Abstract
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.
Highlights
Cannabis is a commonly used recreational drug among pregnant women (Alpár, Di Marzo, & Harkany, 2016; Wu, Jew, & Lu, 2011), and its legalization in many states as well as Canada may lead to the perception that it does not contribute to adverse pregnancy outcomes and is safe to use
While mitochondrial dysfunction is known to be linked to poor placental development (Maloyan, Mele, Muralimanohara, & Myatt, 2012; Mandò et al, 2014; Poidatz, Dos Santos, Gronier, et al, 2015), whether such associations exist for cannabis use during pregnancy is not well defined
Formation of the syncytium is dependent upon the differentiation and fusion of the underlying stem cells, the cytotrophoblasts
Summary
Cannabis is a commonly used recreational drug among pregnant women (Alpár, Di Marzo, & Harkany, 2016; Wu, Jew, & Lu, 2011), and its legalization in many states as well as Canada may lead to the perception that it does not contribute to adverse pregnancy outcomes and is safe to use. We report that exposure of human-derived BeWo cells to concentrations of THC found in frequent users (Cherlet & Scott, 2002; Khare et al, 2006) results in reduced mitochondrial membrane potential, reduced mitochondrial respiration, and increased cellular reactive oxygen production. These changes were concomitant with reduced BeWo cell syncytialization and transcription of important fetal growth hormones. Presented as fold increase in the absorbance measured (normalized to untreated cells)
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