Placental Genomics in the Developmental Consequences of Marijuana Use in Pregnancy

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PROJECT SUMMARY/ABSTRACT This application is responsive to NOT-DA-20-039: Effects of Cannabis Use and Cannabinoids on the Devel- oping Brain. Prenatal cannabis use is common and increasing, with rates as high as 1 in 4 in poor, young, underserved women. Expanding legalization of cannabis has led to increasing availability, use, perceptions of safety as well as increased potency. However, data is lacking regarding the impact of prenatal use of increase- ed-potency cannabis on offspring neurodevelopment. Our group is currently conducting an intensive, prospective investigation of the impact of maternal prenatal cannabis use on infant neurodevelopment (R01DA044504). Our ongoing study has yielded preliminary evidence for an impact of prenatal cannabis on offspring growth and neurodevelopment, but does not involve a comprehensive interrogation of genomic pathways underlying these associations. Pinpointing genomic pathways will allow us to identify biomarkers of fetal harm and develop novel screening tools and intervention targets to protect and treat exposed offspring. The placenta is a unique organ that regulates the intrauterine environment, maternal-fetal communication--including passage of cannabinoids--and plays a critical role in supporting fetal growth and neurodevelopment. Seminal work by our group has revealed that the prenatal environment impacts placenta function, that alterations in placenta function can be informed by genomic profiling of the placenta, and that alterations in placenta genomic profiles are linked to newborn growth and neurobehavior. MicroRNAs (miRNAs) are an understudied aspect of placenta epigenetic regulation; miRNAs are short non-coding RNAs that regulate gene expression post-transcriptionally and are crit- ical regulators of placental- and neuro-development. A recent initial study supports the hypothesis that maternal cannabis may impact placenta immune gene networks, and offspring anxiety, but was not designed to investigate prenatal cannabis, only included a small number of cannabis users, and did not include miRNA. We propose a comprehensive placenta miRNA and mRNA profiling study to define the impact of prenatal cannabis exposure on placenta genomic activity and infant neurodevelopment. We test the central hypothesis that prenatal cannabis exposure leads to unique alterations in placenta endocannabinoid, neuronal development, immune, and stress signaling pathways, and that these functional genomic features will also impact infant de- velopment. We leverage our ongoing cohort (n=100 cannabis users, n=100 non-users) designed to assess the impact of prenatal cannabis on infant neurodevelopment and including placenta collection for candidate methyl- ation assays. Our proposed genomic mechanisms study involves the addition of state-of-the-art whole transcrip- tome RNA-sequencing (mRNA and miRNA) to delineate the functional impacts of prenatal cannabis exposure and links to infant development. Determining genomic profiles underlying the impact of prenatal cannabis on infant development is timely and offers potential to identify biomarkers of exposure and offspring risk as well as molecular targets for future intervention efforts.