Ethanol Impairs NRF2/Antioxidant and Growth Signaling in the Intact Placenta In Vivo and in Human Trophoblasts
NRF2 is a redox-sensitive transcription factor that depending on the duration or magnitude of the stress, either translocates to the nucleus (beneficial) or is degraded in the cytosol (harmful). However, the role of NRF2-based mechanism(s) under ethanol (E)-induced developmental toxicity in the plac...
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| Format: | Article |
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MDPI AG
2019-10-01
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| Series: | Biomolecules |
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| Online Access: | https://www.mdpi.com/2218-273X/9/11/669 |
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| author | Sambantham Shanmugam Dhyanesh Patel John M. Wolpert Caezaan Keshvani Xiaobo Liu Susan E. Bergeson Srivatsan Kidambi Lenin Mahimainathan George I. Henderson Madhusudhanan Narasimhan |
| author_facet | Sambantham Shanmugam Dhyanesh Patel John M. Wolpert Caezaan Keshvani Xiaobo Liu Susan E. Bergeson Srivatsan Kidambi Lenin Mahimainathan George I. Henderson Madhusudhanan Narasimhan |
| author_sort | Sambantham Shanmugam |
| collection | DOAJ |
| description | NRF2 is a redox-sensitive transcription factor that depending on the duration or magnitude of the stress, either translocates to the nucleus (beneficial) or is degraded in the cytosol (harmful). However, the role of NRF2-based mechanism(s) under ethanol (E)-induced developmental toxicity in the placental context remains unknown. Here, we used a rat prenatal model of maternal alcohol stress consisting of intermittent ethanol vapor (IEV) daily from GD11 to GD20 with a 6 h ON/18 h OFF in a vapor chamber and in vitro placental model consisting of HTR-8 trophoblasts exposed to 86 mM of E for either 24 h or 48 h. The role of NRF2 was evaluated through the NRF2-transactivation reporter assay, qRT-PCR, and Western blotting for NRF2 and cell growth-promoting protein, and cell proliferation assay. In utero and in vitro E decreased the nuclear NRF2 content and diminished its transactivation ability along with dysregulation of the proliferation indices, PCNA, CYCLIN-D1, and p21. This was associated with a ~50% reduction in cell proliferation in vitro in trophoblasts. Interestingly, this was found to be partially rescued by ectopic <i>Nrf2</i> overexpression. These results indicate that ethanol-induced dysregulation of NRF2 coordinately regulates PCNA/CYCLIN-D1/p21 involving growth network, at least partially to set a stage for placental perturbations. |
| first_indexed | 2024-12-19T19:38:23Z |
| format | Article |
| id | doaj.art-37860d5c05a846c6a9dd7ab5bb612b75 |
| institution | Directory Open Access Journal |
| issn | 2218-273X |
| language | English |
| last_indexed | 2024-12-19T19:38:23Z |
| publishDate | 2019-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomolecules |
| spelling | doaj.art-37860d5c05a846c6a9dd7ab5bb612b752022-12-21T20:08:20ZengMDPI AGBiomolecules2218-273X2019-10-0191166910.3390/biom9110669biom9110669Ethanol Impairs NRF2/Antioxidant and Growth Signaling in the Intact Placenta In Vivo and in Human TrophoblastsSambantham Shanmugam0Dhyanesh Patel1John M. Wolpert2Caezaan Keshvani3Xiaobo Liu4Susan E. Bergeson5Srivatsan Kidambi6Lenin Mahimainathan7George I. Henderson8Madhusudhanan Narasimhan9Department of Pharmacology and Neuroscience, Texas Tech University Health Sciences Center (TTUHSC), Lubbock, TX 79430, USADepartment of Pharmacology and Neuroscience, Texas Tech University Health Sciences Center (TTUHSC), Lubbock, TX 79430, USADepartment of Pharmacology and Neuroscience, Texas Tech University Health Sciences Center (TTUHSC), Lubbock, TX 79430, USADepartment of Pharmacology and Neuroscience, Texas Tech University Health Sciences Center (TTUHSC), Lubbock, TX 79430, USADepartment of Pharmacology and Neuroscience, Texas Tech University Health Sciences Center (TTUHSC), Lubbock, TX 79430, USADepartment of Pharmacology and Neuroscience, Texas Tech University Health Sciences Center (TTUHSC), Lubbock, TX 79430, USADepartment of Department of Chemical and Biomolecular Engineering, University of Nebraska, Lincoln, NE 68588, USADepartment Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USADepartment of Pharmacology and Neuroscience, Texas Tech University Health Sciences Center (TTUHSC), Lubbock, TX 79430, USADepartment of Pharmacology and Neuroscience, Texas Tech University Health Sciences Center (TTUHSC), Lubbock, TX 79430, USANRF2 is a redox-sensitive transcription factor that depending on the duration or magnitude of the stress, either translocates to the nucleus (beneficial) or is degraded in the cytosol (harmful). However, the role of NRF2-based mechanism(s) under ethanol (E)-induced developmental toxicity in the placental context remains unknown. Here, we used a rat prenatal model of maternal alcohol stress consisting of intermittent ethanol vapor (IEV) daily from GD11 to GD20 with a 6 h ON/18 h OFF in a vapor chamber and in vitro placental model consisting of HTR-8 trophoblasts exposed to 86 mM of E for either 24 h or 48 h. The role of NRF2 was evaluated through the NRF2-transactivation reporter assay, qRT-PCR, and Western blotting for NRF2 and cell growth-promoting protein, and cell proliferation assay. In utero and in vitro E decreased the nuclear NRF2 content and diminished its transactivation ability along with dysregulation of the proliferation indices, PCNA, CYCLIN-D1, and p21. This was associated with a ~50% reduction in cell proliferation in vitro in trophoblasts. Interestingly, this was found to be partially rescued by ectopic <i>Nrf2</i> overexpression. These results indicate that ethanol-induced dysregulation of NRF2 coordinately regulates PCNA/CYCLIN-D1/p21 involving growth network, at least partially to set a stage for placental perturbations.https://www.mdpi.com/2218-273X/9/11/669nrf2placentaethanoltrophoblastsprenatal alcoholcyclin-d1p21 |
| spellingShingle | Sambantham Shanmugam Dhyanesh Patel John M. Wolpert Caezaan Keshvani Xiaobo Liu Susan E. Bergeson Srivatsan Kidambi Lenin Mahimainathan George I. Henderson Madhusudhanan Narasimhan Ethanol Impairs NRF2/Antioxidant and Growth Signaling in the Intact Placenta In Vivo and in Human Trophoblasts Biomolecules nrf2 placenta ethanol trophoblasts prenatal alcohol cyclin-d1 p21 |
| title | Ethanol Impairs NRF2/Antioxidant and Growth Signaling in the Intact Placenta In Vivo and in Human Trophoblasts |
| title_full | Ethanol Impairs NRF2/Antioxidant and Growth Signaling in the Intact Placenta In Vivo and in Human Trophoblasts |
| title_fullStr | Ethanol Impairs NRF2/Antioxidant and Growth Signaling in the Intact Placenta In Vivo and in Human Trophoblasts |
| title_full_unstemmed | Ethanol Impairs NRF2/Antioxidant and Growth Signaling in the Intact Placenta In Vivo and in Human Trophoblasts |
| title_short | Ethanol Impairs NRF2/Antioxidant and Growth Signaling in the Intact Placenta In Vivo and in Human Trophoblasts |
| title_sort | ethanol impairs nrf2 antioxidant and growth signaling in the intact placenta in vivo and in human trophoblasts |
| topic | nrf2 placenta ethanol trophoblasts prenatal alcohol cyclin-d1 p21 |
| url | https://www.mdpi.com/2218-273X/9/11/669 |
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