Mechanistic Evaluation of Black Cohosh Extract-Induced Genotoxicity in Human Cells.

Autor:	Seo JE; Division of Genetic and Molecular Toxicology, National Center for Toxicological Research, Jefferson, Arkansas 72079, USA., Guo X; Division of Genetic and Molecular Toxicology, National Center for Toxicological Research, Jefferson, Arkansas 72079, USA., Petibone DM; Division of Genetic and Molecular Toxicology, National Center for Toxicological Research, Jefferson, Arkansas 72079, USA., Shelton SD; Division of Genetic and Molecular Toxicology, National Center for Toxicological Research, Jefferson, Arkansas 72079, USA., Chen Y; Division of Genetic and Molecular Toxicology, National Center for Toxicological Research, Jefferson, Arkansas 72079, USA., Li X; Division of Genetic and Molecular Toxicology, National Center for Toxicological Research, Jefferson, Arkansas 72079, USA., Tryndyak V; Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, Arkansas 72079, USA., Smith-Roe SL; Division of the National Toxicology Program, National Institute of Environmental Health Sciences (NIEHS), Research Triangle Park, North Carolina 27709, USA., Witt KL; Division of the National Toxicology Program, National Institute of Environmental Health Sciences (NIEHS), Research Triangle Park, North Carolina 27709, USA., Mei N; Division of Genetic and Molecular Toxicology, National Center for Toxicological Research, Jefferson, Arkansas 72079, USA., Manjanatha MG; Division of Genetic and Molecular Toxicology, National Center for Toxicological Research, Jefferson, Arkansas 72079, USA.
Jazyk:	angličtina
Zdroj:	Toxicological sciences : an official journal of the Society of Toxicology [Toxicol Sci] 2021 Jul 16; Vol. 182 (1), pp. 96-106.
DOI:	10.1093/toxsci/kfab044
Abstrakt:	Black cohosh extract (BCE) is marketed to women as an alternative to hormone replacement therapy for alleviating menopausal symptoms. Previous studies by the National Toxicology Program revealed that BCE induced micronuclei (MN) and a nonregenerative macrocytic anemia in rats and mice, likely caused by disruption of the folate metabolism pathway. Additional work using TK6 cells showed that BCE induced aneugenicity by destabilizing microtubules. In the present study, BCE-induced MN were confirmed in TK6 and HepG2 cells. We then evaluated BCE-induced DNA damage using the comet assay at multiple time points (0.5-24 h). Following a 0.5-h exposure, BCE induced significant, concentration-dependent increases in %tail DNA in TK6 cells only. Although DNA damage decreased in TK6 cells over time, likely due to repair, small but statistically significant levels of DNA damage were observed after 2 and 4 h exposures to 250 µg/ml BCE. A G1/S arrest in TK6 cells exposed to 125 µg/ml BCE (24 h) was accompanied by apoptosis and increased expression of γH2A.X, p-Chk1, p-Chk2, p53, and p21. Conditioning TK6 cells to physiological levels of folic acid (120 nM) did not increase the sensitivity of cells to BCE-induced DNA damage. BCE did not alter global DNA methylation in TK6 and HepG2 cells cultured in standard medium. Our results suggest that BCE induces acute DNA strand breaks which are quickly repaired in TK6 cells, whereas DNA damage seen at 4 and 24 h may reflect apoptosis. The present study supports that BCE is genotoxic mainly by inducing MN with an aneugenic mode of action. (Published by Oxford University Press on behalf of the Society of Toxicology 2021. This work is written by US Government employees and is in the public domain in the US.)
Databáze:	MEDLINE
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