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<p>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.</p>

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The NRF2/HO- 1 Pathway: a Potential Regulatory Factor in Fluoride-Induced Colonic Injury under Estrogen Deficiency

  • 期刊论文

  • 发表日期：

    2025年5月3日

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  • Meng Gao,
  • Sai Zhang,
  • Jing Zhao,
  • Wenpeng Zhao,
  • Mohammad Mehdi Ommati,
  • Chengyi Miao,
  • Bianhua Zhou,
  • Hong-Wei Wang

摘要

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.