Underlying Mechanism of Fluoride Inhibits Colonic Gland Cells Proliferation by Inducing an Inflammation Response

Overview

Journal Biol Trace Elem Res

Date 2024 Jul 12

PMID 38995434

Authors

Jing Liu

Jing Zhao

Yu-Ling Zhang

Cai Zhang

Guo-Dong Yang

Wei-Shun Tian

Bian-Hua Zhou

Hong-Wei Wang

Affiliations

Soon will be listed here.

Abstract

The integrity of colonic gland cells is a prerequisite for normal colonic function and maintenance. To evaluate the underlying injury mechanisms in colonic gland cells induced by excessive fluoride (F), forty-eight female Kunming mice were randomly allocated into four groups and treated with different concentrations of NaF (0, 25, 50, and 100 mg F/L) for 70 days. As a result, the integrity of the colonic mucosa and the cell layer was seriously damaged after F treatment, as manifested by atrophy of the colonic glands, colonic cell surface collapse, breakage of microvilli, and mitochondrial vacuolization. Alcian blue and periodic acid Schiff staining revealed that F decreased the number of goblet cells and glycoprotein secretion. Furthermore, F increased the protein expression of TLR4, NF-κB, and ERK1/2 and decreased IL-6, interfered with NF-κB signaling, following induced colonic gland cells inflammation. The accumulation of F inhibited proliferation via the JAK/STAT signaling pathway, as characterized by decreased mRNA and protein expression of JAK, STAT3, STAT5, PCNA, and Ki67 in colon tissue. Additionally, the expression of CDK4 was up-regulated by increased F concentration. In conclusion, excessive F triggered colonic inflammation and inhibited colonic gland cell proliferation via regulation of the NF-κB and JAK/STAT signaling pathways, leading to histopathology and barrier damage in the colon. The results explain the damaging effect of the F-induced inflammatory response on the colon from the perspective of cell proliferation and provide a new idea for explaining the potential mechanism of F-induced intestinal damage.

References

Mohammadi A, Yousefi M, Yaseri M, Jalilzadeh M, Mahvi A . Skeletal fluorosis in relation to drinking water in rural areas of West Azerbaijan, Iran. Sci Rep. 2017; 7(1):17300. PMC: 5725489. DOI: 10.1038/s41598-017-17328-8. View

Wu S, Wang Y, Iqbal M, Mehmood K, Li Y, Tang Z . Challenges of fluoride pollution in environment: Mechanisms and pathological significance of toxicity - A review. Environ Pollut. 2022; 304:119241. DOI: 10.1016/j.envpol.2022.119241. View

Meenakshi , Maheshwari R . Fluoride in drinking water and its removal. J Hazard Mater. 2006; 137(1):456-63. DOI: 10.1016/j.jhazmat.2006.02.024. View

Jin Y, Gao X, Zhao J, Tian W, Zhang Y, Tian E . Estrogen deficiency aggravates fluoride-induced small intestinal mucosa damage and junctional complexes proteins expression disorder in rats. Ecotoxicol Environ Saf. 2022; 246:114181. DOI: 10.1016/j.ecoenv.2022.114181. View

Luo H, Liu R, Lang Y, Zhao J, Zhuang C, Wang J . Melatonin alleviated fluoride-induced impairment of spermatogenesis and sperm maturation process via Interleukin-17A. Food Chem Toxicol. 2023; 178:113867. DOI: 10.1016/j.fct.2023.113867. View

Hu Y, Li Y, Li M, Zhao T, Zhang W, Wang Y . Calcium supplementation attenuates fluoride-induced bone injury via PINK1/Parkin-mediated mitophagy and mitochondrial apoptosis in mice. J Hazard Mater. 2024; 465:133411. DOI: 10.1016/j.jhazmat.2023.133411. View

Elghareeb M, Elshopakey G, Rezk S, Ateya A, El-Ashry E, Shukry M . Nigella sativa oil restores hormonal levels, and endocrine signals among thyroid, ovarian, and uterine tissues of female Wistar rats following sodium fluoride toxicity. Biomed Pharmacother. 2023; 170:116080. DOI: 10.1016/j.biopha.2023.116080. View

Li M, Wang J, Wu P, Kumar Manthari R, Zhao Y, Li W . Self-recovery study of the adverse effects of fluoride on small intestine: Involvement of pyroptosis induced inflammation. Sci Total Environ. 2020; 742:140533. DOI: 10.1016/j.scitotenv.2020.140533. View

Zhang S, Zhao T, Wang Y, Mi J, Liu J, Fan X . Intestinal microbiota regulates colonic inflammation in fluorosis mice by TLR/NF-κB pathway through short-chain fatty acids. Food Chem Toxicol. 2023; 178:113866. DOI: 10.1016/j.fct.2023.113866. View

10.

Gao X, Jin Y, Zhao J, Zhang Y, Wang H, Zhou B . Th17-Related Cytokines Involved in Fluoride-Induced Cecal and Rectal Barrier Damage of Ovariectomized Rats. Biol Trace Elem Res. 2022; 201(9):4497-4507. DOI: 10.1007/s12011-022-03519-6. View

11.

Zhang Y, Zhou B, Tan P, Chen Y, Miao C, Wang H . Key Role of Pro-inflammatory Cytokines in the Toxic Effect of Fluoride on Hepa1-6 Cells. Biol Trace Elem Res. 2020; 197(1):115-122. DOI: 10.1007/s12011-019-01967-1. View

12.

Zhu S, Zhou B, Tan P, Chai J, Yu Y, Wang H . Based on G-Series Mouse TH17 Array Study the Effect of Fluoride on C2C12 Cells Cytokines Expression. Biol Trace Elem Res. 2020; 199(9):3402-3410. DOI: 10.1007/s12011-020-02464-6. View

13.

Zhang X, Wang G, Wang T, Chen J, Feng C, Yun S . Selenomethionine alleviated fluoride-induced toxicity in zebrafish (Danio rerio) embryos by restoring oxidative balance and rebuilding inflammation homeostasis. Aquat Toxicol. 2021; 242:106019. DOI: 10.1016/j.aquatox.2021.106019. View

14.

Arab-Nozari M, Mohammadi E, Shokrzadeh M, Ahangar N, Talebpour Amiri F, Shaki F . Co-exposure to non-toxic levels of cadmium and fluoride induces hepatotoxicity in rats via triggering mitochondrial oxidative damage, apoptosis, and NF-kB pathways. Environ Sci Pollut Res Int. 2020; 27(19):24048-24058. DOI: 10.1007/s11356-020-08791-4. View

15.

Zhang J, Zheng Y, Luo Y, Du Y, Zhang X, Fu J . Curcumin inhibits LPS-induced neuroinflammation by promoting microglial M2 polarization via TREM2/ TLR4/ NF-κB pathways in BV2 cells. Mol Immunol. 2019; 116:29-37. DOI: 10.1016/j.molimm.2019.09.020. View

16.

Zhang C, Hu Z, Hu R, Pi S, Wei Z, Wang C . New insights into crosstalk between pyroptosis and autophagy co-induced by molybdenum and cadmium in duck renal tubular epithelial cells. J Hazard Mater. 2021; 416:126138. DOI: 10.1016/j.jhazmat.2021.126138. View

17.

Martinez-Sanchez L, Ngo P, Pradhan R, Becker L, Boehringer D, Soteriou D . Epithelial RAC1-dependent cytoskeleton dynamics controls cell mechanics, cell shedding and barrier integrity in intestinal inflammation. Gut. 2022; 72(2):275-294. PMC: 9872254. DOI: 10.1136/gutjnl-2021-325520. View

18.

Williams J, Duckworth C, Burkitt M, Watson A, Campbell B, Pritchard D . Epithelial cell shedding and barrier function: a matter of life and death at the small intestinal villus tip. Vet Pathol. 2014; 52(3):445-55. PMC: 4441880. DOI: 10.1177/0300985814559404. View

19.

Villarino A, Kanno Y, OShea J . Mechanisms and consequences of Jak-STAT signaling in the immune system. Nat Immunol. 2017; 18(4):374-384. PMC: 11565648. DOI: 10.1038/ni.3691. View

20.

Hasan S, Hetie P, Matunis E . Niche signaling promotes stem cell survival in the Drosophila testis via the JAK-STAT target DIAP1. Dev Biol. 2015; 404(1):27-39. PMC: 4469572. DOI: 10.1016/j.ydbio.2015.04.017. View