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Estragole DNA adduct accumulation in human liver HepaRG cells upon repeated in vitro exposure
Toxicology Letters ( IF 3.5 ) Pub Date : 2021-02-01 , DOI: 10.1016/j.toxlet.2020.11.009
Shuo Yang , Sebastiaan Wesseling , Ivonne M.C.M. Rietjens

Accumulation of N2-(trans-isoestragol-3'-yl)-2'-deoxyguanosine (E-3'-N2-dG) DNA adducts derived from the alkenylbenzene estragole upon repeated dose exposure was investigated since the repair of this adduct was previously shown to be inefficient. To this end human HepaRG cells were exposed to repeating cycles of 2 h exposure to 50 μM estragole followed by 22 h repair to mimic daily exposure. The E-3'-N2-dG DNA adduct levels were quantified by LC-MS/ MS after each cycle. The results show accumulation of E-3'-N2-dG DNA adducts at a rate of 17.53 adducts / 108 nts / cycle. This rate at the dose level calculated by physiologically based kinetic (PBK) modeling to result in 50 μM was converted to a rate expected at average human daily intake of estragole. The predicted time estimated to reach adduct levels reported at the BMD10 of the related alkenylbenzene methyleugenol of 10-100 adducts /108 nts upon average human daily intake of estragole amounted to 8-80 (in rat) or 6-57 years (in human). It is concluded that the persistent nature of the E-3'-N2-dG DNA adducts may contribute to accumulation of substantial levels of DNA adducts upon prolonged dietary exposure.

中文翻译:

体外反复暴露后,人肝 HepaRG 细胞中雌二醇 DNA 加合物的积累

N2-(trans-isoestragol-3'-yl)-2'-deoxyguanosine (E-3'-N2-dG) DNA 加合物在重复剂量暴露后从链烯基苯雌二醇中的积累进行了研究,因为该加合物的修复是以前的显示效率低下。为此,将人 HepaRG 细胞暴露于 50 μM 草蒿脑暴露 2 小时的重复循环,然后进行 22 小时修复以模拟日常暴露。E-3'-N2-dG DNA 加合物水平在每个循环后通过 LC-MS/MS 进行量化。结果显示 E-3'-N2-dG DNA 加合物的积累率为 17.53 加合物/108 nts/周期。通过基于生理学的动力学 (PBK) 模型计算得出 50 μM 的剂量水平下的该速率被转换为在人类平均每日摄入草蒿脑时的预期速率。预计达到 10-100 加合物/108 nts 相关链烯基苯甲基丁香酚的 BMD10 加合物水平的预计时间为 8-80(大鼠)或 6-57 岁(人类) . 得出的结论是,E-3'-N2-dG DNA 加合物的持久性可能有助于长期饮食暴露后积累大量 DNA 加合物。
更新日期:2021-02-01
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