Delta 9-Tetrahydrocannabinol Signaling Through Cannabinoid Receptor 1 Alters Trophoblast Differentiation

Cannabis use during pregnancy is increasing. In rodent models of delta-9 tetrahydrocannabinol (Δ9-THC) exposure during pregnancy, placental pathology, including compromised labyrinth development, is reported. Cannabinoid receptor 1 (CB1/Cnr1) is the primary mediator of Δ9-THC action, with its expression reportedly limited to the placental junctional zone in the rodent. Given a Δ9-THC-induced labyrinth-specific pathology, we predicted more diverse expression. This study aimed to elucidate the spatiotemporal expression of CB1/Cnr1 in the rodent and assess whether it mediates Δ9-THC-induced alterations in trophoblast differentiation. Results revealed CB1 expression in all maternal blood-facing trophoblast cells. Furthermore, Δ9-THC exposure (at levels matching those reported in maternal serum) had a more significant effect on the expression of markers associated with differentiating trophoblast cells than on proliferating trophoblast stem (TS) cells. Δ9-THC impacted mouse (m) TS cell differentiation in a CB1-dependent manner, reducing the expression of syncytiotrophoblast (SynT) markers, driving differentiation along the junctional zone/trophoblast giant cell pathway. mTS cells without Cnr1/CB1 (mTS^Cnr1KO) did not express markers of SynT cells or the differentiated junctional zone cell types. However, at a higher than physiologically relevant concentration, Δ9-THC (15 μM) induced Gcm1 (SynT) expression in mTS^Cnr1KO cells. This study reveals a mechanism by which Δ9-THC may impact placental growth.