Δ⁹-Tetrahydrocannabinol inhibits cytotrophoblast cell proliferation and modulates gene transcription

Abstract

Cannabis use in pregnancy is associated with a range of obstetrical conditions. The molecular mechanisms underlying these effects have not been elucidated but are attributed to the actions of delta-9-tetrahydrocannabinol (Δ⁹-THC). In this study, concentrations of Δ⁹-THC equivalent to those found in the serum of cannabis users, i.e. ∼20 µM, inhibited proliferation and activated a restricted tight transcriptional programme in the BeWo trophoblast cell line. Employing genome-wide expression profiling methods, we found that the pattern of gene expression differs from that described in the placenta of patients with fetal growth restriction (FGR), associated with either hypoxia or discordant dichorionic twins, or of patients with pre-eclampsia. It was also dissimilar to the patterns obtained from the transcriptome of other tissues, such as the mouse brain, treated with Δ⁹-THC. The expression of transcription factors, such as thyroid hormone receptor-β1 (TRβ1), and transcriptional co-repressors, such as histone deactylase 3 (HDAC3), was affected by Δ⁹-THC in a dose-dependent manner, whereby 15 µM Δ⁹-THC caused a 2.8-fold inhibition of TRβ1 expression, but a 3.5-fold increase in HDAC3 expression. These data were confirmed by end-point RT–PCR analyses and underpin the observed Δ⁹-THC-induced inhibition of BeWo cell proliferation. Genes encoding for growth, apoptosis, cell morphology and ion exchange pathways were modulated by 15 µM Δ⁹-THC. This study may provide insight into the mechanisms underlying the effects of Δ⁹-THC and cannabis use upon placental development during pregnancy.

cannabis, cytotrophoblast, marijuana, microarray, tetrahydrocannabinol