Ethanol Impairs NRF2/Antioxidant and Growth Signaling in the Intact Placenta In Vivo and in Human Trophoblasts
by
Sambantham Shanmugam 1, Dhyanesh Patel 1, John M. Wolpert 1, Caezaan Keshvani 1, Xiaobo Liu 1
, Susan E. Bergeson 1, Srivatsan Kidambi 2, Lenin Mahimainathan 3, George I. Henderson 1 and Madhusudhanan Narasimhan 1,*
Sambantham Shanmugam 1, Dhyanesh Patel 1, John M. Wolpert 1, Caezaan Keshvani 1, Xiaobo Liu 1, Susan E. Bergeson 1, Srivatsan Kidambi 2, Lenin Mahimainathan 3, George I. Henderson 1 and Madhusudhanan Narasimhan 1,*
1
Department of Pharmacology and Neuroscience, Texas Tech University Health Sciences Center (TTUHSC), Lubbock, TX 79430, USA
2
Department of Department of Chemical and Biomolecular Engineering, University of Nebraska, Lincoln, NE 68588, USA
3
Department Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
*
Author to whom correspondence should be addressed.
Biomolecules 2019, 9(11), 669; https://doi.org/10.3390/biom9110669
Received: 24 September 2019 / Revised: 25 October 2019 / Accepted: 27 October 2019 / Published: 30 October 2019
(This article belongs to the Collection Multi-Organ Alcohol-Related Damage: Mechanisms and Treatment)
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 Nrf2 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.
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Keywords:
NRF2; placenta; ethanol; trophoblasts; prenatal alcohol; CYCLIN-D1; p21
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MDPI and ACS Style
Shanmugam, S.; Patel, D.; Wolpert, J.M.; Keshvani, C.; Liu, X.; Bergeson, S.E.; Kidambi, S.; Mahimainathan, L.; Henderson, G.I.; Narasimhan, M. Ethanol Impairs NRF2/Antioxidant and Growth Signaling in the Intact Placenta In Vivo and in Human Trophoblasts. Biomolecules 2019, 9, 669.
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