i>in utero</i> electronic cigarette exposure

Emerging studies find arteriolar dysfunction in offspring with in utero electronic-cigarette (Ecig) exposure, but the long-term effects on offspring's cerebrovascular and neurocognitive health are poorly understood. Ecigs provides a unique opportunity to directly evaluate the contributions of inhaled nicotine from the vehicle e-liquid, which was not possible with cigarettes. Moreover, many Ecigs have variable power settings, which can alter aerosol toxicity. We hypothesize that maternal vaping at different wattages will have variable effects on offspring cerebrovascular function and would be independent of nicotine. We used time-mated female Sprague-Dawley rats with Ecig exposure from gestation day (GD)2 to 21. We studied male and female offspring at 1, 3, 6 and 12 months of age, and found the magnitude of middle cerebral artery (MCA) impairment in offspring was greater at 30 W vs. 5 W, but that both conditions significantly impaired MCA function. Vascular dysfunction was evident with or without nicotine in the e-liquid, but nicotine exposure (50 mg/ml e-liquid) resulted in short-term memory deficits, evidence of neuronal damage, and increased astrocyte interaction with endothelial cells in 6- and 12-month-old offspring. We also observed altered expression of clock genes and antioxidant signalling pathways, along with a decrease in sirtuin-1 expression, a decreased ratio of beta-amyloid (Aβ) 42/40 protein expression, and an increase in NADPH oxidase 1, which are consistent with redox imbalance, neuroinflammation and advancing cellular senescence. These preclinical data provide evidence suggesting that in utero exposure to Ecigs from maternal vaping adversely affects the brain health of offspring in their adult life and that neurocognitive outcomes are worsened with exposure to nicotine. KEY POINTS: Cerebrovascular impairment in offspring with maternal electronic-cigarette (Ecig) exposure is dependent on the wattage of the Ecig device and not the presence of nicotine. While nicotine is not implicated in the aetiology of cerebrovascular impairment, it did contribute to neurocognitive deficits and the severity of neuronal damage. Offspring with Ecig exposure during pregnancy, regardless of wattage or nicotine presence, had decreased sirtuin 1 (SIRT1), elevated NADPH oxidase 1, and exhibited Alzheimer's like pathology. Rodent offspring with in utero exposure to Ecig exhibit long-lasting cerebrovascular and neurocognitive dysfunction into adult life, indicating the vaping during pregnancy is not harmless.