Developmental Toxicity of Cannabidiol and ?9-Tetrahydrocannabinol The University of Mississippi ABSTRACT The goal of this project is to compare the relative morphological, behavioral, reproductive and multigenerational phenotypes that result after developmental exposures to cannabidiol (CBD) and ?9- tetrahydrocannabinol (THC). Due to relaxed prohibitions on marijuana use and therapeutic potential of cannabis constituents in the treatment of early-onset pharmaco-resistant epilepsy, exposure of children to these chemicals is increasing. CBD and/or mixtures containing it is now legal in 23 states for drug-resistant epilepsy. While CBD shows anecdotal efficacy in reducing seizure frequency, little is known about the potential adverse side-effects of cannabinoids on child physiology, brain development, adult disease, and/or F1 offspring. In this study we will leverage the advantages of the zebrafish model including high fecundity, low culture costs, transparent and conserved developmental biology and genomics. We will comprehensively assess phenotypic alterations caused by two developmental exposures (either during organogenesis or sexual differentiation) and mechanistically link the adverse outcomes with targeted and global transcriptomic analyses. This research will address the significant knowledge gap that exists related to adult and multigenerational behavioral and reproductive consequences of early life cannabinoid exposure. Using an adverse outcome pathway paradigm will allow us to rigorously differentiate the unique dose-, tissue-, sex- and developmental stage-dependent effects of CBD and THC and will provide insight into the molecular pathways underlying the morphological, behavioral and neuroendocrine/reproductive toxicities of cannabinoids. Importantly, this proposed project addresses the NIH emphasis on understanding the functional consequences of cannabis and cannabinoid exposures on the developing brain as outlined in PA-14-162.