Tanshinone IIA alleviates tri-ortho-cresyl phosphate-induced ovarian damage through Hippo signaling pathway activation in mice
Abstract Background Tri-ortho-cresyl phosphate (TOCP), a widely used plasticizer, has been shown to impair ovarian function. While tanshinone IIA exhibits ovarian protective effects in aging models, its potential to counteract TOCP-induced ovarian damage and associated signaling mechanisms remains u...
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| Language: | English |
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BMC
2025-04-01
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| Series: | Journal of Ovarian Research |
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| Online Access: | https://doi.org/10.1186/s13048-025-01671-w |
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| author | Zhangqiang Ma Na Hu Liping Zheng Yue Xue Chong Zhou Wencan Wang Xiu Cheng Tao Luo Jianlin Yu Liaoliao Hu |
| author_facet | Zhangqiang Ma Na Hu Liping Zheng Yue Xue Chong Zhou Wencan Wang Xiu Cheng Tao Luo Jianlin Yu Liaoliao Hu |
| author_sort | Zhangqiang Ma |
| collection | DOAJ |
| description | Abstract Background Tri-ortho-cresyl phosphate (TOCP), a widely used plasticizer, has been shown to impair ovarian function. While tanshinone IIA exhibits ovarian protective effects in aging models, its potential to counteract TOCP-induced ovarian damage and associated signaling mechanisms remains unexplored. This study investigates the therapeutic effects of tanshinone IIA on TOCP-damaged ovaries in mice, with focus on Hippo, AKT, and MAPK pathways. Results TOCP exposure (200 mg/kg/d for 28 days) significantly reduced ovarian follicle counts (primordial, preovulatory, and mature follicles) and disrupted hormone levels (elevated Estrogen(E2), decreased Follicle stimulating hormone(FSH)/ Anti-Mueller tube hormone(AMH)) in mice. Treatment with high-dose tanshinone IIA restored ovarian structure and function: growing follicle counts increased significantly (p < 0.001), FSH (p < 0.001) and AMH (p < 0.001) levels surged to marked degrees, while E2 (p < 0.001) levels decreased significantly. All changes were statistically significant. Immunohistochemistry and Western blot analysis revealed that tanshinone IIA restored ovarian AMH and Follicle-Stimulating Hormone Receptor (FSHR) protein expression, which were suppressed by TOCP. In vitro experiments further demonstrated that TOCP dose-dependently inhibited granulosa cell viability (p < 0.001) and proliferation (p < 0.001). Co-treatment with tanshinone IIA (0.01 mM) rescued cell viability (p < 0.01) and proliferation (p < 0.05). Mechanistically, tanshinone IIA suppressed ovarian apoptosis (p < 0.01) and modulated multiple signaling pathways: it attenuated Hippo signaling (p < 0.05) and reactivated PI3K/AKT (p < 0.05), p38 (p < 0.05), and ERK1/2 (p < 0.01) pathways. Conclusions Tanshinone IIA alleviates TOCP-induced ovarian dysfunction primarily through coordinated modulation of Hippo signaling and AKT/MAPK pathway activities, offering a potential therapeutic strategy for chemical-induced ovarian injury. |
| format | Article |
| id | doaj-art-8f246762df3c44bd90f232bd30869713 |
| institution | OA Journals |
| issn | 1757-2215 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | BMC |
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| series | Journal of Ovarian Research |
| spelling | doaj-art-8f246762df3c44bd90f232bd308697132025-08-20T02:30:25ZengBMCJournal of Ovarian Research1757-22152025-04-0118111610.1186/s13048-025-01671-wTanshinone IIA alleviates tri-ortho-cresyl phosphate-induced ovarian damage through Hippo signaling pathway activation in miceZhangqiang Ma0Na Hu1Liping Zheng2Yue Xue3Chong Zhou4Wencan Wang5Xiu Cheng6Tao Luo7Jianlin Yu8Liaoliao Hu9School of Public Health, Jiangxi Medical College, Nanchang UniversitySchool of Public Health, Jiangxi Medical College, Nanchang UniversitySchool of Public Health, Jiangxi Medical College, Nanchang UniversitySchool of Basic Medical Sciences, Jiangxi Medical College, Nanchang UniversitySchool of Basic Medical Sciences, Jiangxi Medical College, Nanchang UniversitySchool of Public Health, Jiangxi Medical College, Nanchang UniversitySchool of Public Health, Jiangxi Medical College, Nanchang UniversityInstitute of Biomedical Innovation, Jiangxi Medical College, Nanchang UniversityJiangxi Province Key Laboratory of Immunology and Inflammation, Jiangxi Provincial Clinical Research Center for Laboratory Medicine, Department of Clinical Laboratory, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang UniversityJiangxi Province Key Laboratory of Immunology and Inflammation, Jiangxi Provincial Clinical Research Center for Laboratory Medicine, Department of Clinical Laboratory, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang UniversityAbstract Background Tri-ortho-cresyl phosphate (TOCP), a widely used plasticizer, has been shown to impair ovarian function. While tanshinone IIA exhibits ovarian protective effects in aging models, its potential to counteract TOCP-induced ovarian damage and associated signaling mechanisms remains unexplored. This study investigates the therapeutic effects of tanshinone IIA on TOCP-damaged ovaries in mice, with focus on Hippo, AKT, and MAPK pathways. Results TOCP exposure (200 mg/kg/d for 28 days) significantly reduced ovarian follicle counts (primordial, preovulatory, and mature follicles) and disrupted hormone levels (elevated Estrogen(E2), decreased Follicle stimulating hormone(FSH)/ Anti-Mueller tube hormone(AMH)) in mice. Treatment with high-dose tanshinone IIA restored ovarian structure and function: growing follicle counts increased significantly (p < 0.001), FSH (p < 0.001) and AMH (p < 0.001) levels surged to marked degrees, while E2 (p < 0.001) levels decreased significantly. All changes were statistically significant. Immunohistochemistry and Western blot analysis revealed that tanshinone IIA restored ovarian AMH and Follicle-Stimulating Hormone Receptor (FSHR) protein expression, which were suppressed by TOCP. In vitro experiments further demonstrated that TOCP dose-dependently inhibited granulosa cell viability (p < 0.001) and proliferation (p < 0.001). Co-treatment with tanshinone IIA (0.01 mM) rescued cell viability (p < 0.01) and proliferation (p < 0.05). Mechanistically, tanshinone IIA suppressed ovarian apoptosis (p < 0.01) and modulated multiple signaling pathways: it attenuated Hippo signaling (p < 0.05) and reactivated PI3K/AKT (p < 0.05), p38 (p < 0.05), and ERK1/2 (p < 0.01) pathways. Conclusions Tanshinone IIA alleviates TOCP-induced ovarian dysfunction primarily through coordinated modulation of Hippo signaling and AKT/MAPK pathway activities, offering a potential therapeutic strategy for chemical-induced ovarian injury.https://doi.org/10.1186/s13048-025-01671-wHippo signaling pathwayApoptosisTanshinone IIATri-ortho-cresyl phosphateGranulosa cells |
| spellingShingle | Zhangqiang Ma Na Hu Liping Zheng Yue Xue Chong Zhou Wencan Wang Xiu Cheng Tao Luo Jianlin Yu Liaoliao Hu Tanshinone IIA alleviates tri-ortho-cresyl phosphate-induced ovarian damage through Hippo signaling pathway activation in mice Journal of Ovarian Research Hippo signaling pathway Apoptosis Tanshinone IIA Tri-ortho-cresyl phosphate Granulosa cells |
| title | Tanshinone IIA alleviates tri-ortho-cresyl phosphate-induced ovarian damage through Hippo signaling pathway activation in mice |
| title_full | Tanshinone IIA alleviates tri-ortho-cresyl phosphate-induced ovarian damage through Hippo signaling pathway activation in mice |
| title_fullStr | Tanshinone IIA alleviates tri-ortho-cresyl phosphate-induced ovarian damage through Hippo signaling pathway activation in mice |
| title_full_unstemmed | Tanshinone IIA alleviates tri-ortho-cresyl phosphate-induced ovarian damage through Hippo signaling pathway activation in mice |
| title_short | Tanshinone IIA alleviates tri-ortho-cresyl phosphate-induced ovarian damage through Hippo signaling pathway activation in mice |
| title_sort | tanshinone iia alleviates tri ortho cresyl phosphate induced ovarian damage through hippo signaling pathway activation in mice |
| topic | Hippo signaling pathway Apoptosis Tanshinone IIA Tri-ortho-cresyl phosphate Granulosa cells |
| url | https://doi.org/10.1186/s13048-025-01671-w |
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