E-Cigarette Aerosols and the Brain: Behavioral and Neuroinflammatory Changes in Prenatally Exposed Adult Mice

Abstract

Growing evidence supports various health risks for e-cigarette users1 and, possibly, for bystanders.2 The developing fetus constitutes another, especially vulnerable group that may experience harm from vaping during pregnancy.3 Many users perceive e-cigarettes as a safer alternative to combustible cigarettes during pregnancy,4 and in surveys published between 2007 and 2017, up to 15% of pregnant women in the United States reported using e-cigarettes.4^,5 However, a recent study in Environmental Health Perspectives6 adds to the evidence that e-cigarettes are not risk free.

The new study showed that, in a mouse model, the well-known neurodevelopmental effects of prenatal nicotine exposure occur with e-cigarette aerosols as well; moreover, these effects persist into adulthood. In addition, maternal exposure to e-liquid solvents alone, without nicotine, was associated with reduced cognitive performance and a potentially impaired immune system in the adult offspring.

Vaping does not expose users to all the toxicants produced by tobacco combustion. However, it presents its own unique exposures—such as the solvents in e-liquid—and potential health risks.18 Image: © zef art/Shutterstock.

The study was led by Judith Zelikoff, a professor of environmental medicine at New York University School of Medicine, and Jared Schwartzer, an associate professor of psychology and education at Mount Holyoke College in South Hadley, Massachusetts. The investigators exposed three groups of pregnant mice to whole-body aerosols—meaning the rodents moved freely about an aerosol-filled chamber—for 3 hours per day throughout gestation. The three exposure types were filtered air (control) and aerosols produced by a $50/50$ mixture of solvents (propylene glycol and vegetable glycerol, $\mathrm{P}\mathrm{G}/\mathrm{V}\mathrm{G}$) without nicotine or with $16\mathrm{m}\mathrm{g}/\mathrm{m}\mathrm{L}$ nicotine. Starting at 8 weeks of age (adulthood for mice), male and female offspring of the exposed dams completed a series of neurobehavioral tasks, spaced one week apart. After 2–3 weeks, the researchers measured levels of four cytokines in four distinct brain regions.

Developmental nicotine exposure resulted in increased locomotor activity of the adult offspring in the elevated plus maze. This nicotine-induced hyperactivity is consistent with results for combustible cigarettes, based on animal models7^,8^,9^,10 and human studies.11^,12

Nicotine also reduced interferon-gamma ($\text{IFN}\mathrm{\gamma }$) levels in some brain regions. Moderate correlations between $\text{IFN}\mathrm{\gamma }$ levels and performance in the forced swim task suggested potentially altered stress-coping mechanisms, according to the researchers. Exposure to $\mathrm{P}\mathrm{G}/\mathrm{V}\mathrm{G}$ aerosol, with or without nicotine, led to similarly reduced memory performance in the novel object recognition task.

For Schwartzer, the results of maternal exposure to the $\mathrm{P}\mathrm{G}/\mathrm{V}\mathrm{G}$ solvent aerosol alone were especially noteworthy. “We observed a twofold increase in levels of the proinflammatory cytokine IL-6 in the adult offspring’s cerebellum, compared to controls,” he says. “This suggests that prenatal exposure to the e-liquid vehicle may have long-lasting adverse consequences for the adult neuroimmune system.”

Catherine Gorrie is an associate professor of neuroscience at the University of Technology Sydney, Australia, who found broadly similar results in her own research.13^,14 “I think the most striking findings are the chronic inflammatory changes that are completely attributable to the base fluid,” says Gorrie, who was not involved in the new study. “Although the solvents have regulatory approval for use in food and cosmetic products, heating and inhaling them seems to produce effects on the developing brain that persist into adulthood.”

Gorrie notes that a relationship between brain cytokines and behavior hints at potential underlying mechanisms but requires validation in independent studies. She adds that testing whether epigenetic changes at earlier developmental stages precede altered adult behavior will be another important next step.

Heidi O’Neill, who also was not involved in the new study, examined the consequences of developmental nicotine exposure in animal models as a postdoctoral fellow at the University of Colorado, Boulder. That study found evidence of adverse behavioral outcomes, potentially linked to specific genetic and epigenetic mechanisms, in first- and second-generation adolescent offspring of exposed female mice.10^,15

“To follow up on the new findings, I would study dose–response effects for different $\mathrm{P}\mathrm{G}/\mathrm{V}\mathrm{G}$ ratios and nicotine concentrations,” says O’Neill, who is now a senior health scientist at the consulting company Cardno ChemRisk. This is especially relevant, she adds, because e-cigarette users can customize their devices and mix their own e-liquids.16 This produces wide-ranging exposure profiles of the inhaled aerosols.

Zelikoff notes that the new neurobehavorial data confirmed and extended her group’s earlier toxicological findings.3^,17 “Emerging evidence indicates that vaping during pregnancy is likely harmful to the fetus, even in the absence of nicotine,” she says. “We need to get that message out to adolescents and pregnant women.”

Biography

Silke Schmidt, PhD, writes about science, health, and the environment from Madison, Wisconsin.