Evaluation of the adverse effects of cadmium on rat lung tissue and the preventive roles of vitamin D and magnesium through regulation of VEGF and BMP-4 signaling pathways

Subject Areas :

Paria Amanpour ¹ , Zohre Eftekhari ^{2 *} , Akram Eidi ³ , Parvin Khodarahmi ⁴

1 - Research Sciences Branch, Islamic Azad University, Tehran, Iran
2 - Biotechnology Department, Institute of Pasteur, Tehran, Iran
3 - Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran.
4 - Department of Biology, Parand Branch, Islamic Azad University, Tehran, Iran

Received: 2025-07-12 Accepted : 2025-09-15 Published : 2025-09-21

Keywords: Rat, Lung, Cadmium, Vitamin D, Magnesium,

Abstract :

Background: Cadmium (Cd) exposure occurs primarily through ingestion of contaminated food and water, inhalation, and smoking. Magnesium plays an essential role in the synthesis and metabolism of vitamin D. Objective: This study aimed to investigate the protective mechanisms of vitamin D and magnesium against cadmium-induced lung damage. Methods: This study investigated the effects of cadmium on rat lungs and possible defense against cadmium-induced lung injury following vitamin D and magnesium administration. Body weight, toxicity index, blood parameters, liver function, and lung histology were evaluated in this study, along with liver enzyme levels, P53, VEGF, and BMP-4 gene expression levels. Results: After cadmium exposure, a significant increase in liver enzyme levels, toxicity index, VEGF, and BMP-4 expression was observed. The results showed that treatment with vitamin D, magnesium, and vitamin D + magnesium reduced toxicity index, VEGF, and BMP-4 protein expression. Histopathological findings showed increased inflammatory cell infiltration, mucus accumulation, and alveolar wall thickness in the lung tissue, and this trend was reversed after cadmium injection. Conclusion: The present study shows that the combination of vitamin D and magnesium can exert significant protective effects against cadmium-induced pulmonary toxicity through the regulation of VEGF and BMP-4 pathways. These findings may open the way for the development of new therapeutic approaches.

References:

1. Haney J. Development of an inhalation unit risk factor for cadmium. Regul. Toxicol. Pharmacol. [Internet] 2016;77:175–83. Available from: https://www.sciencedirect.com/science/article/pii/S0273230016300472
2. Jomova K, Alomar SY, Nepovimova E, Kuca K, Valko M. Heavy metals: toxicity and human health effects. Arch. Toxicol. 2025;99:153–209.
3. Satarug S. Cadmium sources and toxicity. Toxics2019;7:25.
4. Taha MM, Mahdy-Abdallah H, Shahy EM, Ibrahim KS, Elserougy S. Impact of occupational cadmium exposure on bone in sewage workers. Int. J. Occup. Environ. Health 2018;24:101–8.
5. Đukić-Ćosić D, Baralić K, Javorac D, Djordjevic AB, Bulat Z. An overview of molecular mechanisms in cadmium toxicity. Curr. Opin. Toxicol. 2020;19:56–62.
6. Behnke J, Dippel CM, Choi Y, Rekers L, Schmidt A, Lauer T, et al. Oxygen toxicity
to the immature lung—part II: the unmet clinical need for causal therapy. Int. J. Mol. Sci. 2021;22:10694.
7. Zhu Y, Jing D, Liang H, Li D, Chang Q, Shen M, et al. Vitamin D status and asthma, lung function, and hospitalization among British adults. Front. Nutr. 2022;9:954768.
8. Mohan M, Cherian JJ, Sharma A. Exploring links between vitamin D deficiency and COVID-19. PLoS Pathog. 2020;16:e1008874.
9. Hoşgörler F, Kızıldağ S, Ateş M, Argon A, Koç B, Kandis S, et al. The chronic use of magnesium decreases VEGF levels in the uterine tissue in rats. Biol. Trace Elem. Res. 2020;196:545–51.
10. Amanpour P, Eftekhari Z, Eidi A, Khodarahmi P. Ameliorative mechanism of dietary vitamin d and magnesium on newborn’s pulmonary toxicity induced by cadmium. J. trace Elem. Med. Biol. organ Soc. Miner. Trace Elem. 2024;84:127469.
11. Hafez-Amini M, Eidi A, Mortazavi P, Sotoodehnejadnematalahi F. Effect of astaxanthin on testicular damage induced by cadmium chloride in adult male Wistar rats. Vet. Clin. Pathol. Q. Sci. J. 2022;16:127–40.
12. Lynchak O, Byelinska I, Dziubenko N, Kuznietsova H, Abramchuk O, Prylutska S. Acute toxicity of C60–Cis-Pt nanocomplex in vivo. Appl. Nanosci. 2022;12:439–47.
13. Kardan N, Eftekhari Z, Ozmaie S, Hoseinzadeh HU. The effects of vitamin D on Immunoresponsive gene 1 and Krüppel-like Factor 2 protein expression in the lung due to the cadmium poisoning. Adv. Life Sci. 2023;9:526–33.
14. Rasin P, Ashwathi A V, Basheer SM, Haribabu J, Santibanez JF, Garrote CA, et al. Exposure to cadmium and its impacts on human health: A short review. J. Hazard. Mater. Adv. 2025;100608.
15. Genchi G, Sinicropi MS, Lauria G, Carocci A, Catalano A. The effects of cadmium toxicity. Int. J. Environ. Res. Public Health 2020;17:3782.
16. Wang J, Zhu H, Wang K, Yang Z, Liu Z. Protective effect of quercetin on rat testes against cadmium toxicity by alleviating oxidative stress and autophagy. Environ. Sci. Pollut. Res. 2020;27:25278–86.
17. Nishijo M, Nakagawa H, Honda R, Tanebe K, Saito S, Teranishi H, et al. Effects of maternal exposure to cadmium on pregnancy outcome and breast milk. Occup. Environ. Med. 2002;59:394–7.
18. Ognjanovic BI, Pavlovic SZ, Maletic SD, Zikic R V, Stajn AS, Radojicic RM, et al. Protective influence of vitamin E on antioxidant defense system in the blood of rats treated with cadmium. Physiol. Res. 2003;52:563–70.
19. Kouadria M, Djemli S, Tahraoui A. Hepatoprotective effect of zinc and magnesium against subchronic cadmium toxicity on biochemical, histopathological and neurobehavioral parameters in Wistar rats. J. Anim. Behav. Biometeorol. 2020;8:63–73.
20. Alatawi FS, Faridi UA, Alatawi MS. Effect of treatment with vitamin D plus calcium on oxidative stress in streptozotocin-induced diabetic rats. Saudi Pharm. J. 2018;26:1208–13.
21. Leal LKAM, Lima LA, de Aquino PEA, de Sousa JAC, Gadelha CVJ, Calou IBF, et al. Vitamin D (VD3) antioxidative and anti-inflammatory activities: Peripheral and central effects. Eur. J. Pharmacol. 2020;879:173099.
22. Babaknejad N, Moshtaghie AA, Shahanipour K, Bahrami S. The protective roles of zinc and Magnesium in Cadmium-induced renal toxicity in male wistar rats. Iran. J. Toxicol. 2015;8:1160–7.
23. Wang G, Xie L, Hu J, Lu H, Liu X, Cao Y, et al. Osteopontin, bone morphogenetic protein-4, and vitamin D receptor gene polymorphisms in the susceptibility and clinical severity of spinal tuberculosis. Cell. Physiol. Biochem. 2017;41:1881–93.
24. Domingues-Faria C, Chanet A, Salles J, Berry A, Giraudet C, Patrac V, et al. Vitamin D deficiency down-regulates Notch pathway contributing to skeletal muscle atrophy in old wistar rats. Nutr. Metab. (Lond). 2014;11:1–13.
25. Sánchez-de-Diego C, Valer JA, Pimenta-Lopes C, Rosa JL, Ventura F. Interplay between BMPs and reactive oxygen species in cell signaling and pathology. Biomolecules 2019;9:534.
26. Låg M, Rodionov D, Øvrevik J, Bakke O, Schwarze PE, Refsnes M. Cadmium-induced inflammatory responses in cells relevant for lung toxicity: Expression and release of cytokines in fibroblasts, epithelial cells and macrophages. Toxicol. Lett. 2010;193:252–60.