A Quantitative Study on the Protective Effect of Resveratrol against Bisphenol-A- Induced Oral Mucosa and Tongue Toxicity in Male Rats: A Stereological Study


Oral mucosa

How to Cite

Rahmani-Moghadam, E. ., Nadimi, E. ., Bordbar, A. ., Ayareh, N. ., Bordbar, E. ., & Bordbar, H. (2022). A Quantitative Study on the Protective Effect of Resveratrol against Bisphenol-A- Induced Oral Mucosa and Tongue Toxicity in Male Rats: A Stereological Study. Iranian Red Crescent Medical Journal, 24(1). https://doi.org/10.32592/ircmj.2022.24.1.992


Background: Bisphenol-A (BPA) is one of the hazardous chemicals, which is extensively used. BPA can cause oxidative stress. Resveratrol (RES) is a natural polyphenol that possesses several health benefits, such as antioxidant effects.

Objectives: This study aimed to investigate the protective effects of RES against BPA-induced oral mucosa and tongue toxicity.

Methods: A total of five groups of Sprague-Dawley male rats (n=30) were used in this study. Group 1 was the control group, and group 2 received 50 mg /kg BPA by gavage. Group 3 was given 100 mg/kg of RES, and group 4 received 50 mg/kg BPA plus 100 mg/kg RES. In group 5, the sham group, the volume of the injectable drug received from olive oil was given as gavage for eight weeks. Following that, the paraffinized samples were sectioned in 5µm thickness to estimate the volume.

Results: The results showed that BPA had a different effect on tissues. Moreover, the total volume of lamina propria, mucosal glands, the total glands of the tongue, volumetric density of the epithelium, and glands of the oral mucosa increased in the BPA group, while in the BPA+RES group, these structures reduced, compared to the BPA group. In addition, the total volume of the epithelium of the tongue decreased in the BPA group, whereas this structure increased in the BPA+RES group, compared to the BPA group.

Conclusion: BPA has different effects on the oral mucosa and tongue. These effects can exert influence on the normal function of the cells in these areas. RES, with its antioxidant properties, had a protective effect on these structures against the BPA.



  1. Poormoosavi SM, Najafzadehvarzi H, Behmanesh MA, Amirgholami R. Protective effects of Asparagus officinalis extract against Bisphenol A- induced toxicity in Wistar rats. Toxicol Rep. 2018;5:427-33. https://doi.org/10.1016/j.toxrep.2018.02.010
  2. Dükkancı M. Sono-photo-Fenton oxidation of bisphenol-A over a LaFeO3 perovskite catalyst. Ultra Sonoch. 2018;40:110-6.  DOI: 10.1016/j.ultsonch.2017.04.040
  3. Gules O, Yildiz M, Naseer Z, Tatar M. Effects of folic acid on testicular toxicity induced by bisphenol-A in male Wistar rats. Biot Histo. 2019;94(1):26-35. DOI: 10.1080/10520295.2018.1493222
  4. Zhu X, Wu G, Xing Y, Wang C, Yuan X, Li B. Evaluation of single and combined toxicity of bisphenol A and its analogues using a highly-sensitive micro-biosensor. J Hazard Mater. 2019;381:120908. DOI: 10.1016/j.jhazmat.2019.120908
  5. Mahdavinia M, Alizadeh S, Raesi Vanani A, Dehghani MA, Shirani M, Alipour M, et al. Effects of quercetin on bisphenol A-induced mitochondrial toxicity in rat liver. Ir J Basic Med Sci. 2019;22(5):499-505. PMCID: PMC6556511 DOI: 10.22038/ijbms.2019.32486.7952
  6. Braniste V, Jouault A, Gaultier E, Polizzi A, Buisson-Brenac C, Leveque M, et al. Impact of oral bisphenol A at reference doses on intestinal barrier function and sex differences after perinatal exposure in rats. Proce Nat Acad Sci. 2010;107(1):448-53. PMCID: PMC2806743 DOI: 10.1073/pnas.0907697107
  7. Rameshrad M, Imenshahidi M, Razavi BM, Iranshahi M, Hosseinzadeh H. Bisphenol A vascular toxicity: Protective effect of Vitis vinifera (grape) seed extract and Resveratrol. Phytother Res. 2018;32(12):2396-407. DOI: 10.1002/ptr.6175
  8. Tzatzarakis MN, Vakonaki E, Kavvalakis MP, Barmpas M, Kokkinakis EN, Xenos K, et al. Biomonitoring of bisphenol A in hair of Greek population. Chemosphere. 2015;118:336-41. DOI: 10.1016/j.chemosphere.2014.10.044
  9. Acconcia F, Pallottini V, Marino M. Molecular mechanisms of action of BPA. Dose Res. 2015;13(4):1559325815610582. PMCID: PMC4679188 DOI: 10.1177/1559325815610582
  10. Tong X, Li Y, Zhang F, Chen X, Zhao Y, Hu B, et al. Adsorption of 17beta-estradiol onto humic-mineral complexes and effects of temperature, pH, and bisphenol A on the adsorption process. Environ Pollut. 2019;254(PtA):112924. https://doi.org/10.1016/j.envpol.2019.07.092
  11. Kourouma A, Quan C, Duan P, Qi S, Yu T, Wang Y, et al. Bisphenol A induces apoptosis in liver cells through induction of ROS. Adva Toxic. 2015;2015https://doi.org/10.1155/2015/901983
  12. Morgan AM, El-Ballal SS, El-Bialy BE, El-Borai NB. Studies on the potential protective effect of cinnamon against bisphenol A-and octylphenol-induced oxidative stress in male albino rats. Toxicology reports. 2014;1:92-101. PMCID: PMC5598475 DOI: 10.1016/j.toxrep.2014.04.003
  13. Han C, Hong Y-C. Bisphenol A, hypertension, and cardiovascular diseases: epidemiological, laboratory, and clinical trial evidence. Cur Hypert Reps. 2016;18(2):11-22. DOI: 10.1007/s11906-015-0617-2
  14. Folia M, Boudalia S, Ménétrier F, Decocq L, Pasquis B, Schneider C, et al. Oral homeostasis disruption by medical plasticizer component bisphenol A in adult male rats. Laryng. 2013;123(6):1405-10.  DOI: 10.1002/lary.23791
  15. Seki K, Koshi R, Sugano N, Masutani S, Yoshinuma N, Ito K. Microarray Analysis of Bisphenol A‐induced Changes in Gene Expression in Human Oral Epithelial Cells. Acta Bioch Bioph Sinica. 2007;39(11):879-84.  DOI: 10.1111/j.1745-7270.2007.00351.x
  16. Bradamante S, Barenghi L, Villa A. Cardiovascular protective effects of resveratrol. Cardio Dru Rev. 2004;22(3):169-88. DOI: 10.1111/j.1527-3466.2004.tb00139.x
  17. Liu F-C, Tsai H-I, Yu H-P. Organ-protective effects of red wine extract, Resveratrol, in oxidative stress-mediated reperfusion injury. Oxida Med Cell Long. 2015;2015:56834. PMCID: PMC4487914 DOI: 10.1155/2015/568634
  18. Jia R, Li Y, Cao L, Du J, Zheng T, Qian H, et al. Antioxidative, anti-inflammatory and hepatoprotective effects of Resveratrol on oxidative stress-induced liver damage in tilapia (Oreochromis niloticus). Comparative Biochemistry and Physiology Part - C: Toxic Pharma. 2019;215:56-66. DOI: 10.1016/j.cbpc.2018.10.002
  19. Jia E, Yan Y, Zhou M, Li X, Jiang G, Liu W, et al. Combined effects of dietary quercetin and Resveratrol on growth performance, antioxidant capability and innate immunity of blunt snout bream (Megalobrama amblycephala). Anim Feed Sci Tech. 2019;256:19-25. https://doi.org/10.1016/j.anifeedsci.2019.114268
  20. Han Z, Yang Q, Liu B, Wu J, Li Y, Yang C, et al. MicroRNA-622 functions as a tumor suppressor by targeting K-Ras and enhancing the anticarcinogenic effect of Resveratrol. Carcinog. 2012;33(1):131-9. DOI: 10.1093/carcin/bgr226
  21. Singh D, Mendonsa R, Koli M, Subramanian M, Nayak SK. Antibacterial activity of Resveratrol structural analogues: A mechanistic evaluation of the structure-activity relationship. Toxi App Pharma. 2019;367:23-32. DOI: 10.1016/j.taap.2019.01.025
  22. Vestergaard M, Ingmer H. Antibacterial and antifungal properties of resveratrol. Int J Antiml Ag. 2019;53(6):716-23. DOI: 10.1016/j.ijantimicag.2019.02.015
  23. Zhao X, Tong W, Song X, Jia R, Li L, Zou Y, et al. Antiviral effect of Resveratrol in piglets infected with virulent pseudorabies virus. Viruses. 2018;10(9). PMCID: PMC6164078 DOI: 10.3390/v10090457
  24. Riba A, Deres L, Sumegi B, Toth K, Szabados E, Halmosi R. Cardioprotective effect of Resveratrol in a postinfarction heart failure model. Oxid Med Cell Long. 2017;21-32. https://doi.org/10.1155/2017/6819281
  25. Lin KL, Lin KJ, Wang PW, Chuang JH, Lin HY, Chen SD, et al. Resveratrol provides neuroprotective effects through modulation of mitochondrial dynamics and ERK1/2 regulated autophagy. Free Radic Res. 2018;52(11-12):1371-86. DOI: 10.1080/10715762.2018.1489128
  26. Sticozzi C, Belmonte G, Cervellati F, Muresan XM, Pessina F, Lim Y, et al. Resveratrol protects SR-B1 levels in keratinocytes exposed to cigarette smoke. Free Radic Res. 2014;69:50-7. PMCID: PMC3967961 DOI: 10.1016/j.freeradbiomed.2014.01.007
  27. Cai Y-J, Fang J-G, Ma L-P, Yang L, Liu Z-L. Inhibition of free radical-induced peroxidation of rat liver microsomes by Resveratrol and its analogues. Bioch Bioph Acta (BBA)-Mole Disease. 2003;1637(1):31-8. DOI: 10.1016/s0925-4439(02)00174-6
  28. Rameshrad M, Razavi BM, Imenshahidi M, Hosseinzadeh H. Vitis vinifera (grape) seed extract and Resveratrol alleviate bisphenol-A-induced metabolic syndrome: Biochemical and molecular evidences. Phyto Res. 2019;33(3):832-44. DOI: 10.1002/ptr.6276
  29. Rameshrad M, Imenshahidi M, Razavi BM, Iranshahi M, Hosseinzadeh H. Bisphenol A vascular toxicity: Protective effect of Vitis vinifera (grape) seed extract and Resveratrol. Phyto Res. 2018;32(12):2396-407. DOI: 10.1002/ptr.6175
  30. Hamza RZ, Abu-El-Zahab HS, Al-Juaid NS. Hepatoprotective and antioxidant role of Resveratrol on bisphenol a - Induced toxicity in rats. Toxi Int. 2017;24(3):292-300. https://www.informaticsjournals.com/index.php/toxi/article/view/21106
  31. Biswas P, Dellanoce C, Vezzoli A, Mrakic-Sposta S, Malnati M, Beretta A, et al. Antioxidant Activity with Increased Endogenous Levels of Vitamin C, E and A Following Dietary Supplementation with a Combination of Glutathione and Resveratrol Precursors. Nutrients. 2020;12(11):3224. PMCID: PMC7690269 DOI: 10.3390/nu12113224
  32. Li C-Y, Zhao Y-H, Hao H-S, Wang H-Y, Huang J-M, Yan C-L, et al. Resveratrol significantly improves the fertilisation capacity of bovine sex-sorted semen by inhibiting apoptosis and lipid peroxidation. Sci Rep. 2018;8(1):1-10. PMCID: PMC5954094 DOI: 10.1038/s41598-018-25687-z
  33. Haghighatdoost F, Hariri M. Can Resveratrol supplement change inflammatory mediators? A systematic review and meta-analysis on randomized clinical trials. Euro J Clin Nutr. 2019;73(3):345-55. DOI: 10.1038/s41430-018-0253-4
  34. Bordbar H, Soleymani A, Nadimi E, Yahyavi S-S, Fazelian-Dehkordi K. A Quantitative Study on the Protective Effects of Resveratrol against Bisphenol A-induced Hepatotoxicity in Rats: A Stereological Study. Iran J Med Sci. 2020;46(3):218-227. PMCID: PMC8163701 DOI: 10.30476/ijms.2020.83308.1233
  35. Unal B, Kara A, Aksak S, Unal D. A stereological assessment method for estimating the surface area of cycloids. Eurasian J Med. 2010;42(2):66-73. PMCID: PMC4261337 DOI: 10.5152/eajm.2010.20
  36. Karbalay-Doust S, Noorafshan A. Stereological study of the effects of nandrolone decanoate on the mouse liver. Micron. 2009;40(4):471-5. DOI: 10.1016/j.micron.2008.12.006
  37. Scherle W. A simple method for volumetry of organs in quantitative stereology. Mikroskopie. 1970;26:57-60. PMID: 5530651
  38. Zhang H, Zhang J, Ungvari Z, Zhang C. Resveratrol improves endothelial function: role of TNFα and vascular oxidative stress. Arteriosc Thromb Vasc Biology. 2009;29(8):1164-71. PMCID: PMC2761384 DOI: 10.1161/ATVBAHA.109.187146
  39. Guthrie AR, Chow HHS, Martinez JA. Effects of Resveratrol on drug‐and carcinogen‐metabolizing enzymes, implications for cancer prevention. Pharmacol Res Perspect. 2017;5(1):e00294. PMCID: PMC5461649 DOI: 10.1002/prp2.294
  40. Zhou L, Long J, Sun Y, Chen W, Qiu R, Yuan D. Resveratrol ameliorates atherosclerosis induced by high-fat diet and LPS in ApoE−/− mice and inhibits the activation of CD4+ T cells. Nutr Metab (Lond). 2020;17:1-12. PMCID: PMC7251691 DOI: 10.1186/s12986-020-00461-z
  41. Polonio N, Rocha C, Clemente E. Trans-resveratrol concentrations and antimutagenic potential of juice from the grape cultivars Vênus, BRS Violeta and Isabel. Gene Molec Res. 2014;13(1):1152-9. DOI: 10.4238/2014.February.25.1
  42. Kim JY, Cho KH, Lee HY. Effect of Resveratrol on oral cancer cell invasion induced by lysophosphatidic acid. J Den Hyg Sci. 2018;18(3):188-93. DOI: 10.17135/jdhs.2018.18.3.188
  43. Çiğ B, Yildizhan K. Resveratrol diminishes bisphenol A-induced oxidative stress through TRPM2 channel in the mouse kidney cortical collecting duct cells. J Rece Sig Transd. 2020;1:1-14. DOI: 10.1080/10799893.2020.1769657
  44. Yener A, Mustafa N. Resveratrol attenuates hypoxia-induced neuronal cell death, inflammation and mitochondrial oxidative stress by modulation of TRPM2 channel. Sci Rep. 2020;10(1):11-25. https://doi.org/10.1038/s41598-020-63577-5
  45. Xia N, Daiber A, Förstermann U, Li H. Antioxidant effects of Resveratrol in the cardiovascular system. Br J Pharmacol. 2017;174(12):1633-46. PMCID: PMC5446570 DOI: 10.1111/bph.13492
  46. KL, Beierwaltes WH. Resveratrol induces acute endothelium-dependent renal vasodilation mediated through nitric oxide and reactive oxygen species scavenging. Am J Physiol Renal Physiol. 2014;306(5):F542-F50. PMCID: PMC3949032 DOI: 10.1152/ajprenal.00437.2013
  47. Babich H, Reisbaum A, Zuckerbraun H. In vitro response of human gingival epithelial SG cells to Resveratrol. Toxicol Lett. 2000;114(1-3):143-53. DOI: 10.1016/s0378-4274(99)00288-x
  48. Mikami S, Ota I, Masui T, Itaya‑Hironaka A, Shobatake R, Okamoto H, et al. Effect of Resveratrol on cancer progression through the REG Ⅲ expression pathway in head and neck cancer cells. Int J Oncol. 2016;49(4):1553-60. DOI: 10.3892/ijo.2016.3664
  49. Quagliariello V, Coppola C, Mita D, Piscopo G, Iaffaioli R, Botti G, et al. Low doses of Bisphenol A have pro-inflammatory and pro-oxidant effects, stimulate lipid peroxidation and increase the cardiotoxicity of Doxorubicin in cardiomyoblasts. Envir Toxic Pharmy. 2019;69:1-8. DOI: 10.1016/j.etap.2019.03.006
  50. Lee J, Lim K-T. Expression of TNF-α and IL-6 in HMC-1 cells treated with bisphenol A is attenuated by plant-originating glycoprotein (75 kDa) by blocking p38 MAPK. Nau Schmie Arch Pharma. 2010;382(1):51-61. DOI: 10.1007/s00210-010-0527-4
  51. Wu Y, Pang Y, Wei W, Shao A, Deng C, Li X, et al. Resveratrol protects retinal ganglion cell axons through regulation of the SIRT1-JNK pathway. Exp Eye Res. 2020;200:108249. DOI: 10.1016/j.exer.2020.108249
  52. Csiszar A, Labinskyy N, Pinto JT, Ballabh P, Zhang H, Losonczy G, et al. Resveratrol induces mitochondrial biogenesis in endothelial cells. Am J Physiol Heart Circ Physiol. 2009;297(1):H13-H20. PMCID: PMC2711732 DOI: 10.1152/ajpheart.00368.2009