Gao Meng, Zhang Sai, Zhao Jing, Zhao Wenpeng, Ommati Mohammad Mehdi, Miao Chengyi, Zhou Bianhua, Wang Hong-Wei
Henan Key Laboratory of Environmental and Animal Product Safety, Henan University of Science and Technology, Kaiyuan Avenue 263, Luoyang, 471000, Henan, People's Republic of China.
Biol Trace Elem Res. 2025 May 3. doi: 10.1007/s12011-025-04633-x.
Our previous studies have demonstrated that fluoride (F) overexposure is a risk factor for colonic microenvironment, yet its underlying mechanisms and the influencing factors remain poorly understood. Here, a rat model of F exposure (0, 25, 50, 100 mg/L in drinking water) combined with ovariectomy (OVX)-induced estrogen deficiency was established to investigate the roles of nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway in F-induced colonic damage under the state of estrogen deficiency. Result showed that F exposure significantly reduced occludin and claudin-1 expression, further resulting in the colon's morphology impairment. Concurrently, F suppressed epithelial proliferation, decreased goblet cell numbers, and diminished short-chain fatty acid (SCFA) production. OVX-induced estrogen deficiency exacerbated F-induced colonic barrier damage and SCFA decreased. Mechanistically, estrogen deficiency aggravated F intestinal toxicity by further inhibiting the protein expression of Nrf2 and HO-1 and upregulating Keap1 protein expression, following downregulated Bcl-2 mRNA levels and upregulated Bax and caspase-3 mRNA levels, and promoting colonic epithelial cell apoptosis. These findings identify that Nrf2/HO-1 key protein disorders are involved in F-induced colonic barrier injury, and estrogen deficiency further aggravated F intestinal toxicity.
我们之前的研究表明，氟（F）过量暴露是结肠微环境的一个风险因素，但其潜在机制和影响因素仍知之甚少。在此，建立了一个氟暴露（饮用水中分别为0、25、50、100 mg/L）与卵巢切除术（OVX）诱导的雌激素缺乏相结合的大鼠模型，以研究核因子红细胞2相关因子2（Nrf2）/血红素加氧酶-1（HO-1）通路在雌激素缺乏状态下氟诱导的结肠损伤中的作用。结果显示，氟暴露显著降低了闭合蛋白和紧密连接蛋白-1的表达，进而导致结肠形态受损。同时，氟抑制上皮细胞增殖，减少杯状细胞数量，并降低短链脂肪酸（SCFA）的产生。OVX诱导的雌激素缺乏加剧了氟诱导的结肠屏障损伤和SCFA减少。机制上，雌激素缺乏通过进一步抑制Nrf2和HO-1的蛋白表达、上调Keap1蛋白表达，继而下调Bcl-2 mRNA水平、上调Bax和caspase-3 mRNA水平，并促进结肠上皮细胞凋亡，加重了氟的肠道毒性。这些发现表明，Nrf2/HO-1关键蛋白紊乱参与了氟诱导的结肠屏障损伤，而雌激素缺乏进一步加重了氟的肠道毒性。
