Division of Toxicology, Wageningen University and Research, Stippeneng 4, 6708 WE Wageningen, The Netherlands.
Division of Toxicology, Wageningen University and Research, Stippeneng 4, 6708 WE Wageningen, The Netherlands.
Toxicol Lett. 2021 Feb 1;337:1-6. doi: 10.1016/j.toxlet.2020.11.009. Epub 2020 Nov 12.
Accumulation of N-(trans-isoestragol-3'-yl)-2'-deoxyguanosine (E-3'-N-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'-N-dG DNA adduct levels were quantified by LC-MS/MS after each cycle. The results show accumulation of E-3'-N-dG DNA adducts at a rate of 17.53 adducts/10 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 /10 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'-N-dG DNA adducts may contribute to accumulation of substantial levels of DNA adducts upon prolonged dietary exposure.
重复剂量暴露于烯丙基苯雌烷醇（estragole）时，会积累 N-（反式-异雌二醇-3'-基）-2'-脱氧鸟苷（E-3'-N-dG）DNA 加合物，因为先前的研究表明这种加合物的修复效率较低。为此，人类 HepaRG 细胞接受重复的 2 小时暴露于 50μM estragole 后 22 小时修复的循环，以模拟日常暴露。每个周期后通过 LC-MS/MS 定量 E-3'-N-dG DNA 加合物水平。结果表明，E-3'-N-dG DNA 加合物以 17.53 个加合物/10nt/循环的速度积累。该速率是根据生理相关动力学 (PBK) 建模计算得出的，结果为 50μM，换算为平均人类每日摄入 estragole 时预期的速率。预计达到 BMD10 相关烯丙基苯甲基丁香酚 10-100 个加合物/10nt 的加合物水平所需的时间，相当于人类每天摄入 estragole 的 8-80 年（大鼠）或 6-57 年（人类）。因此，E-3'-N-dG DNA 加合物的持久性可能导致在长期饮食暴露时积累大量 DNA 加合物。
