Journal Article

Delta‐9‐tetrahydrocannabinol disrupts mitochondrial function and attenuates syncytialization in human placental BeWo cells

Walker, O’Llenecia S., Lapierre, Mariah, Ragos, Rehginald, May, Linda L., Raha, Sandeep, Gurm, Harmeet

2020

Overview

The psychoactive component in cannabis, delta‐9‐tetrahydrocannabinol, can restrict fetal growth and development. Delta‐9‐tetrahydrocannabinol has been shown to negatively impact cellular proliferation and target organelles like the mitochondria resulting in reduced cellular respiration. In the placenta, mitochondrial dysfunction leading to oxidative stress prevents proper placental development and function. A key element of placental development is the proliferation and fusion of cytotrophoblasts to form the syncytium that comprises the materno‐fetal interface. The impact of delta‐9‐tetrahydrocannabinol on this process is not well understood. To elucidate the nature of the mitochondrial dysfunction and its consequences on trophoblast fusion, we treated undifferentiated and differentiated BeWo human trophoblast cells, with 20 µM delta‐9‐tetrahydrocannabinol for 48 hr. At this concentration, delta‐9‐tetrahydrocannabinol on BeWo cells reduced the expression of markers involved in syncytialization and mitochondrial dynamics, but had no effect on cell viability. Delta‐9‐tetrahydrocannabinol significantly attenuated the process of syncytialization and induced oxidative stress responses in BeWo cells. Importantly, delta‐9‐tetrahydrocannabinol also caused a reduction in the secretion of human chorionic gonadotropin and the production of human placental lactogen and insulin growth factor 2, three hormones known to be important in facilitating fetal growth. Furthermore, we also demonstrate that delta‐9‐tetrahydrocannabinol attenuated mitochondrial respiration, depleted adenosine triphosphate, and reduced mitochondrial membrane potential. These changes were also associated with an increase in cellular reactive oxygen species, and the expression of stress responsive chaperones, HSP60 and HSP70. These findings have important implications for understanding the role of delta‐9‐tetrahydrocannabinol‐induced mitochondrial injury and the role this might play in compromising human pregnancies. THC disrupted mitochondrial function, increased markers of mitochondrial fission and cellular stress in BeWo cells. This was coincident with reduced BeWo cell fusion and secretion of important fetal growth signals, hPL and IGF2. These changes were mediated, in part, via the CB1 receptor in syncytialized BeWo cells.

• Publisher: John Wiley & Sons, Inc,John Wiley and Sons Inc,Wiley
• Subject: Adenosine triphosphate / Antibodies / cannabinoid / Cannabinoid Receptor Agonists - pharmacology / Cannabis / Cell culture / Cell differentiation / Cell Line, Tumor / Cell Survival / Cell viability / Cellular and Molecular Physiology / Chaperones / Chaperonin 60 - genetics / Chaperonin 60 - metabolism / Chorionic gonadotropin / Development and Regeneration / Dronabinol - pharmacology / Enzymes / Epidermal growth factor / Female / Fetuses / Gene expression / Giant Cells - cytology / Giant Cells - drug effects / Gonadotropins / Gonadotropins - metabolism / Hormones / Hsp60 protein / HSP70 Heat-Shock Proteins - genetics / HSP70 Heat-Shock Proteins - metabolism / Hsp70 protein / Humans / Insulin / Insulin-Like Growth Factor II - metabolism / Marijuana / Maternal, Fetal and Neonatal Physiology / Membrane potential / Mitochondria / Mitochondria - drug effects / Mitochondria - metabolism / Mitochondrial Dynamics / Mitochondrial Proteins - genetics / Mitochondrial Proteins - metabolism / Organelles / Original / Oxidative Stress / Physiology / Pituitary (anterior) / Placenta / Pregnancy / Reactive oxygen species / Respiration / Tetrahydrocannabinol / THC / trophoblasts / Trophoblasts - cytology / Trophoblasts - drug effects