Nrf2‐Mediated Resistance to Oxidant‐Induced Redox Disruption in Embryos

Abstract

Events that control developmental changes occur during specific windows of gestation and if disrupted, can lead to dysmorphogenesis or embryolethality. One largely understudied aspect of developmental control is redox regulation, where the untimely disruption of intracellular redox potentials (E(h) ) may alter development, suggesting that tight control of developmental-stage-specific redox states is necessary to support normal development. In this study, mouse gestational day 8.5 embryos in whole embryo culture were treated with 10 μM dithiole-3-thione (D3T), an inducer of nuclear factor (erythroid-derived 2)-like 2 (Nrf2). After 14 hr, D3T-treated and -untreated conceptuses were challenged with 200 μM hydrogen peroxide (H₂O₂) to induce oxidant-induced change to intracellular E(h) s. Redox potentials of glutathione (GSH), thioredoxin-1 (Trx1), and mitochondrial thioredoxin-2 (Trx2) were then measured over a 2-hr rebounding period following H₂O₂ treatment. D3T treatment increased embryonic expression of known Nrf2-regulated genes, including those responsible for redox regulation of major intracellular redox couples. Exposure to H₂O₂ without prior D3T treatment produced significant oxidation of GSH, Trx1, and Trx2, based on E(h) values, where GSH and Trx2 E(h) recovered, reaching to pre-H₂O₂ E(h) ranges, but Trx1 E(h) remained oxidized. Following H₂O₂ addition in culture to embryos that received D3T pretreatments, GSH, Trx1, and Trx2 were insulated from significant oxidation. These data show that Nrf2 activation may serve as a means to protect the embryo from chemically induced oxidative stress through the preservation of intracellular redox states during development, allowing normal morphogenesis to ensue.

Resveratrol alleviate hypoxic pulmonary hypertension via anti-inflammation and anti-oxidant pathways in rats

“…As a member of transcription factor, Nrf-2 was shown to play a critical coordinator as regulating the redox balance and protecting cells against oxidative and inflammatory lesions32. Nrf-2 exerts its balancing effects through regulating the expression of detoxification enzymes and antioxidant proteins, such as HO-1 and Trx-1, in response to a wide range of oxidant/ antioxidant/ electrophilic stimuli to protect the body33, 34. Additionally, Nrf-2/Trx-1 axis was demonstrated to modulate apoptosis-related signaling pathway through binding with relevant factors35.…”

Sulforaphane protects human umbilical vein cells against lipotoxicity by stimulating autophagy via an AMPK-mediated pathway

“…Therefore, it is possible that activation of the cellular antioxidant system via the Keap1-Nrf2 pathway is associated with SFA-induced lipotoxicity. Recently, SFN was used as an antioxidant that activates phase II enzymes via the Keap1-Nrf2 pathway (Fu et al, 2013;Harris & Hansen, 2012;Thimmulappa et al, 2002). As expected, pretreatment with SFN significantly decreased palmitate-or stearic acid-induced EA.hy926 cell death.…”

“…Nuclear factor (erythroidderived 2)-like 2 (Nrf2) is an essential regulator of cytoprotective responses to oxidative stress and upregulates many genes associated with the regulation of intracellular redox states and ROS detoxification. Nrf2 regulates many key redox enzyme genes, including nicotinamide adenine dinucleotide phosphate (NADPH), glutathione S-transferase (GST), γ-glutamylcysteine synthetase (GCS), uridine diphosphate-glucuronyl transferase (UGT), and epoxide hydrolase (Harris & Hansen, 2012;Kwak, Itoh, Yamamoto, & Kensler, 2002;Thimmulappa et al, 2002).…”

Effects of Pterostilbene on the Activation of Nuclear Factor Erythroid 2-Related Factor 2 Pathway During in vitro Maturation of Mouse Oocytes

“…Numerous studies have revealed that activation of NFE2L2 in ethanol-exposed mouse embryos is involved in increased detoxifying and antioxidant enzymes (Harris & Hansen, 2012). Recently Lin et al (2018) reported that inhibition of NFE2L2 by brusatol prevents early mouse embryo development by affecting cell cycle progression from G2 to M Phase.…”