Efectos protectores de la vitamina C y E sobre la expresión génica inducida por la fluorosis en las vías oxidativas, apoptóticas y PI3K/AKT en los tejidos hepáticos y renales.

• Ahmet Cihat–Öner Van Yuzuncu Yıl University, Faculty of Veterinary Medicine, Department of Pharmacology and Toxicology. Van, Türkiye. https://orcid.org/0000-0001-6614-4347
• Ayşe Usta Van Yuzuncu Yıl University, Faculty of Science, Department of Chemistry. Van, Türkiye. https://orcid.org/0000-0002-5522-3469
• Veysel Yüksek Van Yuzuncu Yıl University, Özalp Vocational School, Department of Medical Laboratory Technician. Van, Türkiye. https://orcid.org/0000-0001-7432-4989
• Sedat Çetin Ankara Yıldırım Beyazıt University, Department of Veterinary Medicine, Vocational School of Health Services. Ankara, Türkiye. https://orcid.org/0000-0002-6102-8571
• Semiha Dede Van Yuzuncu Yıl University, Faculty of Veterinary Medicine, Department of Biochemistry. Van, Türkiye. https://orcid.org/0000-0001-5744-6327
• Ayşegül Öner Van Yüzüncü Yıl University Institute of Health Sciences, Van, Türkiye. https://orcid.org/0000-0002-2906-3035

DOI: https://doi.org/10.52973/rcfcv-e363924

Palabras clave: Fluorosis, antioxidantes, vitamina C, vitamina E, vía fosfoinositida 3–quinasa / proteína quinasa B, apoptosis, estrés oxidativo, expresión génica

Resumen

Este estudio tuvo como objetivo investigar los efectos moduladores de la vitamina C y la vitamina E sobre las alteraciones de la expresión génica inducidas por fluorosis en el estrés oxidativo (Glutatión Peroxidasa 1, Factor Citosólico de Neutrófilos 1, Superóxido Dismutasa 1), la apoptosis (Caspasa 3, Caspasa 8, Caspasa 9) y las vías de señalización de la fosfoinositida 3–quinasa / proteína quinasa B / diana mecanicista de la rapamicina (fosfoinositida 3– quinasa, proteína quinasa B, receptor Erb-B2 tirosina quinasa 2, diana mecanicista de la rapamicina, proteína tumoral p53) en ratas. Se asignaron aleatoriamente cuarenta y ocho ratas Wistar Albino macho a seis grupos. Se administró fluoruro de sodio (150 mg·kg– 1·día–1) a través del agua potable durante 16 semanas, seguido de un suplemento vitamínico (C y E) oral durante 4 semanas. Se analizaron los niveles de expresión del ARNm mediante RT-qPCR. La exposición al fluoruro de sodio aumentó la expresión de Factor Citosólico de Neutrófilos 1 tanto en los tejidos renales como en los hepáticos (P<0,001), al tiempo que redujo los niveles de Glutatión Peroxidasa 1 y Superóxido Dismutasa 1. La vitamina E, la vitamina C y su combinación suprimieron significativamente la expresión de Factor Citosólico de Neutrófilos 1 (P<0,001), mientras que la recuperación de Glutatión Peroxidasa 1 y Superóxido Dismutasa 1 solo fue significativa en los tejidos renales (P<0,05). El fluoruro de sodio también reguló al alza de forma notable los genes apoptóticos Caspasa 3, Caspasa 8 y Caspasa 9 (P<0,05), y los tratamientos antioxidantes atenuaron sustancialmente estos aumentos (P<0,0001). Además, todos los genes relacionados con la vía fosfoinositida 3–quinasa / proteína quinasa B se sobreexpresaron fuertemente tras la administración de fluoruro de sodio (P<0,0001), y la suplementación con vitaminas redujo eficazmente estos aumentos en ambos tejidos (P<0,0001). La vitamina C y la vitamina E, especialmente en combinación, exhiben efectos protectores sustanciales al restaurar los patrones de expresión génica hacia niveles homeostáticos. Esto sugiere que la suplementación combinada con antioxidantes puede servir como una estrategia terapéutica prometedora contra la disfunción celular inducida por la fluorosis.

Citas

Xiong X, Liu J, He W, Xia T, He P, Chen X, Yang K, Wang A. Dose-effect relationship between drinking water fluoride levels and damage to liver and kidney functions in children. Environ. Res. [Internet]. 2007; 103(1):112–116. doi: https://doi.org/b6fsxc DOI: https://doi.org/10.1016/j.envres.2006.05.008

Agalakova NI, Nadei OV. Inorganic fluoride and functions of brain. Crit. Rev. Toxicol. [Internet]. 2020; 50(1):28–46. doi: https://doi.org/rbc2 DOI: https://doi.org/10.1080/10408444.2020.1722061

Peng W, Xu S, Zhang J, Zhang Y. Vitamin C Attenuates Sodium Fluoride-Induced Mitochondrial Oxidative Stress and Apoptosis via Sirt1–SOD2 Pathway in F9 Cells. Biol. Trace Elem. Res. [Internet]. 2019; 191:189–198. doi: https://doi.org/rbcj DOI: https://doi.org/10.1007/s12011-018-1599-0

Strunecka A, Strunecky O. Mechanisms of Fluoride Toxicity: From Enzymes to Underlying Integrative Networks. Appl. Sci. [Internet]. 2020; 10(20):7100. doi: https://doi.org/g9hbtd DOI: https://doi.org/10.3390/app10207100

Usta A, Öner AC, Yüksek V, Dede S, Çetin S. Effect of vitamins C and E on inflammation gene expression in kidney tissue of rats with experimental fluorosis. Van Sağlık Bil. Der. [Internet]. 2021; 14(2):199–208. doi: https://doi.org/rbcm DOI: https://doi.org/10.52976/vansaglik.872528

Dede S, Öner AC, Yüksek V, Çetin S, Usta A. Investigation of the effect of vitamin C and vitamin E on serum protein fractions in experimentally induced fluorosis rats. Kocatepe Vet. J. [Internet]. 2021; 14(2):262–267. doi: https://doi.org/gj9vjd DOI: https://doi.org/10.30607/kvj.826435

Pal P, Jha NK, Pal D, Jha SK, Anand U, Gopalakrishnan AV, Dey A, Mukhopadhyay PK. Molecular basis of fluoride toxicities: Beyond benefits and implications in human disorders. Genes Dis. [Internet]. 2023; 10(4):1470–1493. doi: https://doi.org/rbcn DOI: https://doi.org/10.1016/j.gendis.2022.09.004

Kartlaşmış K, Kökbaş U, Kayrın L. Biochemistry of apoptosis. Arşiv Kaynak Tarama Derg. [Internet]. 2016; 25(1):52–69. doi: https://doi.org/rbcp DOI: https://doi.org/10.17827/aktd.16717

Fu X, Xie FN, Dong P, Li QC, Yu GY, Xiao R. High-Dose fluoride ımpairs the properties of human embryonic stem cells via JNK Signaling. Plos One [Internet]. 2016; 11(2):e0148819. doi: https://doi.org/f8rhc5 DOI: https://doi.org/10.1371/journal.pone.0148819

Fan B, Yu Y, Zhang Y. PI3K-Akt1 expression and its significance in liver tissues with chronic fluorosis. Int. J. Clin. Exp. Pathol. [Internet]. 2015 [cited 12 Dec 2025]; 8(2):1226–1236. PMID: 25973007. Available in: https://goo.su/Pin1uU

Laplante M, Sabatini DM. mTOR signaling in growth control and disease. Cell [Internet]. 2012; 149(2):274–293. doi: https://doi.org/ghxrn4 DOI: https://doi.org/10.1016/j.cell.2012.03.017

Ortiz-Barroso G, Ramírez-Orozco RE, Esparza-Villalpando V, Macedo-Mendoza M, Barrios-García T, Pulido-Hornedo NA. Antioxidants against oxidative stress induced by sodium fluoride toxicity in murine models: A systematic review. J.Trace Elem. Med. Biol. [Internet]. 2025; 88:127619. doi: https://doi.org/rbcq DOI: https://doi.org/10.1016/j.jtemb.2025.127619

Yilmaz B, Erkan M. Effects of vitamin C on sodıum fluoride- induced oxidative damage in sertoli cells. Fluoride. [Internet]. 2015 [cited 12 Dec 2025]; 48(3):241–251. Available in: https://goo.su/cYOz6

Traber MG, Stevens JF. Vitamins C and E: beneficial effects from a mechanistic perspective. Free Radic. Biol. Med. [Internet]. 2011; 51(5):1000–1013. doi: https://doi.org/bk7v9z DOI: https://doi.org/10.1016/j.freeradbiomed.2011.05.017

Li Y, Schellhorn HE. New developments and novel therapeutic perspectives for vitamin C. J. Nutr. [Internet]. 2007; 137(10):2171–2184. doi: https://doi.org/gfkcbm DOI: https://doi.org/10.1093/jn/137.10.2171

Chomczynski P, Mackey K. Modification of the TRI reagent procedure for isolation of RNA from polysaccharide – and proteoglycan-rich sources. Biotechniques [Internet]. 1995 [cited 12 Dec 2025]; 19(6):942–945. Available in: https://goo.su/Flnq

Bustin SA. A-Z of Quantitative PCR. IUL Biotechnology series. No. 5. California (USA): International University Line. 2004.

Kong H, He Z, Li H, Xing D, Lin J. The Association between fluoride and bone mineral density in US children and adolescents: A pilot study. Nutrients [Internet]. 2024; 16(17):2948. doi: https://doi.org/rbcr DOI: https://doi.org/10.3390/nu16172948

Lavanya S, Hdema-Shree K, Ramani P. Fluoride effect on renal and hepatic functions: A comprehensive decade review of In vitro and In vivo studies. J. Oral Biol. Craniofac. Res. [Internet]. 2024; 14(6):735–745. doi: https://doi.org/rbcs DOI: https://doi.org/10.1016/j.jobcr.2024.10.002

Subhashree T, Yashoda R, Manjunath PP. Neurotoxicity of fluoride: A narrative review. Int. J. Med. Sci. Dent. Res. [Internet]. 2024 [cited 11 Nov 2025]; 7(5):59–66. Available in: https://goo.su/rBETV

Basha MP, Sujitha NS. Chronic fluoride toxicity and myocardial damage: antioxidant offered protection in second generation rats. Toxicol. Int. [Internet]. 2011; 18(2):99–104. doi: https://doi.org/dwxrpt DOI: https://doi.org/10.4103/0971-6580.84260

Chinoy N, Sharma A. Amelioration of fluoride toxicity by vitamins E and D İn reproductive functions of male mice. Fluoride [Internet]. 1998 [cited 15 Nov 2025]; 31(4):203–216. Available in: https://goo.su/uxO2C

Azab A, Albasha M, Jbireal J, Adwas A. Sodium fluoride induces hepato-renal oxidative stress and pathophysiological changes in experimental animals. Open J. Apoptosis [Internet]. 2018; 7:1–23. doi: https://doi.org/rbct DOI: https://doi.org/10.4236/ojapo.2018.71001

Yüksek V, Çetin S, Usta A. The effect of vitamin E and selenium combination in repairing fluoride-induced DNA damage to NRK–52E cells. Mol. Biol. Rep. [Internet]. 2020; 47(10):7761– 7770. doi: https://doi.org/rbcv DOI: https://doi.org/10.1007/s11033-020-05852-2

Shao D, Zhang J, Tang L, Yu Q, Hu X, Ruan Q, Ouyang W, Zhang Z. Effects and molecular mechanism of L-type calcium channel on fluoride-induced kidney injury. Biol. Trace Elem. Res. [Internet]. 2020; 197(1):213–223. doi: https://doi.org/rbcw DOI: https://doi.org/10.1007/s12011-019-01987-x

Guo L, Yang B, Chen F, Yuan X, Cheng J, Chen X, Zhou Y, Yang X, Li Y, Liu Y, Tang D, Wang F. Disruption of the SIRT1/PI3K/ AKT signaling axis mediates fluoride-induced cardiotoxicity: Evidence from in vitro and Zebrafish models. Biol. Trace Elem. Res. [Internet]. 2026; 204(4):2411–2426. doi: https://doi.org/rbcx DOI: https://doi.org/10.1007/s12011-025-04828-2

Ma L, Zhang R, Li D, Qiao T, Guo X. Fluoride regulates chondrocyte proliferation and autophagy via PI3K/AKT/mTOR signaling pathway. Chem. Biol. Interact. [Internet]. 2021; 349:109659. doi: https://doi.org/rbcz DOI: https://doi.org/10.1016/j.cbi.2021.109659

Öner AC, Dede S, Yur F, Öner A. The effect of vitamin C and vitamin E on DNA damage, oxidative status, and some biochemical parameters in rats with experimental fluorosis. Fluoride [Internet]. 2020 [cited 11 Jan 2026]; 53(1–2):154–163. Available in: https://goo.su/EJHzK