679 - THC Vaping During Pregnancy Induces Chronic Structural and Functional Brain Changes in the Perinatal Period and Beyond

Publication Number: 2662.679

Lauren E. Guyer, Johns Hopkins University School of Medicine, Baltimore, MD, United States; Eric M. Chin, Kennedy Krieger Institute and Johns Hopkins University School of Medicine, Baltimore, MD, United States; Hawley Helmbrecht, Johns Hopkins University School of Medicine, Baltimore, MD, United States; Riddhi Patel, Johns Hopkins University School of Medicine, Baltimore, MD, United States; Fabiola B. Santiago, Johns Hopkins University School of Medicine, Baltimore, MD, United States; Bryan Jenkins, Johns Hopkins University School of Medicine, Baltimore, MD, United States; Shenandoah Robinson, Johns Hopkins University, Baltimore, MD, United States; Catherine F. Moore, Johns Hopkins University School of Medicine, Baltimore, MD, United States; Elise M. Weerts, Johns Hopkins University School of Medicine, BALTIMORE, MD, United States; Praachi Tiwari, Johns Hopkins University School of Medicine, Baltimore, MD, United States; Lauren Jantzie, Johns Hopkins University School of Medicine, Baltimore, MD, United States

Background: Studies on the effects of delta-9-tetrahydrocannabinol (THC), the primary psychoactive constituent of cannabis, primarily focus on nonpregnant adults. There is an urgent need to understand the effects of THC during pregnancy and define the impact on infants and children. We hypothesized that prenatal THC would increase cerebral and systemic inflammation resulting in brain injury.

Objective: To examine the developmental consequences of prenatal THC exposure during critical periods of neurodevelopment, with a focus on structural and functional brain injury and homeostatic inflammatory mediators.

Design/Methods: Female Sprague-Dawley rats (n=6/group) were exposed to THC vapor(200mg/ml) or vehicle vapor 30 minutes daily throughout pregnancy (Gestational day 1-20). Pups were born and also exposed to THC vapor from Postnatal day (P)1-10 (third trimester equivalent).Pups of both sexes were randomized to inflammatory assays (biomarkers and flow cytometry), magnetic resonance imaging (T2, DTI and fMRI) Digigait analysis and open field (n=10/group).Data were analyzed with Sttudent’s T-tests or Mann-Whitney U-tests; ⍺=0.05.

Results: Fetal brain concentrations of 11-OH-THC, a psychoactive metabolite of THC, were 46-48% of maternal brain concentrations at birth. Adolescent rats exposed to THC were ataxic, flat footed, and hyperactive (p < 0.01 for all). Analyses of functional connectivity matrices revealed global hyperconnectivity in subcortical regions of adult rats exposed to THC compared to controls (p < 0.001). Hyperconnectivity was most evident within sensorimotor cortical networks and between thalamic nuclei. THC reduced fractional anisotropy (p < 0.05) and axial diffusivity (p < 0.05), and increased radial diffusivity (p < 0.01) in the corpus collosum. Myelin basic protein expression was diminished in the cortex and fimbria (p < 0.0001) consistent with impaired myelin development and/or degradation. TNFa and CXCL1 were increased after THC exposure concomitant with increased CXCR2+ neutrophils (p < 0.01). A THC associated reduction in protective cerebral Foxp3+ CD3+/CD4+ T cells was also observed with a systemic reduction in IL-10 and IL-4 (p < 0.05 for all). Microglia from THC animals were spheroid, less complex, with fewer and shorter processes, consistent with phagocytic activity and activation.

Conclusion(s): Prenatal exposure to THC vapor alters immune function through in adulthood concomitant with neural network fragmentation, changes in functional topology, and diminished functional and anatomical connectomes. Investigation of the degree of neurorepair needed in this patient population is urgently needed.