Northern Journal of Health Sciences 3062-2247 Sinop University Histology and Embryology Histoloji ve Embriyoloji Yeni Sentezlenen Bir Kumarin Türevi Olan Etil 7-Hidroksi-2-İmino-2H-Kramen-Karboksilat, Bisfenol A'nın Erkek Sıçanların Kardiyovasküler Sistemi Üzerindeki Biyokimyasal ve Histopatolojik Toksik Etkilerini Önleyebilir Mi? Can Ethyl 7-Hydroxy-2-Imino-2H-Cramen-Carboxylate, a Newly Synthesized Coumarin Derivative, Inhibit the Biochemical and Histopathological Toxic Effects of Bisphenol A on the Cardiovascular System of Male Rats? https://orcid.org/0000-0001-9726-5846 Annaç Ebru Adıyaman Üniversitesi Tıp Fakültesi https://orcid.org/0000-0001-9613-0149 Yanılmaz Elif Merve Betül ADIYAMAN ÜNİVERSİTESİ https://orcid.org/0000-0002-9250-0293 Koca Murat ADIYAMAN ÜNİVERSİTESİ https://orcid.org/0000-0002-0173-3084 Özkaya Ahmet ADIYAMAN ÜNİVERSİTESİ https://orcid.org/0000-0003-1658-3143 Bozat Rıfat Cesur ADIYAMAN ÜNİVERSİTESİ https://orcid.org/0000-0002-6378-3546 Akgül Nadir Bilgin ADIYAMAN ÜNİVERSİTESİ 09 26 2025 1 3 179 189 06 14 2025 08 19 2025 Copyright © 2024, Northern Journal of Health Sciences 2024 Northern Journal of Health Sciences

Amaç: Bu çalışmada, yaygın olarak kullanılan bir endüstriyel kimyasal olan Bisfenol A'nın erkek Wistar albino sıçanlarının kardiyovasküler sistemi üzerindeki toksik etkileri ve yeni sentezlenen bir kumarin türevi olan Etil 7-hidroksi-2-imino-2H-kromon-3-karboksilatın bu toksisiteye karşı potansiyel koruyucu etkileri incelenmiştir.Yöntem: Bu çalışmada toplam 10-12 haftalık ve 250-300 gr ağırlığında 28 erkek Wistar Albino sıçan kullanılmıştır. Sıçanlardan dört grup (kontrol, bisfenol-A, Kumarin ve Bisfenol-A+Kumarin) oluşturulmuştur. Sıçanlara dönüşümlü günlerde orogastrik yolla Bisfenol ve/veya Kumarin verilmiştir. Deneyin sonunda kalp ve damar dokularında biyokimyasal, histopatolojik ve histomorfometrik analizler yapılmıştır. Sonuçlar: Biyokimyasal analizler sonucunda, Bisfenol uygulamasının toplam antioksidan kapasiteyi önemli ölçüde azalttığı ve toplam oksidan durumunu ve malondialdehit seviyelerini artırdığı bulundu; bu da Bisfenolün oksidatif strese neden olduğunu göstermektedir. Kumarin uygulamasının bu parametreleri normal seviyelere döndürerek antioksidan aktivite gösterdiği bulundu. Histopatolojik incelemeler yoluyla Bisfenol grubunun kardiyak dokusunda miyofiber dejenerasyonu ve morfolojik değişiklikler gözlemlenirken, bu etkiler Kumarin tedavisiyle hafifletildi.Sonuç: Molekül Etil 7-hidroksi-2-imino-2H-kromen-3-karboksilatın Bisfenol kaynaklı kardiyovasküler toksisiteye karşı koruyucu bir etkiye sahip olduğu gösterildi; bu da molekülün oksidatif stresle ilişkili kardiyak ve vasküler hasara karşı potansiyel bir terapötik ajan olarak hizmet edebileceğini düşündürmektedir.

Objective: The present study examined the toxic effects of Bisphenol A, which is a commonly used industrial chemical, on male Wistar albino rats’ cardiovascular system, and potential protective effects of Ethyl 7-hydroxy-2-imino-2H-cramen-3-carboxylate, a newly synthesized coumarin derivative, against this toxicity.Method: A total of 10-12 weeks of age and 250-300 g weighing 28 male Wistar Albino rats were used in the present study. Four groups (control, bisphenol-A, Coumarin, and Bisphenol-A+Coumarin) were formed from the rats. The rats were administered Bisphenol and/or Coumarin via orogastric route on alternate days. Biochemical, histopathological, and histomorphometric analyses were performed on heart and vascular tissues at the end of the experiment.Results: As a result of biochemical analyses, Bisphenol administration was found to reduce total antioxidant capacity significantly and increase total oxidant status and malondialdehyde levels, indicating that Bisphenol induces oxidative stress. It was found that administering Coumarin showed antioxidant activity by restoring these parameters toward normal levels. While myofiber degeneration and morphological alterations in the cardiac tissue of the Bisphenol group were observed through histopathological examinations, these effects were alleviated with Coumarin treatment.Conclusion: Molecule Ethyl 7-hydroxy-2-imino-2H-cramen-3-carboxylate was shown to have a protective effect against Bisphenol-induced cardiovascular toxicity, suggesting that the molecule may serve as a potential therapeutic agent against oxidative stress-related cardiac and vascular damage.

 Bisphenol A Antioxidant Cardiovascular system Coumarine Acconcia, F., Pallottini, V., & Marino, M. (2015). Molecular mechanisms of action of BPA. Dose-response, 13(4), 1559325815610582. Akgül, N. B., Üremiş, M. M., Üremiş, N., Annaç, E., Bozat, R. C., Koca, M., Özkaya, A., & Yanılmaz, E. M. B. (2024). Effects of ethyl 7-hydroxy-2-imino-2H-chromene-3-carboxylate, a synthesized coumarin derivative, on bisphenol A-induced kidney toxicity. Adıyaman Üniversitesi Sağlık Bilimleri Dergisi, 10(1), 1–9. Alonso-Magdalena, P., Morimoto, S., Ripoll, C., Fuentes, E., & Nadal, A. (2006). The Estrogenic Effect of Bisphenol A Disrupts Pancreatic β-Cell Function In Vivo and Induces Insulin Resistance. Ehp. Niehs. Nih. Gov, 114 (1), 106–112. Bindhumol, V., Chitra, K. C., & Mathur, P. P. (2003). Bisphenol A induces reactive oxygen species generation in the liver of male rats. Toxicology, 188(2-3), 117-124. Borges, F., Roleira, F., Milhazes, N., Santana, L., & Uriarte, E. (2005). Simple coumarins and analogues in medicinal chemistry: occurrence, synthesis and biological activity. Current Medicinal Chemistry, 12(8), 887-916. Çitil, C. (2022). Protective Effect of 3-Benzoyl-7-Hydroxy Coumarin on Lipid Peroxidation and Minerals on Rat Liver Tissues Induced Oxidative Stress with Lead Acetate. Commagene Journal of Biology, 6(2), 141-145. Flores-Morales, V., Villasana-Ruíz, A. P., Garza-Veloz, I., González-Delgado, S., & Martinez-Fierro, M. L. (2023). Therapeutic effects of coumarins with different substitution patterns. Molecules, 28(5), 2413. Gao, X., & Wang, H. S. (2014). Impact of bisphenol A on the cardiovascular system — Epidemiological and experimental evidence and molecular mechanisms. International Journal of Environmental Research and Public Health, 11(8), 8399–8413. Holbrook, A., Schulman, S., Witt, D. M., Vandvik, P. O., Fish, J., Kovacs, M. J., ... & Guyatt, G. H. (2012). Evidence-based management of anticoagulant therapy: antithrombotic therapy and prevention of thrombosis: American College of Chest Physicians evidence-based clinical practice guidelines. Chest, 141(2), e152S-e184S. Hu, Y., Zhang, L., Wu, X., Hou, L., Li, Z., Ju, J., Li, Q., Qin, W., Li, J., Zhang, Q., Zhou, T., Zhang, L., Xu, C., Fang, Z., & Zhang, Y. (2016). Bisphenol A, an environmental estrogen-like toxic chemical, induces cardiac fibrosis by activating the ERK1/2 pathway. Toxicology Letters, 250–251, 1–9. Kang, J. H., Asai, D., & Toita, R. (2023). Bisphenol A (BPA) and cardiovascular or cardiometabolic diseases. Journal of Xenobiotics, 13(4), 775-810. Kostova, I. (2005). Synthetic and natural coumarins as cytotoxic agents. Current Medicinal Chemistry-Anti-Cancer Agents, 5(1), 29-46. Kumar, S., & Pandey, A. K. (2013). Chemistry and biological activities of flavonoids: an overview. The Scientific World Journal, 2013(1), 162750. Kurt, A., Gündüz, B., Koca, M. (2019). A detailed study on the optical properties of 3-benzoyl-7-hydroxy coumarin compound in different solvents and concentrations. Macedonian Journal of Chemistry and Chemical Engineering, 38(2), 227-236. Lin, H. C., Tsai, H. S., Chen, C. S., Chang, Y. C., Lee, C. M., Lai, Z. Y., & Lin, C. M. (2008). Structure-activity relationship of coumarin derivatives on xanthine oxidase-inhibiting and free radical-scavenging activities. Biochemical Pharmacology, 75(6), 1416-1425. Melzer, D., Rice, N. E., Lewis, C., Henley, W. E., & Galloway, T. S. (2010). Association of urinary bisphenol A concentration with heart disease: Evidence from NHANES 2003/06. PLoS One, 5(1), e8673. Melzer, D., Gates, P., Osborn, N. J., Henley, W. E., Cipelli, R., Young, A., Money, C., Mccormack, P., Schofield, P., Mosedale, D., Grainger, D., & Galloway, T. S. (2012). Urinary bisphenol a concentration and angiography-defined coronary artery stenosis. PLoS One, 7(8). Ohkawa, H., Ohishi, N., & Yagi, K. (1979). Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Analytical Biochemistry, 95(2), 351-358. Rochester, J. R. (2013). Bisphenol A and human health: A review of the literature. Reproductive Toxicology, 42, 132–155. Vandenberg, L. N., Hauser, R., Marcus, M., Olea, N., & Welshons, W. V. (2007). Human exposure to bisphenol A (BPA). Reproductive Toxicology, 24(2), 139–177. Venugopala, K. N., Rashmi, V., & Odhav, B. (2013). Review on Natural Coumarin Lead Compounds for Their Pharmacological Activity. BioMed Research International, 2013(1), 963248. Volmajer, J., Toplak, R., Leban, I., & Le Marechal, A. M. (2005). Synthesis of new iminocoumarins and their transformations into N-chloro and hydrazono compounds. Tetrahedron, 61(29), 7012-7021. Wu, C. R., Huang, M. Y., Lin, Y. T., Ju, H. Y., Ching, H. (2007). Antioxidant properties of Cortex Fraxini and its simple coumarins. Food Chemistry, 104(4), 1464-1471. Yan, S., Chen, Y., Dong, M., Song, W., Belcher, S. M., & Wang, H. S. (2011). Bisphenol A and 17β-estradiol promote arrhythmia in the female heart via alteration of calcium handling. PloS One, 6(9).