Abstract
Cannabidiol (CBD) is a constituent of Cannabis sativa without psychotropic activity, whose medical benefits have been recognised. However, little is known about the potential toxic effects of CBD on reproductive health. Placental development involves tightly controlled processes of cell proliferation, differentiation, apoptosis, autophagy and migration/invasion of trophoblast cells. Cannabis use by pregnant women has been increasing, mainly for the relief of nausea associated with the first trimester, which raises great concern. Regarding the crucial role of cytotrophoblast cells (CTs) and extravillous trophoblasts (EVTs) in placentation, the effects of CBD (1–10 µM) were studied, using in vitro model systems BeWo and HTR-8/SVneo cell lines, respectively. CBD causes cell viability loss in a dose-dependent manner, disrupts cell cycle progression and induces apoptosis through the mitochondrial pathway, on both cell models. Moreover, CBD induces autophagy only in HTR-8/SVneo cells, being this process a promoter of apoptosis. Hypoxia-responsive genes HIF1A and SPP1 were also increased in CBD-treated HTR-8/SVneo cells suggesting a role for HIF-1α in the apoptotic and autophagic processes. In addition, CBD was able to decrease HTR-8/SVneo cell migration. Therefore, CBD interferes with trophoblast turnover and placental remodelling, which can have a considerable impact on pregnancy outcome. Thus, from an in vitro perspective our study adds new evidence for the potential negative impact of cannabis use by pregnant women.
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Abbreviations
- ∆ψm :
-
Mitochondrial membrane potential
- 2-AG:
-
2-Arachidonoylglycerol
- 3-MA:
-
3-Methyladenine
- AEA:
-
Anandamide
- CBD:
-
Cannabidiol
- CCCP:
-
Carbonyl cyanide m-chlorophenylhydrazone
- CPT:
-
Camptothecin
- CT:
-
Cytotrophoblast
- DCDHF- DA:
-
2',7'-Dichlorodihydrofluorescein diacetate
- DiOC6 :
-
3,3'-Dihexyloxacarbocyanine iodide
- EVTs:
-
Extravillous trophoblasts
- FBS:
-
Foetal bovine serum
- HIF-1α:
-
Hypoxia-inducible factor-1α
- IUGR:
-
Intrauterine growth restriction
- PMA:
-
Phorbol 12-myristate 13-acetate
- ROS/RNS:
-
Reactive oxygen and nitrogen species
- ST:
-
Syncytiotrophoblast
- STS:
-
Staurosporine
- THC:
-
Δ9-Tetrahydrocannabinol
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Acknowledgements
Authors thanks to Fundação para a Ciência e Tecnologia (FCT) for P. Alves PhD Grant (UI/BD/151312/2021) and C. Amaral contract under the funding program (DL 57/2016—Norma Transitória) and through the Post-doc grant (SFRH/BPD/98304/2013). This work was supported by the Applied Molecular Biosciences Unit—UCIBIO, which is financed by national funds from FCT (UIDB/04378/2020; UIDP/04378/2020).
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This work was supported by Fundação para a Ciência e Tecnologia (FCT) through Patrícia Alves PhD grant (UI/BD/151312/2021) and Cristina Amaral contract (DL 57/2016—Norma Transitória) and Post-doc grant (SFRH/BPD/98304/2013) and by Applied Molecular Biosciences Unit—UCIBIO (UIDP/04378/2020 and UIDB/04378/2020).
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Alves, P., Amaral, C., Teixeira, N. et al. Cannabidiol disrupts apoptosis, autophagy and invasion processes of placental trophoblasts. Arch Toxicol 95, 3393–3406 (2021). https://doi.org/10.1007/s00204-021-03122-z
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DOI: https://doi.org/10.1007/s00204-021-03122-z