SavedAdd your journal

Journals / Trakya University Journal of Natural Sciences / 2026 / Volume: 26 Issue: 1

Brominated flame retardant BDE-99 promotes apoptosis by intrinsic mitochondrial pathway in rat liver

Ayşegül Çerkezkayabekir(TRAKYA ÜNİVERSİTESİ)0000-0001-5537-1042
Elvan Bakar(TRAKYA ÜNİVERSİTESİ)0000-0001-5703-3469
Deniz Yüksel Yence(TRAKYA ÜNİVERSİTESİ)0000-0001-8696-9725
Pages
—
Publication Date
2025-04-15
🏛️Bibliographic metadata and full text access for this article are provided via DergiPark.
DergiPark Record ↗
✨

AI Summary & Key Takeaways

AI Insight
⚡ TL;DR(Too Long; Didn't Read)

In conclusion, our results point out BDE-99 inducing apoptosis of the intrinsic mitochondrial pathway in rat liver and indicate that exposure to BDE-99 is possible to be a potential risk factor for liver diseases.

📌 3 Key Takeaways

🎯
Objective & Hypothesis:This study examined in vivo effects of 2,2’,4,4’,5-pentabromodiphenyl ether (BDE-99) on the liver of Wistar Albino rats (250-300 gr) in doses of 0.05 mg/kg and 0.1 mg/kg for ten days by gavage.
📊
Key Findings & Data:Our objective was to investigate the effects of BDE-99 on the apoptotic process in the liver.
💡
Conclusion & Impact:In conclusion, our results point out BDE-99 inducing apoptosis of the intrinsic mitochondrial pathway in rat liver and indicate that exposure to BDE-99 is possible to be a potential risk factor for liver diseases.
🔬Design:Research Article
📍Scope:Comprehensive Sample
⚙️Variables:BDE99 · apoptosis · TUNEL

Abstract

This study examined in vivo effects of 2,2’,4,4’,5-pentabromodiphenyl ether (BDE-99) on the liver of Wistar Albino rats (250-300 gr) in doses of 0.05 mg/kg and 0.1 mg/kg for ten days by gavage. Our objective was to investigate the effects of BDE-99 on the apoptotic process in the liver. Previous studies have shown that BDE-99 causes accumulation and oxidative damage in various tissues, especially the liver. Although the primary mechanism of BDE-99 toxicity is known to involve oxidative stress, limited information is available on its specific impact on apoptosis. Therefore, immunoreactivity of Proliferating Cell Nuclear Antigen (PCNA), Vimentin and Topoisomeraz2A (TOP2A) and Topoisomeraz2B (TOP2B) and Terminal deoxynucleotidyl transferase dUTP Nick End Labeling (TUNEL) were determined in the liver. Superoxide dismutase (SOD), Glutathione peroxidase (GPX) and Catalase (CAT) activities were measured in the liver. qRT-PCR analyses for the p53, Bax, Bcl-2, PCNA and Vimentin genes were carried out from paraffin-embedded liver tissues. Cell membrane damage, hypertrophy, endothelial injury, mononuclear cell infiltration in the liver were determined by Hematoxylin & Eosin. Immunoreactivity of TUNEL, Vimentin, TOP2A and TOP2B increased in both doses, but immunoreactivity of PCNA significantly increased only 0.1 mg/kg BDE-99 dose (p < 0.05). SOD and GPX activities increased but CAT activity decreased significantly (p < 0.05) in the liver. Bax, Bcl-2, PCNA, Vimentin gene expressions increased in a dose-dependent manner and p53 expression increased only in 0.1 mg/kg BDE-99. In conclusion, our results point out BDE-99 inducing apoptosis of the intrinsic mitochondrial pathway in rat liver and indicate that exposure to BDE-99 is possible to be a potential risk factor for liver diseases.

Özet

Bu çalışmada 2,2',4,4',5-pentabromodifenil eter (BDE-99), 0,05 mg/kg ve 0,1 mg/kg dozlarıyla Wistar Albino (250-300 gr) sıçanlara on gün boyunca gavaj yoluyla uygulandı ve karaciğer üzerine in vivo etkileri araştırıldı. Amacımız BDE-99'un karaciğerdeki apoptotik süreç üzerindeki etkilerini araştırmaktı. Önceki çalışmalar BDE-99'un çeşitli dokularda birikime ve oksidatif hasara neden olduğunu göstermiştir. BDE-99 toksisitesinin birincil mekanizmasının oksidatif stresi içerdiği bilinse de apoptozis üzerindeki spesifik etkisi hakkında sınırlı bilgi mevcuttur. Bu nedenle, karaciğerde Proliferating Cell Nuclear Antigen (PCNA), Vimentin ve Topoizomeraz2A (TOP2A) ve Topoizomeraz2B (TOP2B)'nin ve Terminal deoxynucleotidyl transferase dUTP Nick End Labeling (TUNEL) ile immünoreaktivitesi belirlendi. Karaciğerde Süperoksit dismutaz (SOD), Glutatyon peroksidaz (GPX) ve Katalaz (CAT) aktivitesi ölçüldü. Parafine gömülmüş karaciğer dokularından izole edilen total RNA kullanılarak sentezlenen cDNA örneklerinde, p53, Bax, Bcl-2, PCNA ve Vimentin genlerine yönelik qRT-PCR analizleri yapıldı. Karaciğerde hücre zarı hasarı, hipertrofi, endotel hasarı, mononükleer hücre infiltrasyonu Hematoksilen & Eozin boyama ile belirlendi. TUNEL, Vimentin, TOP2A ve TOP2B'nin immünreaktivitesi her iki dozda da arttı, ancak PCNA'nın immünreaktivitesi yalnızca 0,1 mg/kg BDE-99 dozunda anlamlı düzeyde arttı (p < 0.05). Karaciğerde SOD ve GPX aktiviteleri arttı ancak CAT aktivitesi anlamlı düzeyde azaldı (p < 0.05). Bax, Bcl-2, PCNA, Vimentin gen ekspresyonu doza bağlı olarak artarken, p53 ekspresyonu sadece 0,1 mg/kg BDE-99 dozunda arttı. Sonuç olarak, bulgularımız sıçan karaciğerinde BDE-99'un intrinsik mitokondriyal yolda apoptozu indüklediğine işaret etmekte ve BDE-99'a maruz kalmanın karaciğer hastalıkları için potansiyel bir risk faktörü olabileceğini göstermektedir.

🔖

Cite This Article

Çerkezkayabekir, A., Bakar, E., Yence, D. Y. (2025). Brominated flame retardant BDE-99 promotes apoptosis by intrinsic mitochondrial pathway in rat liver. Trakya University Journal of Natural Sciences, Volume: 26 Issue: 1. https://doi.org/10.23902/trkjnat.1366842

📄 Full Text PDF Viewer

📄

PDF görüntüleyici hazırlanıyor...

References (37)

  1. Aebi, H. 1974. Catalase, 673-684. In H. U. Bergmeyer (Ed.), Methods of Enzymatic Analysis (Second Edition), Academic Press, 673-684 pp.
  2. Alaee, M., Arias, P., Sjodin, A. & Bergman, A. 2003. An overview of commercially used brominated flame retardants, their applications, their use patterns in different countries/regions and possible modes of release. Environment International, 29(6): 683-689. https://doi.org/10.1016/S0160-4120(03)00121-1
  3. Albina, M.L., Alonso, V., Linares, V., Belles, M., Sirvent, J.J., Domingo, J.L. & Sanchez, D.J. 2010. Effects of exposure to BDE-99 on oxidative status of liver and kidney in adult rats. Toxicology, 271(1-2): 51-56. https://doi.org/10.1016/j.tox.2010.03.006
  4. Armstrong, L.E., Akinbo, S. & Slitt, A.L. 2020. 2,2',4,4',5-Pentabromodiphenyl ether induces lipid accumulation throughout differentiation in 3T3-L1 and human preadipocytes in vitro. Journal of Biochemical And Molecular Toxicology, 34(6): e22485. https://doi.org/10.1002/jbt.22485
  5. Arthur, J.R. & Boyne, R. 1985. Superoxide dismutase and glutathione peroxidase activities in neutrophils from selenium deficient and copper deficient cattle. Life Science, 36(16): 1569-1575. https://doi.org/10.1016/0024-3205(85)90381-9
  6. Bakar, E., Ulucam, E. & Cerkezkayabekir, A. 2015a. Investigation of the protective effects of proanthocyanidin and vitamin E against the toxic effect caused by formaldehyde on the liver tissue. Environmental Toxicology, 30(12): 1406-1415. https://doi.org/10.1002/tox.22010
  7. Bakar, E., Ulucam, E. & Cerkezkayabekir, A. 2015b. Protective effects of proanthocyanidin and vitamin E against toxic effects of formaldehyde in kidney tissue. Biotechnic & Histochemistry, 90(1): 69-78. https://doi.org/10.3109/10520295.2014.954620
  8. Bakker, M.I., de Winter-Sorkina, R., de Mul, A., Boon, P.E., van Donkersgoed, G., van Klaveren, J.D., Baumann, B.A., Hijman, W.C., van Leeuwen, S.P., de Boer, J. & Zeilmaker, M.J. 2008. Dietary intake and risk evaluation of polybrominated diphenyl ethers in The Netherlands. Molecular Nutrition & Food Research, 52(2): 204-216. https://doi.org/10.1002/mnfr.200700112
  9. Birnbaum, L.S. & Staskal, D.F. 2004. Brominated flame retardants: cause for concern? Environmental Health Perspectives, 112(1): 9-17. https://doi.org/10.1289/ehp.6559
  10. Chen, L.J., Lebetkin, E.H., Sanders, J.M. & Burka, L.T. 2006. Metabolism and disposition of 2,2',4,4',5-pentabromodiphenyl ether (BDE99) following a single or repeated administration to rats or mice. Xenobiotica, 36(6): 515-534. https://doi.org/10.1080/00498250600674477
  11. Darnerud, P.O., Eriksen, G.S., Johannesson, T., Larsen, P.B. & Viluksela, M. 2001. Polybrominated diphenyl ethers: occurrence, dietary exposure, and toxicology. Environmental Health Perspectives, 109 Suppl 1: 49-68. https://doi.org/10.1289/ehp.01109s149
  12. Die, Q., Nie, Z., Huang, Q., Yang, Y., Fang, Y., Yang, J. & He, J. 2019. Concentrations and occupational exposure assessment of polybrominated diphenyl ethers in modern Chinese e-waste dismantling workshops. Chemosphere, 214: 379-388. https://doi.org/10.1016/j.chemosphere.2018.09.130 13. Dong, Y., Li, L., Bie, P., Jia, S., Wang, Q., Huang, Z., Qiu, X., Zhang, J. & Hu, J. 2014. Polybrominated diphenyl ethers in farmland soils: Source characterization, deposition contribution and apportionment. Science of The Total Environment, 466-467: 524-532. https://doi.org/10.1016/j.scitotenv.2013.07.058
  13. Dunnick, J.K. & Nyska, A. 2009. Characterization of liver toxicity in F344/N rats and B6C3F1 mice after exposure to a flame retardant containing lower molecular weight polybrominated diphenyl ethers. Experimental and Toxicologic Pathology, 61(1): 1-12. https://doi.org/10.1016/j.etp.2008.06.008
  14. Gudkov, A.V. & Komarova, E.A. 2010. Pathologies associated with the p53 response. Cold Spring Harbor Perspectives in Biology, 2(7): a001180. https://doi.org/10.1101/cshperspect.a001180
  15. Guvenius, D., Bergman, A. & Norén, K. 2001. Polybrominated Diphenyl Ethers in Swedish Human Liver and Adipose Tissue. Archives Of Environmental Contamination And Toxicology, 40: 564-570. https://doi.org/10.1007/s002440010211
  16. Hakk, H., Larsen, G. & Klasson-Wehler, E. 2002. Tissue disposition, excretion and metabolism of 2,2',4,4',5-pentabromodiphenyl ether (BDE-99) in the male Sprague-Dawley rat. Xenobiotica, 32(5): 369-382. https://doi.org/10.1080/00498250110119117
  17. Hooper, K. & McDonald, T.A. 2000. The PBDEs: an emerging environmental challenge and another reason for breast-milk monitoring programs. Environmental Health Perspectives, 108(5): 387-392. https://doi.org/10.1289/ehp.00108387
  18. Hoppe, A.A. & Carey, G.B. 2007. Polybrominated diphenyl ethers as endocrine disruptors of adipocyte metabolism. Obesity (Silver Spring), 15(12): 2942-2950. https://doi.org/10.1038/oby.2007.351
  19. Hou, Y., Fu, J., Sun, S., Jin, Y., Wang, X. & Zhang, L. 2019. BDE-209 induces autophagy and apoptosis via IRE1α/Akt/mTOR signaling pathway in human umbilical vein endothelial cells. Environmental Pollution, 253: 429-438. https://doi.org/10.1016/j.envpol.2019.07.030
  20. Johnson-Restrepo, B., Kannan, K., Rapaport, D.P. & Rodan, B.D. 2005. Polybrominated diphenyl ethers and polychlorinated biphenyls in human adipose tissue from New York. Environmental Science & Technology, 39(14): 5177-5182. https://doi.org/10.1021/es050399x
  21. Kraus, R.J. & Ganther, H.E. 1980. Reaction of cyanide with glutathione peroxidase. Biochemical And Biophysical Research Communications, 96(3): 1116-1122. https://doi.org/10.1016/0006-291x(80)90067-4
  22. Kuriyama, S.N., Talsness, C.E., Grote, K. & Chahoud, I. 2005. Developmental exposure to low dose PBDE 99: effects on male fertility and neurobehavior in rat offspring. Environmental Health Perspectives, 113(2): 149-154. https://doi.org/10.1289/ehp.7421
  23. Livak, K.J. & Schmittgen, T.D. 2001. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods, 25(4): 402-408. https://doi.org/10.1006/meth.2001.1262
  24. Lowry, O.H., Rosebrough, N.J., Farr, A.L. & Randall, R.J. 1951. Protein measurement with the Folin phenol reagent. The Journal of Biological Chemistry, 193(1): 265-275. https://doi.org/10.1016/S0021-9258(19)52451-6
  25. Madia, F., Giordano, G., Fattori, V., Vitalone, A., Branchi, I., Capone, F. & Costa, L.G. 2004. Differential in vitro neurotoxicity of the flame retardant PBDE-99 and of the PCB Aroclor 1254 in human astrocytoma cells. Toxicol Lett, 154(1-2): 11-21. https://doi.org/10.1016/j.toxlet.2004.06.013
  26. Moldovan, G.L., Pfander, B. & Jentsch, S. 2007. PCNA, the maestro of the replication fork. Cell, 129(4): 665-679. https://doi.org/10.1016/j.cell.2007.05.003
  27. Pflaum, J., Schlosser, S. & Muller, M. 2014. p53 Family and Cellular Stress Responses in Cancer. Frontiers in Oncology, 4: 285. https://doi.org/10.3389/fonc.2014.00285
  28. Potmesil, M., Hsiang, Y.H., Liu, L.F., Bank, B., Grossberg, H., Kirschenbaum, S., Forlenza, T.J., Penziner, A., Kanganis, D. & et al. 1988. Resistance of human leukemic and normal lymphocytes to drug-induced DNA cleavage and low levels of DNA topoisomerase II. Cancer Research, 48(12): 3537-3543.
  29. Souza, A.O., Pereira, L.C., Oliveira, D.P. & Dorta, D.J. 2013. BDE-99 congener induces cell death by apoptosis of human hepatoblastoma cell line - HepG2. Toxicology In Vitro, 27(2): 580-587. https://doi.org/10.1016/j.tiv.2012.09.022
  30. Staskal, D.F., Hakk, H., Bauer, D., Diliberto, J.J. & Birnbaum, L.S. 2006. Toxicokinetics of polybrominated diphenyl ether congeners 47, 99, 100, and 153 in mice. Toxicological Sciences, 94(1): 28-37. https://doi.org/10.1093/toxsci/kfl091
  31. Topcu-Tarladacalisir, Y., Akpolat, M., Uz, Y.H., Kizilay, G., Sapmaz-Metin, M., Cerkezkayabekir, A. & Omurlu, I.K. 2013. Effects of curcumin on apoptosis and oxidoinflammatory regulation in a rat model of acetic acid-induced colitis: the roles of c-Jun N-terminal kinase and p38 mitogen-activated protein kinase. Journal of Medicinal Food, 16(4): 296-305. https://doi.org/10.1089/jmf.2012.2550
  32. Vaseva, A.V., Marchenko, N.D., Ji, K., Tsirka, S.E., Holzmann, S. & Moll, U.M. 2012. p53 opens the mitochondrial permeability transition pore to trigger necrosis. Cell, 149(7): 1536-1548. https://doi.org/10.1016/j.cell.2012.05.014
  33. Wang, F., Fang, M., Hinton, D.E., Chernick, M., Jia, S., Zhang, Y., Xie, L., Dong, W. & Dong, W. 2018. Increased coiling frequency linked to apoptosis in the brain and altered thyroid signaling in zebrafish embryos (Danio rerio) exposed to the PBDE metabolite 6-OH-BDE-47. Chemosphere, 198: 342-350. https://doi.org/10.1016/j.chemosphere.2018.01.081
  34. Wang, F., Ruan, X.J. & Zhang, H.Y. 2015. BDE-99 (2,2',4,4',5-pentabromodiphenyl ether) triggers epithelial-mesenchymal transition in colorectal cancer cells via PI3K/Akt/Snail signaling pathway. Tumori, 101(2): 238-245. https://doi.org/10.5301/tj.5000229
  35. Wu, J., Deng, F., Tang, X., Chen, W., Zhou, R., Zhao, T., Mao, X. & Shu, F. 2023. Long-term effect of PBDE-99 prenatal exposure on spermatogenic injuries via the dysregulation of autophagy. Journal of Hazardous Materials, 452: 131234. https://doi.org/10.1016/j.jhazmat.2023.131234
  36. Yang, Y., Wang, L., Zhao, Y., Ma, F., Lin, Z., Liu, Y., Dong, Z., Chen, G. & Liu, D. 2022. PBDEs disrupt homeostasis maintenance and regeneration of planarians due to DNA damage, proliferation and apoptosis anomaly. Ecotoxicology and Environmental Safety, 248: 114287. https://doi.org/10.1016/j.ecoenv.2022.114287
  37. Zaragoza, R., Garcia, C., Rus, A.D., Pallardo, F.V., Barber, T., Torres, L., Miralles, V.J. & Vina, J.R. 2003. Inhibition of liver trans-sulphuration pathway by propargylglycine mimics gene expression changes found in the mammary gland of weaned lactating rats: role of glutathione. The Biochemical Journal, 373 (Pt 3): 825-834. https://doi.org/10.1042/BJ20030387