School of Life Sciences, Yunnan Normal University, Kunming, Yunnan 650500, China.
Yunnan Environmental Mutagen Society, Kunming, Yunnan 650500, China.
Mutagenesis. 2022 Apr 2;37(1):34-43. doi: 10.1093/mutage/geab041.
Obese subjects have a high baseline of genotoxic stress, but the underlying mechanism is poorly understood. Given that obesity is associated with high bile acids (BA) and low folate, we aimed to determine the interactive effect of folate deficient or supplementation to the genotoxicity and cytotoxicity of BA in human colon and liver cells. NCM460 and L-02 cells were cultured in folate-deficient (22.6 nM) and replete (2260 nM) Roswell Park Memorial Institute (RPMI)-1640 medium with or without 50 μM deoxycholic acid (DCA) or lithocholic acid (LCA) for 7 days. Moreover, these cells were cultured in folate supplemented (5.65, 11.3 and 22.6 μM) and standard (2.26 μM) medium with 200 μM DCA or LCA for 7 days. Genotoxicity and cytotoxicity were measured using the cytokinesis-block micronucleus cytome assay. Our results showed that under folate-replete condition, 50 μM DCA or LCA significantly increased the rate of micronuclei (MN) in NCM460 and L-02 cells. Significantly, the MN-inducing effect of 50 μM DCA or LCA was further enhanced by folate deficiency. Interestingly, folate supplementation exerted a dose-dependent manner to significantly decrease the rates of MN, nucleoplasmic bridges, nuclear buds, apoptosis, and necrosis induced by 200 μM DCA or LCA in NCM460 and L-02 cells. In conclusion, the genotoxicity of moderate BA (50 μM) was exacerbated by folate deficiency and folate supplementation could efficiently protect cells against the genotoxicity and cytotoxicity of high BA (200 μM).
肥胖受试者有很高的遗传毒性应激基线，但潜在机制尚不清楚。鉴于肥胖与高胆汁酸（BA）和低叶酸有关，我们旨在确定叶酸缺乏或补充对人结肠和肝细胞中 BA 的遗传毒性和细胞毒性的相互作用。NCM460 和 L-02 细胞在叶酸缺乏（22.6 nM）和补充（2260 nM）罗格斯大学纪念医院（RPMI）-1640 培养基中培养，有或没有 50 μM 脱氧胆酸（DCA）或石胆酸（LCA），培养 7 天。此外，这些细胞在叶酸补充（5.65、11.3 和 22.6 μM）和标准（2.26 μM）培养基中培养，有或没有 200 μM DCA 或 LCA，培养 7 天。采用细胞有丝分裂阻断微核细胞胞质试验测量遗传毒性和细胞毒性。结果表明，在叶酸充足的条件下，50 μM DCA 或 LCA 显著增加 NCM460 和 L-02 细胞的微核（MN）率。重要的是，叶酸缺乏进一步增强了 50 μM DCA 或 LCA 的 MN 诱导作用。有趣的是，叶酸补充以剂量依赖的方式显著降低了 200 μM DCA 或 LCA 诱导的 NCM460 和 L-02 细胞的 MN、核质桥、核芽、凋亡和坏死率。总之，中等 BA（50 μM）的遗传毒性因叶酸缺乏而加剧，而叶酸补充可有效保护细胞免受高 BA（200 μM）的遗传毒性和细胞毒性的影响。
