Synergies of dibutyl phthalate on high-fat diet can aggravate cardiac fibrosis/dysfunction and the protective effects of vitamin E and salidroside: A molecular toxicological study in Sprague-Dawley rats
Background: Dibutyl phthalate (DBP) is a pollutant associated with plastic contamination and is commonly used as a plasticizer. It is linked to various adverse health effects, including cardiovascular disease (CVD). There is an association between DBP and high-fat diet (HFD), with HFD also contribut...
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Elsevier
2025-09-01
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| Series: | Ecotoxicology and Environmental Safety |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S014765132501053X |
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| author | Xiao Liang Yang Wu Qing Feng Deyu Zhu Qi Huang Zhuangzhuang Wei Ping Ma Xu Yang Cuiyu Bao Xinyu Bao |
| author_facet | Xiao Liang Yang Wu Qing Feng Deyu Zhu Qi Huang Zhuangzhuang Wei Ping Ma Xu Yang Cuiyu Bao Xinyu Bao |
| author_sort | Xiao Liang |
| collection | DOAJ |
| description | Background: Dibutyl phthalate (DBP) is a pollutant associated with plastic contamination and is commonly used as a plasticizer. It is linked to various adverse health effects, including cardiovascular disease (CVD). There is an association between DBP and high-fat diet (HFD), with HFD also contributing to the development of CVD, including cardiac fibrosis. Cardiac fibrosis is characterized by chronic inflammation of myocardial tissue and is a significant contributor to CVD pathogenesis. Recent research provides evidence suggesting a potential link between environmental exposure to DBP and cardiac damage. However, it remains unclear whether DBP has a synergistic effect on HFD and whether the interaction between the two exacerbates cardiac fibrosis and dysfunction. Objectives: The aim of this study was to investigate the synergistic effects of DBP on cardiac fibrosis induced by HFD. Specifically, we elucidated the mechanisms underlying the synergistic effect of DBP on HFD-induced cardiac fibrosis, with a focus on oxidative stress, pyroptosis, and the disruption of hepatic lipid metabolism. Furthermore, we explored the protective effects of two antioxidants, salidroside (Sal) and vitamin E (VitE), against the exacerbation of cardiac fibrosis caused by the synergistic action of DBP and HFD. Methods: Male Sprague-Dawley (SD) rats were divided into ten groups: a blank control group (Saline); separate groups exposed to low, medium, and high doses of DBP (DBP0.01, DBP1, DBP50 mg/kg/day); a high-fat diet group (HFD); a synergy group combining high concentrations of DBP and a high-fat diet (DBP50 +HFD); and treatment groups with Vitamin E and salidroside (DBP50 +VitE, DBP50 +Sal, DBP50 +HFD+VitE, DBP50 +HFD+Sal). The entire experimental period lasted for 12 weeks. We assessed the effects of DBP and HFD on cardiac function using echocardiography, as well as their impact on the development of cardiac fibrosis through histopathological analysis of the heart. Additionally, we examined the histopathology of liver tissue, lipid levels (Total cholesterol, Triglycerides, High-density lipoprotein, Low-density lipoprotein, Very low-density lipoprotein, Oxidized low-density lipoprotein), oxidative stress biomarkers (Reactive oxygen species, Malondialdehyde, Glutathione), pyroptosis-related proteins (NLRP3, Caspase-1, GSDMD, Interleukin-1β, Interleukin-18), and serum metabolomics (Data Credibility Analysis, Metabolite Differential Analysis, Metabolic Pathway Analysis and Metabolism-related analysis). Results: Our findings revealed that, compared to the saline group, both the high-dose DBP group and the HFD group exhibited significant cardiotoxic effects, inducing alterations in oxidative stress markers (ROS, MDA, and GSH) and levels of pyroptosis-related proteins (NLRP3, Caspase-1, and GSDMD) in myocardial tissue. Concurrently, the high-dose DBP and HFD groups demonstrated notable endocrine-disrupting effects, triggering hepatic steatosis (H&E and Oil Red O) and hyperlipidemia (TC, TG, HDL, LDL, VLDL, and ox-LDL). Ultimately, the combined action of DBP and HFD exacerbated the progression of cardiac fibrosis (H&E and Masson) and dysfunction (Echocardiography). Furthermore, metabolomics results suggest that the relevant pathways and metabolites involved in the citrate cycle (TCA cycle), arginine biosynthesis, tryptophan metabolism, and linoleic acid metabolism may also play significant roles. However, intervention with the inhibitors vitamin E and salidroside demonstrated protective effects against these adverse outcomes. Notably, salidroside exhibited superior efficacy compared to vitamin E in ameliorating lipid metabolism disorders, indicating its potential for preventing and treating cardiac fibrosis and dysfunction exacerbated by the synergistic effects of DBP and HFD. Conclusion: This study reveals, for the first time, the synergistic effect of DBP on HFD-induced cardiac fibrosis and dysfunction, suggesting that salidroside has a protective effect against cardiac fibrosis. These findings provide new insights into the multifaceted mechanisms involved in the pathology of cardiac fibrosis induced by DBP and HFD, and offer potential intervention targets for the prevention and treatment of cardiac fibrosis and dysfunction exacerbated by the synergistic effects of DBP and HFD. |
| format | Article |
| id | doaj-art-7c3fd95312ee49a99b7e9947e2a358f4 |
| institution | Kabale University |
| issn | 0147-6513 |
| language | English |
| publishDate | 2025-09-01 |
| publisher | Elsevier |
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| series | Ecotoxicology and Environmental Safety |
| spelling | doaj-art-7c3fd95312ee49a99b7e9947e2a358f42025-08-20T03:41:19ZengElsevierEcotoxicology and Environmental Safety0147-65132025-09-0130211870810.1016/j.ecoenv.2025.118708Synergies of dibutyl phthalate on high-fat diet can aggravate cardiac fibrosis/dysfunction and the protective effects of vitamin E and salidroside: A molecular toxicological study in Sprague-Dawley ratsXiao Liang0Yang Wu1Qing Feng2Deyu Zhu3Qi Huang4Zhuangzhuang Wei5Ping Ma6Xu Yang7Cuiyu Bao8Xinyu Bao9Key Laboratory of Environmental Related Diseases and One Health, Xianning Medical College, Hubei University of Science and Technology, Xianning 437100, China; School of Public Health and Nursing, Hubei University of Science and Technology, Xianning 437100, ChinaKey Laboratory of Environmental Related Diseases and One Health, Xianning Medical College, Hubei University of Science and Technology, Xianning 437100, ChinaKey Laboratory of Environmental Related Diseases and One Health, Xianning Medical College, Hubei University of Science and Technology, Xianning 437100, ChinaKey Laboratory of Environmental Related Diseases and One Health, Xianning Medical College, Hubei University of Science and Technology, Xianning 437100, ChinaKey Laboratory of Environmental Related Diseases and One Health, Xianning Medical College, Hubei University of Science and Technology, Xianning 437100, ChinaKey Laboratory of Environmental Related Diseases and One Health, Xianning Medical College, Hubei University of Science and Technology, Xianning 437100, ChinaKey Laboratory of Environmental Related Diseases and One Health, Xianning Medical College, Hubei University of Science and Technology, Xianning 437100, ChinaKey Laboratory of Environmental Related Diseases and One Health, Xianning Medical College, Hubei University of Science and Technology, Xianning 437100, China; Institute of Natural Antioxidants and Antioxidant Inflammation, Dali University, Dali 671003, ChinaKey Laboratory of Environmental Related Diseases and One Health, Xianning Medical College, Hubei University of Science and Technology, Xianning 437100, ChinaKey Laboratory of Environmental Related Diseases and One Health, Xianning Medical College, Hubei University of Science and Technology, Xianning 437100, China; School of Public Health and Nursing, Hubei University of Science and Technology, Xianning 437100, China; Correspondence to: Hubei University of Science and Technology, No. 88 Xianning avenue, Xianning 437100, China.Background: Dibutyl phthalate (DBP) is a pollutant associated with plastic contamination and is commonly used as a plasticizer. It is linked to various adverse health effects, including cardiovascular disease (CVD). There is an association between DBP and high-fat diet (HFD), with HFD also contributing to the development of CVD, including cardiac fibrosis. Cardiac fibrosis is characterized by chronic inflammation of myocardial tissue and is a significant contributor to CVD pathogenesis. Recent research provides evidence suggesting a potential link between environmental exposure to DBP and cardiac damage. However, it remains unclear whether DBP has a synergistic effect on HFD and whether the interaction between the two exacerbates cardiac fibrosis and dysfunction. Objectives: The aim of this study was to investigate the synergistic effects of DBP on cardiac fibrosis induced by HFD. Specifically, we elucidated the mechanisms underlying the synergistic effect of DBP on HFD-induced cardiac fibrosis, with a focus on oxidative stress, pyroptosis, and the disruption of hepatic lipid metabolism. Furthermore, we explored the protective effects of two antioxidants, salidroside (Sal) and vitamin E (VitE), against the exacerbation of cardiac fibrosis caused by the synergistic action of DBP and HFD. Methods: Male Sprague-Dawley (SD) rats were divided into ten groups: a blank control group (Saline); separate groups exposed to low, medium, and high doses of DBP (DBP0.01, DBP1, DBP50 mg/kg/day); a high-fat diet group (HFD); a synergy group combining high concentrations of DBP and a high-fat diet (DBP50 +HFD); and treatment groups with Vitamin E and salidroside (DBP50 +VitE, DBP50 +Sal, DBP50 +HFD+VitE, DBP50 +HFD+Sal). The entire experimental period lasted for 12 weeks. We assessed the effects of DBP and HFD on cardiac function using echocardiography, as well as their impact on the development of cardiac fibrosis through histopathological analysis of the heart. Additionally, we examined the histopathology of liver tissue, lipid levels (Total cholesterol, Triglycerides, High-density lipoprotein, Low-density lipoprotein, Very low-density lipoprotein, Oxidized low-density lipoprotein), oxidative stress biomarkers (Reactive oxygen species, Malondialdehyde, Glutathione), pyroptosis-related proteins (NLRP3, Caspase-1, GSDMD, Interleukin-1β, Interleukin-18), and serum metabolomics (Data Credibility Analysis, Metabolite Differential Analysis, Metabolic Pathway Analysis and Metabolism-related analysis). Results: Our findings revealed that, compared to the saline group, both the high-dose DBP group and the HFD group exhibited significant cardiotoxic effects, inducing alterations in oxidative stress markers (ROS, MDA, and GSH) and levels of pyroptosis-related proteins (NLRP3, Caspase-1, and GSDMD) in myocardial tissue. Concurrently, the high-dose DBP and HFD groups demonstrated notable endocrine-disrupting effects, triggering hepatic steatosis (H&E and Oil Red O) and hyperlipidemia (TC, TG, HDL, LDL, VLDL, and ox-LDL). Ultimately, the combined action of DBP and HFD exacerbated the progression of cardiac fibrosis (H&E and Masson) and dysfunction (Echocardiography). Furthermore, metabolomics results suggest that the relevant pathways and metabolites involved in the citrate cycle (TCA cycle), arginine biosynthesis, tryptophan metabolism, and linoleic acid metabolism may also play significant roles. However, intervention with the inhibitors vitamin E and salidroside demonstrated protective effects against these adverse outcomes. Notably, salidroside exhibited superior efficacy compared to vitamin E in ameliorating lipid metabolism disorders, indicating its potential for preventing and treating cardiac fibrosis and dysfunction exacerbated by the synergistic effects of DBP and HFD. Conclusion: This study reveals, for the first time, the synergistic effect of DBP on HFD-induced cardiac fibrosis and dysfunction, suggesting that salidroside has a protective effect against cardiac fibrosis. These findings provide new insights into the multifaceted mechanisms involved in the pathology of cardiac fibrosis induced by DBP and HFD, and offer potential intervention targets for the prevention and treatment of cardiac fibrosis and dysfunction exacerbated by the synergistic effects of DBP and HFD.http://www.sciencedirect.com/science/article/pii/S014765132501053XPlastic-pollution derivativeDibutyl phthalateHigh fat dietCardiac fibrosisCardiac dysfunctionPyroptosis |
| spellingShingle | Xiao Liang Yang Wu Qing Feng Deyu Zhu Qi Huang Zhuangzhuang Wei Ping Ma Xu Yang Cuiyu Bao Xinyu Bao Synergies of dibutyl phthalate on high-fat diet can aggravate cardiac fibrosis/dysfunction and the protective effects of vitamin E and salidroside: A molecular toxicological study in Sprague-Dawley rats Ecotoxicology and Environmental Safety Plastic-pollution derivative Dibutyl phthalate High fat diet Cardiac fibrosis Cardiac dysfunction Pyroptosis |
| title | Synergies of dibutyl phthalate on high-fat diet can aggravate cardiac fibrosis/dysfunction and the protective effects of vitamin E and salidroside: A molecular toxicological study in Sprague-Dawley rats |
| title_full | Synergies of dibutyl phthalate on high-fat diet can aggravate cardiac fibrosis/dysfunction and the protective effects of vitamin E and salidroside: A molecular toxicological study in Sprague-Dawley rats |
| title_fullStr | Synergies of dibutyl phthalate on high-fat diet can aggravate cardiac fibrosis/dysfunction and the protective effects of vitamin E and salidroside: A molecular toxicological study in Sprague-Dawley rats |
| title_full_unstemmed | Synergies of dibutyl phthalate on high-fat diet can aggravate cardiac fibrosis/dysfunction and the protective effects of vitamin E and salidroside: A molecular toxicological study in Sprague-Dawley rats |
| title_short | Synergies of dibutyl phthalate on high-fat diet can aggravate cardiac fibrosis/dysfunction and the protective effects of vitamin E and salidroside: A molecular toxicological study in Sprague-Dawley rats |
| title_sort | synergies of dibutyl phthalate on high fat diet can aggravate cardiac fibrosis dysfunction and the protective effects of vitamin e and salidroside a molecular toxicological study in sprague dawley rats |
| topic | Plastic-pollution derivative Dibutyl phthalate High fat diet Cardiac fibrosis Cardiac dysfunction Pyroptosis |
| url | http://www.sciencedirect.com/science/article/pii/S014765132501053X |
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