Effects of maternal e-cigarette aerosol exposure on nicotine's addiction-related behavioral and neurobiological effects in offspring - SUMMARY/ABSTRACT The goal of this project is to use animal models to understand how maternal exposure to electronic nicotine delivery system (ENDS) aerosols during pregnancy adversely impacts addiction-related behaviors and reinforcement-related neurocircuitry in offspring. An increasing number (up to 15%) of pregnant women are using ENDS, exposing several hundred thousand fetuses per year in the U.S. alone. Combustible cigarettes have long-term developmental consequences in offspring including increased risk of impulsivity-related disorders such as attention deficit hyperactivity disorder (ADHD) and addiction to tobacco. These adverse effects are generally attributable to nicotine, but other toxicants in tobacco smoke may also play a role. Although ENDS contain lower levels of many of those toxicants, ENDS can deliver as much or more nicotine as combustible cigarettes, and contain additional chemicals (e.g., propylene glycol, ethanol, unique flavorants, toxic byproducts) that are not present in tobacco or tobacco smoke. Thus, ENDS use may pose not only many of the same risks to pregnant women and their children as smoking, but unique risks as well. These issues have received only limited attention, leaving the adverse effects of ENDS use during pregnancy largely unknown. Research to date shows that prenatal ENDS exposure in rodents has adverse effects on several behavioral and genetic outcomes in offspring that are attributable to nicotine and/or non-nicotine constituents in ENDS. However, no studies have examined other potential adverse outcomes, such as increased impulsivity or abuse liability of nicotine and associated adaptations in reinforcement-related circuitry. To address this issue, this project will examine the effects of maternal inhalational exposure to commercial ENDS aerosols (fruit- and tobacco-flavor) on these outcomes in rat offspring. Endpoints will include measures of impulsive action and impulsive choice (Aim 1), nicotine abuse liability in nicotine self-administration models (Aim 2), and function of reinforcement-related neurocircuitry following acute or chronic nicotine in intracranial self-stimulation models (Aim 3). Cell-specific changes in gene expression and chromatin accessibility, as well as degree of nAChR upregulation, in key reinforcement-related mesocorticolimbic areas (NAc, PFC), will also be analyzed to examine potential neurobiological mechanisms mediating behavioral effects in these and other studies and generate hypotheses for future studies (Aim 4). Inclusion of nicotine-free ENDS aerosol and aerosolized nicotine alone will allow us to assess the relative contribution of nicotine versus other constituents in the effects of nicotine-containing ENDS aerosol. Given the ability of certain non-nicotine constituents in ENDS aerosol to enhance the effects of nicotine or produce adverse prenatal effects of their own, our overall hypothesis is that prenatal exposure to nicotine- containing ENDS aerosol will produce greater adverse effects than the other exposure conditions. Findings will provide new information to the public and the FDA on the potential risks of ENDS use during pregnancy and suggest neural mechanisms of interest for future preclinical studies and brain imaging studies in humans.
