The Cannabinoid Delta-9-tetrahydrocannabinol Disrupts Estrogen Signaling in Human Placenta

• Type: Article in International Scientific Journal
• Date: 2020

Authors

Maia, J (Author) Other; Almada, M (Author) Other; Midao, L (Author) Other; Fonseca, BM (Author) Other; Braga, J (Author) Other; Goncalves, D (Author) Other; Teixeira, N (Author) Other; Georgina Correia da Silva (Author) FFUP

Journal

Title: Toxicological Sciences

Vol. 177

Pages: 420-430

ISSN: 1096-6080

Publisher: Oxford University Press

Indexing

ISI Web of Knowledge - 16 Citations

Scopus - 17 Citations

Other information

Authenticus ID: P-00S-WX8

DOI: 10.1093/toxsci/kfaa110

Abstract (EN): Cannabis consumption is increasing worldwide either for recreational or medical purposes. Its use during gestation is associated with negative pregnancy outcomes such as, intrauterine growth restriction, preterm birth, low birth weight, and increased risk of miscarriage, though the underlying molecular mechanisms are unknown. Cannabis sativa main psychoactive compound, Delta(9)-tetrahydrocannabinol (THC) is highly lipophilic, and as such, readily crosses the placenta. Consequently, THC may alter normal placental development and function. Here, we hypothesize alterations of placental steroidogenesis caused by THC exposure. The impact on placental estrogenic signaling was examined by studying THC effects upon the enzyme involved in estrogens production, aromatase and on estrogen receptor alpha (ER alpha), using placental explants, and the cytotrophoblast cell model BeWo. Aromatase expression was upregulated by THC, being this effect potentiated by estradiol. THC also increased ER alpha expression. Actions on aromatase were ER alpha-mediated, as were abolished by the selective ER downregulator ICI-182780 and dependent on the cannabinoid receptor CB1 activation. Furthermore, the presence of the aromatase inhibitor Exemestane did not affect THC-induced increase in ER alpha expression. However, THC effects on ER alpha levels were reversed by the antagonists of CB1 and CB2 receptors AM281 and AM630, respectively. Thus, we demonstrate major alterations in estrogen signaling caused by THC, providing new insight on how cannabis consumption leads to negative pregnancy outcomes, likely through placental endocrine alterations. Data presented in this study, together with our recently reported evidence on THC disruption of placental endocannabinoid homeostasis, represent a step forward into a deeper comprehension of the puzzling actions of THC.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 11