Prenatal delta-9-tetrahydrocannabinol exposure is associated with changes in rhesus macaque DNA methylation enriched for autism genes

Abstract

Background With the growing availability of cannabis and the popularization of additional routes of cannabis use beyond smoking, including edibles, the prevalence of cannabis use in pregnancy is rapidly increasing. However, the potential effects of prenatal cannabis use on fetal developmental programming remain unknown. Results We designed this study to determine whether the use of edible cannabis during pregnancy is deleterious to the fetal and placental epigenome. Pregnant rhesus macaques consumed a daily edible containing either delta-9-tetrahydrocannabinol (THC) (2.5 mg/7 kg/day) or placebo. DNA methylation was measured in 5 tissues collected at cesarean delivery (placenta, lung, cerebellum, prefrontal cortex, and right ventricle of the heart) using the Illumina MethylationEPIC platform and filtering for probes previously validated in rhesus macaque. In utero exposure to THC was associated with differential methylation at 581 CpGs, with 573 (98%) identified in placenta. Loci differentially methylated with THC were enriched for candidate autism spectrum disorder (ASD) genes from the Simons Foundation Autism Research Initiative (SFARI) database in all tissues. The placenta demonstrated greatest SFARI gene enrichment, including genes differentially methylated in placentas from a prospective ASD study. Conclusions Overall, our findings reveal that prenatal THC exposure alters placental and fetal DNA methylation at genes involved in neurobehavioral development that may influence longer-term offspring outcomes. The data from this study add to the limited existing literature to help guide patient counseling and public health polices focused on prenatal cannabis use in the future.

Prenatal delta-9-tetrahydrocannabinol exposure alters fetal neurodevelopment in rhesus macaques

“…THC-exposed fetal brains were notable for microscopic findings on histology, including increased Iba-1 and GFAP staining, suggestive of increased microglia activity, gliosis, and brain dysregulation that may have long term implications for offspring development. This is consistent with our prior reported findings, using this rhesus macaque model, that noted prenatal THC exposure alters fetal brain DNA methylation at genes involved in neurobehavioral development 20 . Also, this supports the placental-brain-axis, which suggests that many neurobehavioral disorders and neurodevelopmental disruptions are linked to pathophysiological changes in the placenta 29 .…”

“…Methods are reported in accordance with the ARRIVE guidelines ( https://arriveguidelines.org ) 63 . The generation of pregnancies in this rhesus macaque model of THC consumption has been previously published, examining on the effects of prenatal THC exposure on placental function and development 19 , and the placental and fetal transcriptome and epigenome 20 . This study focused on the impact of in utero THC exposure on fetal neurodevelopment.…”

“…To address this gap, we leveraged our translational rhesus macaque model of chronic THC edible consumption. With this model, we have previously demonstrated that in utero THC exposure significantly reduces placental perfusion and oxygenation 19 , and alters DNA methylation of key developmental genes in the placenta as well as multiple fetal tissues (e.g., lung, brain, and heart), including genes associated with autism spectrum disorder 20 . For this study, we extended our model to examine the impact of prenatal THC exposure on fetal brain function and development using a combination of advanced in utero imaging, molecular studies, and histologic assessment.…”

Cannabis Use and Perinatal Health Research

“…Rompala et al reported that maternal cannabis use was associated with changes in the placental transcriptome as a mediator of risk for anxiety-related problems in early childhood. In the nonhuman primate, Δ 9 -THC–induced changes in placental and fetal DNA methylation were in genes involved in neurodevelopment and autism spectrum disorder, which provides a potential underlying mechanism for reported altered gene expression and offspring neurobehavioral abnormalities observed with maternal cannabis use in pregnancy in the literature . This work highlights the need for additional mechanistic studies that can also inform the development of targeted therapeutics for individuals unable to abstain from cannabis use during pregnancy.…”

“…Recent findings of preclinical and human studies suggest that prenatal Δ 9 -tetrahydrocannabinol (THC, the main psychoactive component of cannabis) can affect the placental transcriptome and the placental and fetal epigenome (Figure). Rompala et al reported that maternal cannabis use was associated with changes in the placental transcriptome as a mediator of risk for anxiety-related problems in early childhood.…”