Esketamine induces embryonic and cardiac malformation through regulating the nkx2.5 and gata4 in zebrafish
Abstract Esketamine (EK) has been widely used in the treatment of depression, but the effects of EK prenatal treatment on embryonic heart development have been rarely reported. This study assesses the effects of varying concentrations of EK on embryonic development and cardiogenesis to determine the...
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Nature Portfolio
2025-02-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-025-91315-2 |
| _version_ | 1826560200904015872 |
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| author | Shuang Li Xiang Li Rui Zhao Tingyu Jiang Qiuyun Ou Huansen Huang Jiancheng Tang |
| author_facet | Shuang Li Xiang Li Rui Zhao Tingyu Jiang Qiuyun Ou Huansen Huang Jiancheng Tang |
| author_sort | Shuang Li |
| collection | DOAJ |
| description | Abstract Esketamine (EK) has been widely used in the treatment of depression, but the effects of EK prenatal treatment on embryonic heart development have been rarely reported. This study assesses the effects of varying concentrations of EK on embryonic development and cardiogenesis to determine the teratogenic concentration in the zebrafish model, centering on the interaction between the genes nkx2.5 and gata4 to elucidate the mechanisms underlying cardiac morphogenesis. Zebrafish embryos were classified into six distinct groups and exposed to either a vehicle or EK to ascertain the median lethal concentration (LC50) at 48 and 72 h post-fertilization (hpf) analyzing mortality rate data. Embryonic and cardiac morphologies were assessed utilizing live embryo imaging techniques and stereo microscopy. Nkx2.5 and gata4 were identified via whole-mount in situ hybridization (WISH) and reverse transcription quantitative polymerase chain reaction (RT-qPCR). Exposure to EK leads to significant teratogenic effects on zebrafish embryos, which are both concentration- and time-dependent. The 48 h- and 72 h-LC50 of EK for zebrafish embryos were 1.30 (95% CI 0.92, 1.60) millimolar (mM) and 0.71 (95% CI 0.46, 1.01) mM, respectively. A significant reduction in heart rates and body length were observed and the distance between the sinus venosus and bulbar artery (SV-BA) was found expanded, the pericardial edema area showed significant swelling, and the body axis curvature was more pronounced in the EK exposure groups. Both WISH an RT-qPCR analysis showed nkx2.5 staining intensity and expression significantly decreased, while gata4 assay results were in the opposite direction. Our findings indicate that exposure of zebrafish embryos to EK results in embryonic and cardiac malformations, primarily due to the down-regulation of nkx2.5 and the over-expression of gata4. Equilibrium maintenance and compensatory mechanisms are crucial in spatiotemporal gene regulation. |
| first_indexed | 2025-03-14T09:12:30Z |
| format | Article |
| id | doaj.art-dbc897abf0dc4be9b8e93ec1cceeca3a |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2025-03-14T09:12:30Z |
| publishDate | 2025-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-dbc897abf0dc4be9b8e93ec1cceeca3a2025-03-02T12:26:29ZengNature PortfolioScientific Reports2045-23222025-02-0115111110.1038/s41598-025-91315-2Esketamine induces embryonic and cardiac malformation through regulating the nkx2.5 and gata4 in zebrafishShuang Li0Xiang Li1Rui Zhao2Tingyu Jiang3Qiuyun Ou4Huansen Huang5Jiancheng Tang6School of Pharmaceutical Sciences, Guangzhou Medical UniversityDepartment of Anesthesiology, Third Affiliated Hospital of Sun Yat-Sen UniversityDepartment of Anesthesiology, Second Affiliated Hospital of Guangzhou Medical UniversityDepartment of Anesthesiology, Second Affiliated Hospital of Guangzhou Medical UniversitySecond Clinical College of Guangzhou Medical UniversityDepartment of Anesthesiology, Second Affiliated Hospital of Guangzhou Medical UniversityDepartment of Anesthesiology, Second Affiliated Hospital of Guangzhou Medical UniversityAbstract Esketamine (EK) has been widely used in the treatment of depression, but the effects of EK prenatal treatment on embryonic heart development have been rarely reported. This study assesses the effects of varying concentrations of EK on embryonic development and cardiogenesis to determine the teratogenic concentration in the zebrafish model, centering on the interaction between the genes nkx2.5 and gata4 to elucidate the mechanisms underlying cardiac morphogenesis. Zebrafish embryos were classified into six distinct groups and exposed to either a vehicle or EK to ascertain the median lethal concentration (LC50) at 48 and 72 h post-fertilization (hpf) analyzing mortality rate data. Embryonic and cardiac morphologies were assessed utilizing live embryo imaging techniques and stereo microscopy. Nkx2.5 and gata4 were identified via whole-mount in situ hybridization (WISH) and reverse transcription quantitative polymerase chain reaction (RT-qPCR). Exposure to EK leads to significant teratogenic effects on zebrafish embryos, which are both concentration- and time-dependent. The 48 h- and 72 h-LC50 of EK for zebrafish embryos were 1.30 (95% CI 0.92, 1.60) millimolar (mM) and 0.71 (95% CI 0.46, 1.01) mM, respectively. A significant reduction in heart rates and body length were observed and the distance between the sinus venosus and bulbar artery (SV-BA) was found expanded, the pericardial edema area showed significant swelling, and the body axis curvature was more pronounced in the EK exposure groups. Both WISH an RT-qPCR analysis showed nkx2.5 staining intensity and expression significantly decreased, while gata4 assay results were in the opposite direction. Our findings indicate that exposure of zebrafish embryos to EK results in embryonic and cardiac malformations, primarily due to the down-regulation of nkx2.5 and the over-expression of gata4. Equilibrium maintenance and compensatory mechanisms are crucial in spatiotemporal gene regulation.https://doi.org/10.1038/s41598-025-91315-2 |
| spellingShingle | Shuang Li Xiang Li Rui Zhao Tingyu Jiang Qiuyun Ou Huansen Huang Jiancheng Tang Esketamine induces embryonic and cardiac malformation through regulating the nkx2.5 and gata4 in zebrafish Scientific Reports |
| title | Esketamine induces embryonic and cardiac malformation through regulating the nkx2.5 and gata4 in zebrafish |
| title_full | Esketamine induces embryonic and cardiac malformation through regulating the nkx2.5 and gata4 in zebrafish |
| title_fullStr | Esketamine induces embryonic and cardiac malformation through regulating the nkx2.5 and gata4 in zebrafish |
| title_full_unstemmed | Esketamine induces embryonic and cardiac malformation through regulating the nkx2.5 and gata4 in zebrafish |
| title_short | Esketamine induces embryonic and cardiac malformation through regulating the nkx2.5 and gata4 in zebrafish |
| title_sort | esketamine induces embryonic and cardiac malformation through regulating the nkx2 5 and gata4 in zebrafish |
| url | https://doi.org/10.1038/s41598-025-91315-2 |
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