Exposure to second hand smoke (SHS) from tobacco products impacts behavioral and cognitive performance through oxidative stress induced DNA damage and DNA repair and disruption of the gut microbiome
Smoking affects the gut microbiome and, vice versa, smoking behaviors may be influenced by specific taxa that produce neurotransmitter-associated metabolites, such as tryptophan and tyrosine. Inhalation of SHS affects both the gut tissue and the composition of the gut microbiome. These observations raise the question of whether environmental exposure to SHS might impact the gut microbiome to drive cognitive injury. We hypothesize that SHS inhalation drives changes in the gut microbiome to impact behavioral and cognitive performance, and neuropathology.We assessed the effects of chronic SHS exposure (10 months to ~30 mg/m3) on behavioral and cognitive performance, metabolism, and neuropathology in 2-month old wild-type (WT) mice and mice expressing wild-type human tau, a genetic model pertinent to Alzheimer's disease in which there is a spread of neurofibrillary tangles, consisting of hyperphosphorylated tau aggregates, that is associated with disease severity. In our gut microbiome analysis, we included a non-mutant human tau (htau) mouse model that exhibits age-dependent tau dysregulation, neurofibrillary tangles, neuronal loss, neuroinflammation, and oxidative stress starting at 3-4 months and in which tau dysregulation and neuronal loss correlate with synaptic dysfunction and cognitive decline.In addition to behavioral and cognitive performance and neuropathology, the lungs of mice were examined for pathology and alterations in geneexpression. The brains of WT mice, and especially WT male mice, were especially susceptible to the effects of chronic SHS exposure. In a follow-up study, we reported increased levels of 8-hydroxy-2'-deoxyguanosine (8-OH-dG), a marker of oxidative DNA damage and a biomarker of DNA damage following exposure to cancer-causing agents, generated following oxidative stress induced damage to2'-deoxyguanosine in the prefrontal cortex of SHS as compared to air controls and a trend towards increased levels in the CA1 area of the hippocampus. In the prefrontal cortex, levels of the oxidative DNA repair marker AP endonuclease 1 (APE1), which is involved in the repair of oxidative DNA damage, were also higher in SHS than air-exposed mice. As SHS might also increase markers of cell senescence in the brain, such as beta-galactosidase and cell cycle, we also assessed if the composition of the gut microbiome from the mice in this prior study varies (1) as afunction of SHS exposure and (2) whether the composition of the gut microbiome links to behavioral or cognitive phenotypes in these mice. In addition, we assessed whether the oxidative stress induced DNA damage that were higher in the hippocampus and prefrontal cortex of SHS exposedmice correlated with performance in the object recognition test. As beta-galactosidase is a marker of senescent cells and cigarette smoke induces p21 expression, an early marker of senescence, we also assessed whether beta-galactosidase and p21 levels were elevated in the hippocampus or prefrontal cortex following SHS exposure.