Placental RTN3L‐dependent ER‐Phagy Contributes to Fetal Testicular Dysplasia Upon Environmental Stress
Abstract Prenatal environmental stress damages fetal testicular development, leading to male infertility. However, the precise mechanisms underlying the impact of gestational environmental stress on fetal testicular development require further investigation. This study demonstrates that gestational...
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| Format: | Article |
| Language: | English |
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Wiley
2025-07-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202500924 |
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| author | Ye‐Xin Luo Hua‐Long Zhu Bin‐Bin Huang Cheng‐Fang Sun Xin‐Xin Zhang Xin‐Run Wang Yi‐Fan Hu Xu‐Dong Zhang Shen‐Dong Xu Huan Zhou Rui Pan Wei Chang Zhi Yuan Yong‐Wei Xiong Xiao‐Feng Xu Ling‐Li Zhao De‐Xiang Xu Hua Wang |
| author_facet | Ye‐Xin Luo Hua‐Long Zhu Bin‐Bin Huang Cheng‐Fang Sun Xin‐Xin Zhang Xin‐Run Wang Yi‐Fan Hu Xu‐Dong Zhang Shen‐Dong Xu Huan Zhou Rui Pan Wei Chang Zhi Yuan Yong‐Wei Xiong Xiao‐Feng Xu Ling‐Li Zhao De‐Xiang Xu Hua Wang |
| author_sort | Ye‐Xin Luo |
| collection | DOAJ |
| description | Abstract Prenatal environmental stress damages fetal testicular development, leading to male infertility. However, the precise mechanisms underlying the impact of gestational environmental stress on fetal testicular development require further investigation. This study demonstrates that gestational environmental stressor cadmium exposure caused placental estradiol synthesis inhibition and fetal testicular dysplasia. Gestational estradiol supplementation restores fetal testicular dysplasia caused by environmental stress‐induced placental estradiol synthesis inhibition. Analysis of human placentae and cadmium‐stimulated human primary placental trophoblasts confirmed that ER‐phagy is associated with the inhibition of estradiol synthesis in placentae. Subsequently, the data reveals that environmental stress significantly activates RTN3L‐mediated ER‐phagy. RTN3L‐deficient cells and placental Rtn3l‐specific knockout mice confirm that environmental stress‐activated RTN3L‐mediated ER‐phagy inhibited placental estradiol synthesis. Total N6‐methyladenosine level increasing in gestational environmental stress‐exposed placentae. METTL3‐mediated N6‐methyladenosine modification suppression obviously restrains environmental stress‐activated RTN3L‐dependent ER‐phagy. In conclusion, gestational environmental stress activates ER‐phagy by increasing placental Rtn3l mRNA N6‐methyladenosine modification, inhibiting placental estradiol synthesis, and contributing to fetal testicular dysplasia. The study demonstrates the early prevention and treatment of adult male infertility from the perspective of fetal‐derived diseases. |
| format | Article |
| id | doaj-art-e9c0350569124083a5bcb8f3ee3e7063 |
| institution | DOAJ |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-e9c0350569124083a5bcb8f3ee3e70632025-08-20T03:15:35ZengWileyAdvanced Science2198-38442025-07-011225n/an/a10.1002/advs.202500924Placental RTN3L‐dependent ER‐Phagy Contributes to Fetal Testicular Dysplasia Upon Environmental StressYe‐Xin Luo0Hua‐Long Zhu1Bin‐Bin Huang2Cheng‐Fang Sun3Xin‐Xin Zhang4Xin‐Run Wang5Yi‐Fan Hu6Xu‐Dong Zhang7Shen‐Dong Xu8Huan Zhou9Rui Pan10Wei Chang11Zhi Yuan12Yong‐Wei Xiong13Xiao‐Feng Xu14Ling‐Li Zhao15De‐Xiang Xu16Hua Wang17Department of Toxicology Center for Big Data and Population Health of IHM School of Public Health Anhui Medical University Hefei 230022 ChinaDepartment of Toxicology Center for Big Data and Population Health of IHM School of Public Health Anhui Medical University Hefei 230022 ChinaDepartment of Maternal Child & Adolescent Health School of Public Health Anhui Medical University Hefei 230022 ChinaDepartment of Toxicology Center for Big Data and Population Health of IHM School of Public Health Anhui Medical University Hefei 230022 ChinaDepartment of Toxicology Center for Big Data and Population Health of IHM School of Public Health Anhui Medical University Hefei 230022 ChinaDepartment of Toxicology Center for Big Data and Population Health of IHM School of Public Health Anhui Medical University Hefei 230022 ChinaDepartment of Toxicology Center for Big Data and Population Health of IHM School of Public Health Anhui Medical University Hefei 230022 ChinaDepartment of Toxicology Center for Big Data and Population Health of IHM School of Public Health Anhui Medical University Hefei 230022 ChinaDepartment of Toxicology Center for Big Data and Population Health of IHM School of Public Health Anhui Medical University Hefei 230022 ChinaDepartment of Toxicology Center for Big Data and Population Health of IHM School of Public Health Anhui Medical University Hefei 230022 ChinaDepartment of Toxicology Center for Big Data and Population Health of IHM School of Public Health Anhui Medical University Hefei 230022 ChinaDepartment of Toxicology Center for Big Data and Population Health of IHM School of Public Health Anhui Medical University Hefei 230022 ChinaDepartment of Toxicology Center for Big Data and Population Health of IHM School of Public Health Anhui Medical University Hefei 230022 ChinaDepartment of Toxicology Center for Big Data and Population Health of IHM School of Public Health Anhui Medical University Hefei 230022 ChinaReproductive Medicine Center Department of Obstetrics and Gynecology the First Affiliated Hospital of Anhui Medical University Hefei 230022 ChinaDepartment of Toxicology Center for Big Data and Population Health of IHM School of Public Health Anhui Medical University Hefei 230022 ChinaDepartment of Toxicology Center for Big Data and Population Health of IHM School of Public Health Anhui Medical University Hefei 230022 ChinaDepartment of Toxicology Center for Big Data and Population Health of IHM School of Public Health Anhui Medical University Hefei 230022 ChinaAbstract Prenatal environmental stress damages fetal testicular development, leading to male infertility. However, the precise mechanisms underlying the impact of gestational environmental stress on fetal testicular development require further investigation. This study demonstrates that gestational environmental stressor cadmium exposure caused placental estradiol synthesis inhibition and fetal testicular dysplasia. Gestational estradiol supplementation restores fetal testicular dysplasia caused by environmental stress‐induced placental estradiol synthesis inhibition. Analysis of human placentae and cadmium‐stimulated human primary placental trophoblasts confirmed that ER‐phagy is associated with the inhibition of estradiol synthesis in placentae. Subsequently, the data reveals that environmental stress significantly activates RTN3L‐mediated ER‐phagy. RTN3L‐deficient cells and placental Rtn3l‐specific knockout mice confirm that environmental stress‐activated RTN3L‐mediated ER‐phagy inhibited placental estradiol synthesis. Total N6‐methyladenosine level increasing in gestational environmental stress‐exposed placentae. METTL3‐mediated N6‐methyladenosine modification suppression obviously restrains environmental stress‐activated RTN3L‐dependent ER‐phagy. In conclusion, gestational environmental stress activates ER‐phagy by increasing placental Rtn3l mRNA N6‐methyladenosine modification, inhibiting placental estradiol synthesis, and contributing to fetal testicular dysplasia. The study demonstrates the early prevention and treatment of adult male infertility from the perspective of fetal‐derived diseases.https://doi.org/10.1002/advs.202500924environmental stressER‐phagyfetal testis developmentm6Aplacental estradiol |
| spellingShingle | Ye‐Xin Luo Hua‐Long Zhu Bin‐Bin Huang Cheng‐Fang Sun Xin‐Xin Zhang Xin‐Run Wang Yi‐Fan Hu Xu‐Dong Zhang Shen‐Dong Xu Huan Zhou Rui Pan Wei Chang Zhi Yuan Yong‐Wei Xiong Xiao‐Feng Xu Ling‐Li Zhao De‐Xiang Xu Hua Wang Placental RTN3L‐dependent ER‐Phagy Contributes to Fetal Testicular Dysplasia Upon Environmental Stress Advanced Science environmental stress ER‐phagy fetal testis development m6A placental estradiol |
| title | Placental RTN3L‐dependent ER‐Phagy Contributes to Fetal Testicular Dysplasia Upon Environmental Stress |
| title_full | Placental RTN3L‐dependent ER‐Phagy Contributes to Fetal Testicular Dysplasia Upon Environmental Stress |
| title_fullStr | Placental RTN3L‐dependent ER‐Phagy Contributes to Fetal Testicular Dysplasia Upon Environmental Stress |
| title_full_unstemmed | Placental RTN3L‐dependent ER‐Phagy Contributes to Fetal Testicular Dysplasia Upon Environmental Stress |
| title_short | Placental RTN3L‐dependent ER‐Phagy Contributes to Fetal Testicular Dysplasia Upon Environmental Stress |
| title_sort | placental rtn3l dependent er phagy contributes to fetal testicular dysplasia upon environmental stress |
| topic | environmental stress ER‐phagy fetal testis development m6A placental estradiol |
| url | https://doi.org/10.1002/advs.202500924 |
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