Pilot: Center for Appalachian Research in Environmental Sciences: Interactions of E-Cigarette Vapor and Estrogen on Microglia within the Brain Reward Pathway in Females

There has been a surge in electronic nicotine delivery systems use, which is increasingly being linked to health issues such as cancer. The availability of chemical flavorants in e-cigarette products contributes to their use as they are otherwise banned in combustible products. However, green apple flavorants alter reward- related behavior and midbrain reward pathway function. The surge in the use of these products is a major health concern, as this is a new source of pollution and toxins in the environment given that flavorants contain hazardous chemicals which are especially harmful when heated. There is some preliminary evidence that vapor from the solvent contained in e-cigarette vapor, propylene glycol, increases inflammatory genes in rat brain regions and specifically, in glial cells6 including astrocytes. However, there are no prior studies evaluating the impact of contaminants found in e-cigarette vapor on microglia, another glial cell that rapidly responds to environmental stimuli and plays a critical role in neuronal health. We have shown that nicotine self-administration (SA) induces microgliosis, a form of microglia cell death, in the nucleus accumbens core (a key brain region in the reward pathway). Importantly, this is reversed by steroid hormone treatment, showing that sex steroid hormones regulate neuroimmune dysregulations induced by nicotine exposure. We have also shown that nicotine and progesterone interact to significantly decrease uterine horn weights, demonstrating an important interactive relationship between steroid hormones and nicotine SA that is consequential to women who concurrently utilize progesterone-containing contraceptives and are exposed to nicotine. Thus, the overarching goal of this study is to determine how passive exposure to chemicals contained in e-cigarettes impact neuroimmune signaling and the health of uterine horns, and how the steroid hormone 17β-estradiol (E2) impacts these associations. E2 will be studied here because it has been associated within increased nicotine addiction vulnerability in women. In these experiments, rats will be passively exposed to a combination of nicotine and one of three chemical flavorants contained in green apple e-cigarette e-liquid products and injected daily prior to exposure sessions with E2. Following exposure, NAcore microglia will be evaluated for structural changes in reactivity. We hypothesize that E2 and nicotine SA will interact to induce pathological changes in NAcore microglia and uterine horn weights.