DNA Damage and Repair and Epigenetic Modification in the Role of Oxoguanine Glycosylase 1 in Brain Development.

Oxoguanine glycosylase 1 (OGG1) repairs the predominant reactive oxygen species-initiated DNA lesion 8-oxoguanine. Human OGG1 polymorphisms resulting in reduced DNA repair associate with an increased risk for disorders like cancer and diabetes, but the role of OGG1 in brain development is unclear. Herein, we show that Ogg1 knockout mice at 2-3 months of age exhibit enhanced gene- and sex-dependent DNA damage (strand breaks) and decreased epigenetic DNA methylation marks (5-methylcytosine, 5-hydroxymethylcytosine), both of which were associated with increased cerebellar calbindin levels, reduced hippocampal postsynaptic function, altered body weight with age and disorders of brain function reflected in behavioral tests for goal-directed repetitive behavior, anxiety and fear, object recognition and spatial memory, motor coordination and startle response. These results suggest that OGG1 plays an important role in normal brain development, possibly via both its DNA repair activity and its role as an epigenetic modifier, with OGG1 deficiencies potentially contributing to neurodevelopmental disorders.

Preliminary Eye-Tracking Data as a Nonintrusive Marker for Blood Δ-9-Tetrahydrocannabinol Concentration and Drugged Driving.

Background: Cannabis is one of the drugs most often found in drivers involved in serious motor vehicle collisions. Validity and reliability of roadside cannabis detection strategies are questioned. This pilot study aimed to investigate the relationship between eye characteristics and cannabis effects in simulated driving to inform potential development of an alternative detection strategy. Materials and Methods: Multimodal data, including blood samples, eye-tracking recordings, and driving performance data, were acquired from 10 participants during a prolonged single-session driving simulator experiment. The study session included a baseline driving trial before cannabis exposure and seven trials at various times over ∼5 h after exposure. The multidimensional eye-tracking recording from each driving trial for each participant was segmented into nonoverlapping epochs (time windows); 34 features were extracted from each epoch. Blood Δ-9-tetrahydrocannabinol (THC) concentration, standard deviation of lateral position (SDLP), and mean vehicle speed were target variables. The cross-correlation between the temporal profile of each eye-tracking feature and target variable was assessed and a nonlinear regression analysis evaluated temporal trend of features following cannabis exposure. Results: Mean pupil diameter (r=0.81-0.86) and gaze pitch angle standard deviation (r=0.79-0.87) were significantly correlated with blood THC concentration (p<0.01) for all epoch lengths. For driving performance variables, saccade-related features were among those showing the most significant correlation (r=0.61-0.83, p<0.05). Epoch length significantly affected correlations between eye-tracking features and speed (p<0.05), but not SDLP or blood THC concentration (p>0.1). Temporal trend analysis of eye-tracking features after cannabis also showed a significant increasing trend (p<0.01) in saccade-related features, including velocity, scanpath, and duration, as the influence of cannabis decreased by time. A decreasing trend was observed for fixation percentage and mean pupil diameter. Due to the lack of placebo control in this study, these results are considered preliminary. Conclusion: Specific eye characteristics could potentially be used as nonintrusive markers of THC presence and driving-related effects of cannabis. clinicaltrials.gov (NCT03813602).