W4. VALIDATION OF A HUMAN STEM CELL MODEL OF PRENATAL CANNABIS EXPOSURE

Background There is urgent public health need to uncover gene x environment interactions in the context of prenatal cannabis exposure. Widespread legalization has accelerated cannabis use across the United States. As a result, cannabis use during pregnancy is increasing, particularly to combat nausea and stress. Foundational clinical studies associate prenatal cannabis exposure with lifelong risk for neuropsychiatric disorders, including schizophrenia, autism spectrum disorder, and attention deficit hyperactivity disorder. Recent genome-wide association studies implicate common variants, each with small effect sizes, in neuropsychiatric disorder risk. Many of these variants are in non-coding regulatory regions of the genome that are specific to humans. Thus, animal models are limited in their ability to interrogate neuropsychiatric disorder risk and models that better recapitulate human genetic complexity are needed. Methods Using human induced pluripotent stem cell (hiPSC)-derived neural progenitor cells (NPCs) as models of developing fetal brain cells, we tested three doses (50 nM, 1 uM, and 3 uM) of delta-nine-tetrahydrocannabinol (THC), the psychoactive constituent of cannabis, relative to vehicle controls across three donors and two timeframes (24 hours and seven days). Results Differentially expressed genes (DEGs) were apparent in the 1 uM and 3 uM doses after 24 hours, and in all doses after seven days (pFDR ≤ 0.05). There was substantial overlap of DEGs between the 1uM and 3uM doses in seven-day paradigm. Gene ontology terms of these DEGs showed enrichment for neurodevelopment-associated processes, including regulation of neuron projection development, axonogenesis, and focal adhesion, consistent with data from animal models of prenatal cannabis exposure. Discussion These findings indicate that hiPSC-derived brain cells are a viable model for investigating the genomic impact of prenatal cannabis exposure. Future work will harness high throughput genetic engineering technology such as massively parallel reporter assays and CRISPR screens in this model system to test THC-dynamic regulation of neuropsychiatric risk variants.