Chronic prenatal delta-9-tetrahydrocannabinol exposure adversely impacts placental function and development in a rhesus macaque model

Abstract

Cannabis use in pregnancy is associated with adverse perinatal outcomes, which are likely mediated by the placenta. However, the underlying mechanisms and specific vasoactive effects of cannabis on the placenta are unknown. Our objective was to determine the impact of chronic prenatal delta-tetrahydrocannabinol (THC, main psychoactive component of cannabis) exposure on placental function and development in a rhesus macaque model using advanced imaging. Animals were divided into two groups, control (CON, n = 5) and THC-exposed (THC, n = 5). THC-exposed animals received a THC edible daily pre-conception and throughout pregnancy. Animals underwent serial ultrasound and MRI at gestational days 85 (G85), G110, G135 and G155 (full term is ~ G168). Animals underwent cesarean delivery and placental collection at G155 for histologic and RNA-Seq analysis. THC-exposed pregnancies had significantly decreased amniotic fluid volume (p < 0.001), placental perfusion (p < 0.05), and fetal oxygen availability (p < 0.05), all indicators of placental insufficiency. Placental histological analysis demonstrated evidence of ischemic injury with microinfarctions present in THC-exposed animals only. Bulk RNA-seq demonstrated that THC alters the placental transcriptome and pathway analysis suggests dysregulated vasculature development and angiogenesis pathways. The longer-term consequences of these adverse placental findings are unknown, but they suggest that use of THC during pregnancy may deleteriously impact offspring development.

Emerging Roles of Endocannabinoids as Key Lipid Mediators for a Successful Pregnancy

“…These findings in rodents are supported by a recent study on the effects of chronic prenatal cannabinoid exposure on placenta structure and functions in a translational rhesus macaque model [ 148 ]. In this study, ∆9-THC was administered in an edible form for 4 months before conception with incremental dosing until reaching 2.5 mg/7 kg/day, then maintained throughout pregnancy.…”

“…Reduced placenta perfusion and oxygenation were found in ∆9-THC-exposed pregnant animals, together with increased microinfarction rates and reduced amniotic fluid volume, indicative of a dysfunctional state of the placenta. The placental insufficiency was also associated with wide-scale alterations of transcriptional profiling as assessed by RNA-sequencing, which primarily involved pathways related to angiogenesis and vascular development [ 148 ].…”

Cannabis and Pregnancy: A Review

“…122 Nonhuman primate studies have similarly reported that chronic prenatal THC exposure adversely impacts placental development and function. 123 Roberts et al 123 showed that THC-exposed pregnancies had significantly decreased placental perfusion and fetal oxygen availability suggestive of placental insufficiency. In addition, placental histological analyses demonstrated evidence of ischemic injury with microinfarctions in THC-exposed placentas only.…”

Ultrasound evaluation of normal rhesus macaque fetal biometry and uteroplacental hemodynamics

“…Some of these studies also used regression analysis to develop models for predicting the gestational age if the date of mating was unknown (Tarantal & Hendrickx, 1988). More recent studies by our group in rhesus macaque models of environmental perturbations, including maternal nicotine (Lo et al, 2015), alcohol (Lo et al, 2017), and cannabis use (Roberts et al, 2022), demonstrated detection of placental insufficiency using clinical obstetric ultrasound measurements of uteroplacental hemodynamics such as Doppler velocity waveforms from the umbilical artery (UA; Kelleher et al, 2020), uterine artery (UtA; Lo et al, 2017;Roberts et al, 2018), and ductus venosus (DV; Lo et al, 2015).…”