Cannabis sativa L. stem ethanol extract suppresses ERα-mediated endocrine disrupting effects induced by bisphenol A in a breast cancer cell line.

Cannabis sativa L. (hemp), a Cannabaceae family member, has been extensively studied for its diverse secondary metabolites with physiological activities. However, stems that lack detectable levels of the delta-9-tetrahydrocannabinol have been understudied. Herein, we aimed to investigate the antagonistic effects using C. sativa L. stem ethanol extract (CSE) and its bioactive compounds on human ERα activity induced by exogenous estrogen, bisphenol A (BPA), through genomic and non-genomic pathways. CSE inhibited BPA-induced ERα transcriptional activation in VM7Luc4E2 cells and suppressed cell proliferation. Among the secondary metabolites in CSE, cyclopentane-1,2-dione (CPD), 4-vinylguaiacol (4-VG), and 4-([1E]-hydroxy-1-propenyl)-2-methoxyphenol (4-HMP) exhibited antagonistic effects on ERα transcriptional activation and inhibited cell proliferation. Cell proliferation suppression was mediated by downregulation of p38 phosphorylation in the MAPK signaling pathway. CPD inhibited exogenous estrogen-induced activation of ERα without significant affecting the translocation of cytosolic ERα to the nucleus. In contrast, 4-VG and 4-HMP exerted antagonistic effect based on suppressing the nuclear translocation of cytosolic ERα. Collectively, the results showed that CSE suppressed ERα-mediated endocrine disruption induced by exogenous estrogen, suggesting its potential as a natural ingredient to reduce endocrine disruption from dietary sources.