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

Tina Lojpur; Zachary Easton; Sergio Raez-Villanueva; Steven Laviolette; Alison C Holloway; Daniel B Hardy

doi:10.1016/j.reprotox.2019.04.008

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

Reprod Toxicol. 2019 Aug:87:21-31. doi: 10.1016/j.reprotox.2019.04.008. Epub 2019 May 1.

Authors

Tina Lojpur¹, Zachary Easton¹, Sergio Raez-Villanueva², Steven Laviolette³, Alison C Holloway², Daniel B Hardy⁴

Affiliations

¹ Department of Physiology and Pharmacology, Western University, London, Ontario, Canada; Departments of Obstetrics and Gynecology, Children's Health Research Institute, Lawson, Health Research Institute, Western University, London, Ontario, Canada.
² Department of Obstetrics and Gynecology, McMaster University, Hamilton, Ontario, Canada.
³ Department of Anatomy and Cell Biology, Western University, London, Ontario, Canada.
⁴ Department of Physiology and Pharmacology, Western University, London, Ontario, Canada; Departments of Obstetrics and Gynecology, Children's Health Research Institute, Lawson, Health Research Institute, Western University, London, Ontario, Canada. Electronic address: daniel.hardy@schulich.uwo.ca.

PMID: 31054322
DOI: 10.1016/j.reprotox.2019.04.008

Abstract

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.

Keywords: 11-COOH-THC; Cannabinoid receptor; Endoplasmic reticulum stress; Estrogen related receptor (ERR)-γ; Mitochondria; Placenta; Tauroursodeoxycholic acid (TUDCA); Uncoupled protein response (UPR); Vascular endothelial growth factor (VEGF)-A; Δ9-Tetrahydrocannabinol.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cannabinoid Receptor Antagonists / pharmacology
Cell Line, Tumor
Dronabinol / toxicity*
Endoplasmic Reticulum Stress / drug effects*
Hallucinogens / toxicity*
Humans
Mitochondria / drug effects*
Mitochondria / metabolism
Receptor, Cannabinoid, CB1 / antagonists & inhibitors
Receptor, Cannabinoid, CB2 / antagonists & inhibitors
Trophoblasts / drug effects*
Trophoblasts / metabolism

Substances

Cannabinoid Receptor Antagonists
Hallucinogens
Receptor, Cannabinoid, CB1
Receptor, Cannabinoid, CB2
Dronabinol

Abstract

Publication types

MeSH terms

Substances

Grants and funding