Prenatal Cannabis Exposure (PreCE) and Immune-Endocannabinoid Pathways to Development of Offspring Brain and Behavior up to Age 6

PROJECT SUMMARY/ABSTRACT Recent estimates from the United States suggest that 8% of pregnant women used cannabis in the past month. While evidence remains mixed, emerging research documents an association between prenatal cannabis exposure (PreCE) and offspring birthweight, brain development (e.g., white matter microstructure), and behavior, especially inattention, impulsivity and broader externalizing symptoms. The Cannabis Use During Development and Early Life (CUDDEL; DA046224) study collected data on pregnant women who reported cannabis use during pregnancy (validated using self-report and urine screens; PreCE, n=200) and women who used cannabis prior to but never during pregnancy (NPreCE, n=200). Of these women, 150 PreCE and 100 NPreCE mother- child dyads were recruited to participate in the postpartum arm of the project where neonatal brain imaging was conducted soon after birth, and children were followed up with behavioral assessments at ages 6, 12 and 18 months. In this renewal application, we propose to longitudinally follow-up this cohort of mother-child dyads, which includes women who predominantly self-identify as African-American (~87%) with almost half living below the federal poverty threshold, up to child age 6 years. Children will participate in brain imaging and behavioral assessments at ages 3-4 and 5-6 years providing data that will outline whether PreCE exerts an enduring effect into childhood. As cannabis becomes more common place in our recruitment area, and as our sample primarily reports smoking cannabis with high rates of second hand exposure, second hand cannabis exposure (SCE) will be assessed using maternal self-report and quantification of THC-COOH in biospecimens from mother and child. In addition to studying the longitudinal associations between PreCE, SCE and brain and behavioral development, placental and offspring blood signatures of endogenous cannabinoid (eCB) signaling and immune markers (cytokines, transcriptomics, brain imaging derived) will allow for a comprehensive examination of the role of eCB- mediate immune mechanisms in PreCE and SCE effects on child health. The specific aims of the CUDDELup renewal project are to: (i) examine enduring effects of PreCE (N=150; with N=100 NPreCE) and postnatal second-hand cannabis exposure (SCE) on offspring behavior; (ii) assess contributions of PreCE and SCE to longitudinal alterations in brain structure and resting state functional connectivity and test whether these neural phenotypes shape trajectories of early childhood cognition and behavior; (iii) evaluate whether PreCE and SCE are associated with eCB and immune function; and (iv) identify the multifaceted nature through which biomarkers and neural phenotypes are associated with child behavior. With these data, CUDDELup will be uniquely poised to disarticulate cannabis-specific sequelae and test a plausible eCB-immune mechanism of PreCE effects, thus contributing to ongoing dialogue regarding federal legalization and prenatal clinical guidance in a sample of mothers and children typically underrepresented in maternal and child research.