Δ9-Tetrahydrocannabinol leads to endoplasmic reticulum stress and mitochondrial dysfunction in human BeWo trophoblasts

•Δ9-tetrahydrocannabinol directly induces endoplasmic stress in placental BeWo cells.•This helps elucidate why Δ9-tetrahydrocannabinol in vivo leads to placental insufficiency.•Δ9-tetrahydrocannabinol, via the CB1 and CB2 receptor, induces ER stress.•TUDCA prevents both Δ9-THC-induced ER stress and induction of EERγ, VEGFA, and FLT-1.•Δ9-THC impedes mitochondrial size, respiration and ATP-coupling. While studies have demonstrated that the main psychoactive component of cannabis, Δ9-tetrahydrocannabinol (Δ9-THC) alone induces placental insufficiency and fetal growth restriction, the underlying mechanisms remain elusive. Given that both (i) endoplasmic reticulum (ER) stress in pregnancy and (ii) gestational exposure to Δ9-THC leads to placental deficiency, we hypothesized that Δ9-THC may directly induce placental ER stress, influencing trophoblast gene expression and mitochondrial function. BeWo human trophoblast cells treated with Δ9-THC (3–30 μM) led to a dose-dependent increase in all ER stress markers and CHOP; these effects could be blocked with CB1R/CB2R antagonists. Moreover, expression of ER stress-sensitive genes ERRγ, VEGFA, and FLT-1 were increased by Δ9-THC, and abrogated with the ER stress inhibitor TUDCA. Δ9-THC also diminished mitochondrial respiration and ATP-coupling due to decreased abundance of mitochondrial chain complex proteins. Collectively, these findings indicate that Δ9-THC can directly augment ER stress resulting in aberrant placental gene expression and impaired mitochondrial function.