Research Studies
Study Tracker
Inflammation May Mediate the Effects of Fluoride on Liver and Kidney Function of Adults: Cross-Sectional Studies in China.Abstract
To assess associations among fluoride exposure, the inflammation, and liver and kidney functions, a total of 1646 adults aged >18 years were recruited in cross-sectional studies conducted in 2017 and 2022 in fluorosis areas. Questionnaire surveys were administered to obtain the demographic information. Urine and blood samples were collected for determinations of urinary fluoride (UF), aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin (TBIL), blood urea nitrogen (BUN), serum creatinine (SCr), serum uric acid (SUA), and white blood cell (WBC) counts. Linear regressions, generalized linear models, and mediation analyses were employed here. We found that AST, BUN, and SUA increased by 0.589, 0.087, and 4.226 with a 1 mg/L increment of UF, and the SCr showed a negative linear association with UF (B = -0.790) in all. Similar results were also observed in female. However, we only found the positive linear association between UF and AST/ALT in male. We also detected a significant modification by gender on associations between UF and values of AST, ALT, BUN, and SCr. Besides, participants with higher UF levels had higher counts of monocytes (B = 0.014) and neutrophils (B = 0.147) both in all and in stratified analyses of gender. Associations between AST/ALT, TBIL, SCr, SUA, and counts of WBC were revealed. In addition, there were mediator effects of monocytes and neutrophils in associations between UF and BUN (or SUA). We observed similar results in the age group of 46–64 years with those in all participants. This study observed a statistically significant association between UF and adult levels of AST, SCr, BUN, SUA, as well as monocyte and neutrophil counts, particularly in females. Furthermore, alterations in monocyte and neutrophil counts partially mediate the association between UF and BUN (or SUA). Our findings reveal the effects of fluoride exposure on liver and kidney function and provide clues for analyzing the relevant mechanism from an inflammatory perspective.
Supplementary Information
Below is the link to the electronic supplementary material.
ESM 1 (DOC 510 KB)
ABSTRACT ONLINE AT https://link.springer.com/article/10.1007/s12011-025-04583-4
References
-
Iheozor-Ejiofor Z, Walsh T, Lewis SR, Riley P, Boyers D, Clarkson JE, Worthington HV, Glenny AM, O’Malley L (2024) Water fluoridation for the prevention of dental caries. Cochrane Database Syst Rev 10:CD010856. https://doi.org/10.1002/14651858.CD010856.pub3
-
Hung M, Hon ES, Mohajeri A, Moparthi H, Vu T, Jeon J, Lipsky MS (2023) A national study exploring the association between fluoride levels and dental fluorosis. JAMA Netw Open 6:e2318406. https://doi.org/10.1001/jamanetworkopen.2023.18406
-
Hu Y, Li Y, Li M, Zhao T, Zhang W, Wang Y, He Y, Zhao H, Li H, Wang T, Zhao Y, Wang J, Wang J (2024) Calcium supplementation attenuates fluoride-induced bone injury via PINK1/Parkin-mediated mitophagy and mitochondrial apoptosis in mice. J Hazard Mater 465:133411. https://doi.org/10.1016/j.jhazmat.2023.133411
-
Tang H, Hou H, Song L, Tian Z, Liu W, Xia T, Wang A (2024) The role of mTORC1/TFEB axis mediated lysosomal biogenesis and autophagy impairment in fluoride neurotoxicity and the intervention effects of resveratrol. J Hazard Mater 467:133634. https://doi.org/10.1016/j.jhazmat.2024.133634
-
Guo X, Wang L, Xuan J, Chen T, Du Y, Qiao H, Zhang S, Sun Z, Wang J, Niu R (2025) Fluoride induces spermatocyte apoptosis by IP3R1/MCU-mediated mitochondrial calcium overload through MAMs. J Hazard Mater 489:137514. https://doi.org/10.1016/j.jhazmat.2025.137514
-
Ommati MM, Zuo Q, Sabouri S, Retana-Marquez S, Nategh Ahmadi H, Gholami A, Eftekhari A, Shojaei S, Lijuan L, Heidari R, Wang HW (2025) Fluoride-induced autophagy and apoptosis in the mouse ovary: genomic insights into IL-17 signaling and gut microbiota dysbiosis. J Agric Food Chem 73:2138–2155. https://doi.org/10.1021/acs.jafc.4c10165
-
World Health Organization (2004) Fluoride in drinking-water, background document for development of WHO guidelines for drinking-water quality. Page 2. https://www.who.int/docs/default-source/wash-documents/wash-chemicals/fluoride-background-document.pdf
-
Singh G, Kumari B, Sinam G, Kriti Kumar N (2018) Mallick S Fluoride distribution and contamination in the water, soil and plants continuum and its remedial technologies, an Indian perspective- a review. Environ Pollut 239:95–108. https://doi.org/10.1016/j.envpol.2018.04.002
-
Zhao Q, Zhou GY, Niu Q, Chen JW, Li P, Tian ZY, Li DJ, Xia T, Zhang S, Wang AG (2024) SIRT1, a target of miR-708-3p, alleviates fluoride-induced neuronal damage via remodeling mitochondrial network dynamics. J Adv Res 65:197–210. https://doi.org/10.1016/j.jare.2023.11.032
-
Li X, Yang J, Luo H, Qiao Y, Zhao L, Cheng C, Fu W, Tan Y, Wang J, Liang C, Zhang J (2024) Riboflavin attenuates fluoride-induced testicular injury via interleukin 17A-mediated classical pyroptosis. J Agric Food Chem 72:6143–6154. https://doi.org/10.1021/acs.jafc.3c09071
-
Qiao Y, Cui Y, Tan Y, Zhuang C, Li X, Yong Y, Zhang X, Ren X, Cai M, Yang J, Lang Y, Wang J, Liang C, Zhang J (2024) Fluoride induces immunotoxicity by regulating riboflavin transport and metabolism partly through IL-17A in the spleen. J Hazard Mater 476:135085. https://doi.org/10.1016/j.jhazmat.2024.135085
-
Ommati MM, Jin Y, Zamiri MJ, Retana-Marquez S, Nategh Ahmadi H, Sabouri S, Song SZ, Heidari R, Wang HW (2025) Sex-Specific mechanisms of fluoride-induced gonadal injury: a multi-omics investigation into reproductive toxicity and gut microbiota disruption. J Agric Food Chem 73:2527–2550. https://doi.org/10.1021/acs.jafc.4c10190
-
Whitford GM, Pashley DH, Reynolds KE (1979) Fluoride tissue distribution: short-term kinetics. Am J Physiol 236:F141-148. https://doi.org/10.1152/ajprenal.1979.236.2.F141
-
Malin AJ, Lesseur C, Busgang SA, Curtin P, Wright RO, Sanders AP (2019) Fluoride exposure and kidney and liver function among adolescents in the United States: NHANES, 2013–2016. Environ Int 132:105012. https://doi.org/10.1016/j.envint.2019.105012
-
Wu L, Fan C, Zhang Z, Zhang X, Lou Q, Guo N, Huang W, Zhang M, Yin F, Guan Z, Yang Y, Gao Y (2021) Association between fluoride exposure and kidney function in adults: a cross-sectional study based on endemic fluorosis area in China. Ecotoxicol Environ Saf 225:112735. https://doi.org/10.1016/j.ecoenv.2021.112735
-
Shashi A, Bhardwaj M (2011) Study on blood biochemical diagnostic indices for hepatic function biomarkers in endemic skeletal fluorosis. Biol Trace Elem Res 143:803–814. https://doi.org/10.1007/s12011-010-8944-2
-
Xiong X, Liu J, He W, Xia T, He P, Chen X, Yang K, Wang A (2007) Dose-effect relationship between drinking water fluoride levels and damage to liver and kidney functions in children. Environ Res 103:112–116. https://doi.org/10.1016/j.envres.2006.05.008
-
Ahmed I, Salman S, Iqbal S, Siddiqui A, Fatima I (2021) Effect of drinking high fluoride water on liver enzymes a comparitive cross-sectional study. J Community Hosp Intern Med Perspect 11:350–353. https://doi.org/10.1080/20009666.2021.1898088
-
Yu Y, Niu R, Zhao F, Zhao Y, Wang J, Wang J, Cao Q, Fu R, Nateghahmadi MH, Sun Z (2022) Moderate exercise relieves fluoride-induced liver and kidney inflammatory responses through the IKKbeta/NFkappaB pathway. Environ Sci Pollut Res Int 29:78429–78443. https://doi.org/10.1007/s11356-022-21360-1
-
Caglayan C, Kandemir FM, Darendelioglu E, Kucukler S, Ayna A (2021) Hesperidin protects liver and kidney against sodium fluoride-induced toxicity through anti-apoptotic and anti-autophagic mechanisms. Life Sci 281:119730. https://doi.org/10.1016/j.lfs.2021.119730
-
Zhao Y, Wang J, Zhang J, Sun Z, Niu R, Manthari RK, Ommati MM, Wang S, Wang J (2022) Fluoride exposure induces mitochondrial damage and mitophagy via activation of the IL-17A pathway in hepatocytes. Sci Total Environ 804:150184. https://doi.org/10.1016/j.scitotenv.2021.150184
-
Du WJ, Zhen JH, Zeng ZQ, Zheng ZM, Xu Y, Qin LY, Chen SJ (2013) Expression of interleukin-17 associated with disease progression and liver fibrosis with hepatitis B virus infection: IL-17 in HBV infection. Diagn Pathol 8:40. https://doi.org/10.1186/1746-1596-8-40
-
Mussbacher M, Derler M, Basilio J, Schmid JA (2023) NF-kappaB in monocytes and macrophages – an inflammatory master regulator in multitalented immune cells. Front Immunol 14:1134661. https://doi.org/10.3389/fimmu.2023.1134661
-
Angmar-Mansson B, Whitford GM (1984) Enamel fluorosis related to plasma F levels in the rat. Caries Res 18:25–32. https://doi.org/10.1159/000260743
-
Kratofil RM, Kubes P, Deniset JF (2017) Monocyte conversion during inflammation and injury. Arterioscler Thromb Vasc Biol 37:35–42. https://doi.org/10.1161/ATVBAHA.116.308198
-
Wang D, Yin K, Zhang Y, Lu H, Hou L, Zhao H, Xing M (2023) Fluoride induces neutrophil extracellular traps and aggravates brain inflammation by disrupting neutrophil calcium homeostasis and causing ferroptosis. Environ Pollut 331:121847. https://doi.org/10.1016/j.envpol.2023.121847
-
Den Besten P, Wells CR, Abduweli Uyghurturk D (2022) Fluoride exposure and blood cell markers of inflammation in children and adolescents in the United States: NHANES, 2013–2016. Environ Health 21:102. https://doi.org/10.1186/s12940-022-00911-6
-
Yanhua X, Deming Z, Ward SNH (2019) Investigation of the relationship between serum bilirubin levels and coronary heart disease. Shanghai Med Pharm J 15:52–54
-
Du Y, Fu X, Jin J, Li Z, Xu K, Guo M, Hou X, Feng Z, Ding L, Gong Y, Liu B, Yu F, Zhou G, Ba Y (2022) Effects of SNPs in SOD2 and SOD3 interacted with fluoride exposure on the susceptibility of dental fluorosis. Int J Hyg Environ Health 239:113879. https://doi.org/10.1016/j.ijheh.2021.113879
-
Ward LD, Tu HC, Quenneville CB, Tsour S, Flynn-Carroll AO, Parker MM, Deaton AM, Haslett PAJ, Lotta LA, Verweij N, Ferreira MAR, Regeneron Genetics C, Geisinger-Regeneron Discov EHRC, Baras A, Hinkle G, Nioi P (2021) GWAS of serum ALT and AST reveals an association of SLC30A10 Thr95Ile with hypermanganesemia symptoms. Nat Commun 12:4571. https://doi.org/10.1038/s41467-021-24563-1
-
Wang T, Li H, Li Y, Li M, Zhao H, Zhang W, Zhao T, Wang Y, Wang J, Wang J (2024) Selenomethionine supplementation mitigates fluoride-induced liver apoptosis and inflammatory reactions by blocking Parkin-mediated mitophagy in mice. Sci Total Environ 951:175458. https://doi.org/10.1016/j.scitotenv.2024.175458
-
Sutoh Y, Hachiya T, Suzuki Y, Komaki S, Ohmomo H, Kakisaka K, Wang T, Takikawa Y, Shimizu A (2020) ALDH2 genotype modulates the association between alcohol consumption and AST/ALT ratio among middle-aged Japanese men: a genome-wide G x E interaction analysis. Sci Rep 10:16227. https://doi.org/10.1038/s41598-020-73263-1
-
Macedo E (2011) Blood urea nitrogen beyond estimation of renal function. Crit Care Med 39:405–406. https://doi.org/10.1097/CCM.0b013e318205c33a
-
Fathallah-Shaykh SA, Cramer MT (2014) Uric acid and the kidney. Pediatr Nephrol 29:999–1008. https://doi.org/10.1007/s00467-013-2549-x
-
Li D, Yang C, Sun L, Zhao Z, Liu J, Zhang C, Sun D, Zhang Q (2024) High fluoride aggravates cadmium-mediated nephrotoxicity of renal tubular epithelial cells through ROS-PINK1/Parkin pathway. Sci Total Environ 953:175927. https://doi.org/10.1016/j.scitotenv.2024.175927
-
Quadri JA, Sarwar S, Sinha A, Kalaivani M, Dinda AK, Bagga A, Roy TS, Das TK, Shariff A (2018) Fluoride-associated ultrastructural changes and apoptosis in human renal tubule: a pilot study. Hum Exp Toxicol 37:1199–1206. https://doi.org/10.1177/0960327118755257
-
Shao D, Zhang J, Tang L, Yu Q, Hu X, Ruan Q, Ouyang W, Zhang Z (2020) Effects and molecular mechanism of L-type calcium channel on fluoride-induced kidney injury. Biol Trace Elem Res 197:213–223. https://doi.org/10.1007/s12011-019-01987-x
-
Kashani K, Rosner MH, Ostermann M (2020) Creatinine: from physiology to clinical application. Eur J Intern Med 72:9–14. https://doi.org/10.1016/j.ejim.2019.10.025
-
Ma L, Zhang C, Gui Y, Zou T, Xi S, Guo X (2023) Fluoride regulates the differentiation and atrophy through FGF21/ERK signaling pathway in C2C12 cells. Ecotoxicol Environ Saf 252:114626. https://doi.org/10.1016/j.ecoenv.2023.114626
-
Aslan A, Can MI, Gok O, Beyaz S, Parlak G, Ozercan IH (2022) The inducing of caspase and Bcl-2 pathway with royal jelly decreases the muscle tissue damage exposed with fluoride in rats. Environ Sci Pollut Res Int 29:10547–10557. https://doi.org/10.1007/s11356-021-16456-z
-
Ford ES, Gillespie C, Ballew C, Sowell A, Mannino DM (2002) Serum carotenoid concentrations in US children and adolescents. Am J Clin Nutr 76:818–827. https://doi.org/10.1093/ajcn/76.4.818
-
Liu J, Yang S, Luo MJ, Zhao X, Zhang YM, Luo Y (2018) Association of dietary carotenoids intake with skeletal fluorosis in the coal-burning fluorosis area of Guizhou province. Biomed Environ Sci 31:438–447. https://doi.org/10.3967/bes2018.057
-
Li W, Jiang B, Cao X, Xie Y, Huang T (2017) Protective effect of lycopene on fluoride-induced ameloblasts apoptosis and dental fluorosis through oxidative stress-mediated Caspase pathways. Chem Biol Interact 261:27–34. https://doi.org/10.1016/j.cbi.2016.11.021
-
Inkielewicz-Stepniak I, Knap N (2012) Effect of exposure to fluoride and acetaminophen on oxidative/nitrosative status of liver and kidney in male and female rats. Pharmacol Rep 64:902–911. https://doi.org/10.1016/s1734-1140(12)70885-x
-
Citro A, Campo F, Dugnani E, Piemonti L (2020) Innate immunity mediated inflammation and beta cell function: neighbors or enemies? Front Endocrinol (Lausanne) 11:606332. https://doi.org/10.3389/fendo.2020.606332
-
Stone KD, Prussin C, Metcalfe DD (2010) IgE, mast cells, basophils, and eosinophils. J Allergy Clin Immunol 125:S73-80. https://doi.org/10.1016/j.jaci.2009.11.017
-
Chen X, Wei W, Li Y, Huang J, Ci X (2019) Hesperetin relieves cisplatin-induced acute kidney injury by mitigating oxidative stress, inflammation and apoptosis. Chem Biol Interact 308:269–278. https://doi.org/10.1016/j.cbi.2019.05.040
-
Owumi SE, Aliyu-Banjo NO, Danso OF (2019) Fluoride and diethylnitrosamine coexposure enhances oxido-inflammatory responses and caspase-3 activation in liver and kidney of adult rats. J Biochem Mol Toxicol 33:e22327. https://doi.org/10.1002/jbt.22327
-
Zohouri FV, Swinbank CM, Maguire A, Moynihan PJ (2006) Is the fluoride/creatinine ratio of a spot urine sample indicative of 24-h urinary fluoride? Community Dent Oral Epidemiol 34:130–138. https://doi.org/10.1111/j.1600-0528.2006.00269.x
Funding
This work was supported by the National Natural Science Foundation of China [Grant numbers: 81972981 and 82003401], the China Postdoctoral Science Foundation [Grant numbers: 2022T150586 and 2021M692904], the Henan Provincial Science and Technology Department Research Project [Grant number: 242102310118], and the key project of the Innovation and Entrepreneurship Training Program for College Students [Grant number: 202410459060].
