Effects of unburned tobacco smoke on inflammatory and oxidative mediators in the rat prefrontal cortex

Abstract

Although the Food and Drug Administration has authorized the marketing of “heat-not-burn” (HnB) electronic cigarettes as a modified risk tobacco product (MRTP), toxicological effects of HnB smoke exposure on the brain are still unexplored. Here, paramagnetic resonance of the prefrontal cortex (PFC) of HnB-exposed rats shows a dramatic increase in reactive radical species (RRS) yield coupled with an inflammatory response mediated by NF-κB-target genes including TNF-α, IL-1β, and IL-6 and the downregulation of peroxisome proliferator-activated receptor (PPAR) alpha and gamma expression. The PFC shows higher levels of 8-hydroxyguanosine, a marker of DNA oxidative damage, along with the activation of antioxidant machinery and DNA repair systems, including xeroderma pigmentosum group C (XPC) protein complex and 8-oxoguanine DNA glycosylase 1. HnB also induces the expression of drug-metabolizing enzymes such as CYP1A1, CYP2A6, CYP2B6, and CYP2E, particularly involved in the biotransformation of nicotine and several carcinogenic agents such as aldehydes and polycyclic aromatic hydrocarbons here recorded in the HnB stick smoke. Taken together, these effects, from disruption of redox homeostasis, inflammation, PPAR manipulation along with enhanced bioactivation of neurotoxicants, and upregulation of cMYC protooncogene to impairment of primary cellular defense mechanisms, suggest a possible increased risk of brain cancer. Although the HnB device reduces the emission of tobacco toxicants, our findings indicate that its consumption may carry a risk of potential adverse health effects, especially in non-smokers so far. Further studies are needed to fully understand the long-term effects of these devices.

Unburned Tobacco Smoke Affects Neuroinflammation-Related Pathways in the Rat Mesolimbic System

“…Different from what has been previously observed in the PFC [11], no significant alterations in KDM6A gene expression have been detected in the VTA, thus suggesting reduced involvement of this specific epigenetic enzyme isoform in the alterations induced by prolonged nicotine exposure in this area.…”

“…In light of these results and together with the previous observations in the prefrontal cortex [11], it seems that the molecular pathways involved in inflammatory process regulation are engaged differently along the starting or projection nodes of the mesocorticolimbic pathway.…”

“…After one week of acclimatization, the animals were separated into two groups, a control (n = 6 rats) and an exposed (n = 6 rats) group. The rats assigned to the latter were transferred to an inhalation chamber (two animals per chamber), in which they were exposed using whole-body mode to nicotine (delivered by the heat-not-burn THS 2.2 model produced by PMI) for a total period of 28 days (5 days/week) as previously described [11,43,44]. Total mainstream smoke exposure was limited to 8 tobacco sticks/day/chamber, never exceeding 3h/day.…”

“…Furthermore, it is important to emphasize that the effects induced by nicotine exposure through these devices are still poorly understood, and recent studies seem to confirm the development of oxidative and neuroinflammatory phenomena associated with the use of these systems, which could significantly affect the proper functioning of the CNS. In fact, our previous work, along with other literature results, has shown how exposure to HnB devices can induce neuroinflammation, promoting an increase in specific cytokines and the dysregulation of some transcriptional activity regulators including peroxisome proliferator-activated receptors (PPARs) [11,12].…”

“…On these bases and given the widespread use of HnB devices, we sought to better analyze the role of neuroinflammatory processes in the development of nicotine use disorder [18]. Hence, in light of our previous results [11] in the prefrontal cortex (PFC), we focused this investigation on two other relevant nodes of the mesocorticolimbic reward circuitry represented by VTA and NAc. To this end, we evaluated the effects of prolonged exposure to HnB mainstream smoke on the PPARs, PTEN, and KDM6s gene expression as well as on ERK1/2 and AKT phosphorylated protein levels.…”