The effects of Nrf2 deletion on placental morphology and exchange capacity in the mouse

Kweider, Nisreen; Huppertz, Berthold; Rath, Werner; Lambertz, Jessica; Caspers, Rebecca; ElMoursi, Mohamed; Pecks, Ulrich; Kadyrov, Mamed; Fragoulis, Athanassios; Wruck, Christoph Jan

doi:10.1080/14767058.2016.1236251

Cited by 20 publications

(20 citation statements)

References 29 publications

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“…Placental antioxidant status appears to play an important role in both placental adaptations to stress as well as in the maintenance of nutrient transfer capacity [45]. Hence, as expected, female placentas from ozone-exposed, placebo pregnancies (group 2) also demonstrated increases in a number of nutrient markers in the current study.…”

Section: Discussionsupporting

confidence: 75%

Aspirin pre-treatment modulates ozone-induced fetal growth restriction and alterations in uterine blood flow in rats

Miller

Kodavanti

Stewart

et al. 2019

Reproductive Toxicology

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Prenatal exposure to ozone has been linked to low birth weight in people and fetal growth restriction in rats. Clinical recommendations suggest use of low dose aspirin to lower risk of preeclampsia and intrauterine growth restriction in high-risk pregnancies, yet its utility in mitigating the postnatal effects of gestational ozone exposure is unknown. The present study investigated the possibility of low dose aspirin to mitigate the effects of ozone exposure during pregnancy. Exposure to ozone impaired uterine arterial flow and induced growth restriction in fetuses of both sexes. Aspirin treatment induced marginal improvements in ozone-induced uterine blood flow impairment. However, this resulted in a protection of fetal weight in dams given aspirin only in early pregnancy. Aspirin administration for the entirety of gestation increased placental weight and reduced antioxidant status, suggesting that prolonged exposure to low dose aspirin may induce placental inefficiency in our model of growth restriction.

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Section: Discussionsupporting

confidence: 75%

Aspirin pre-treatment modulates ozone-induced fetal growth restriction and alterations in uterine blood flow in rats

Miller

Kodavanti

Stewart

et al. 2019

Reproductive Toxicology

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“…We did not observe a significant reduction in birthweight of PBS-treated Nrf2 −/− mice. However, Nrf2 −/− mice were recently demonstrated to exhibit intrauterine growth restriction35. In our current study, PBS-treated Nrf2 −/− mice exhibited a slight delay in delivery compared to WT controls that was not significant and a slight decrease in birthweight that was not significant.…”

Section: Discussioncontrasting

confidence: 60%

Nrf2 regulates gene-environment interactions in an animal model of intrauterine inflammation: Implications for preterm birth and prematurity

Sussan

Sudini

Talbot

et al. 2017

Sci Rep

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Preterm birth (PTB) is the leading cause of neonatal mortality, and surviving infants are at increased risk for lifelong disabilities. Intrauterine inflammation is an etiological factor that drives PTB, and oxidative stress is associated with PTB. Nuclear erythroid 2-related factor 2 (Nrf2) is a redox-sensitive transcription factor that is the key regulator of the response to oxidative and inflammatory stress. Here, we used the established mouse model of intrauterine inflammation-induced PTB to determine whether Nrf2 is a modifier of susceptibility to PTB and prematurity-related morbidity and mortality in the offspring. We determined that Nr2-deficient (Nrf2−/−) mice exhibited a greater sensitivity to intrauterine inflammation, as indicated by decreased time to delivery, reduced birthweight, and 100% mortality. Placentas from preterm Nrf2−/− mice showed elevated levels of markers of inflammation, oxidative stress, and cell death, and transcriptomic analysis identified numerous key signaling pathways that were differentially expressed between wild-type (WT) and Nrf2−/− mice in both preterm and control samples. Thus, Nrf2 could be a critical factor for gene-environment interactions that may determine susceptibility to PTB. Further studies are needed to determine if Nrf2 is a viable therapeutic target in women who are at risk for PTB and associated complications in the affected offspring.

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“…Numerous reports demonstrated that Nrf2/Keap1 pathway activation played an important role in alleviating placental damage through inhibiting oxidative stress [52, 53]. A recent study found that weight and both total and labyrinth layer volume were significantly reduced in the placenta of Nrf2 knockout mice, highlighting deficiency in Nrf2 signaling impair placental development and dysfunction [54]. The present study found that the protein level of Keap1 was downregulated in OCA-treated pregnant mice, whereas the protein level of nuclear Nrf2 was upregulated in OCA-treated pregnant mice.…”

Section: Discussionmentioning

confidence: 99%

Obeticholic Acid Protects against Gestational Cholestasis-Induced Fetal Intrauterine Growth Restriction in Mice

Chen

Gao

et al. 2019

Oxidative Medicine and Cellular Longevity

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Gestational cholestasis is a common disease and is associated with adverse pregnancy outcomes. However, there are still no effective treatments. We investigated the effects of obeticholic acid (OCA) on fetal intrauterine growth restriction (IUGR) during 17α-ethynylestradiol- (E2-) induced gestational cholestasis in mice. All pregnant mice except controls were subcutaneously injected with E2 (0.625 mg/kg) daily from gestational day (GD) 13 to GD17. Some pregnant mice were orally administered with OCA (5 mg/kg) daily from GD12 to GD17. As expected, OCA activated placental, maternal, and fetal hepatic FXR signaling. Additionally, exposure with E2 during late pregnancy induced cholestasis, whereas OCA alleviated E2-induced cholestasis. Gestational cholestasis caused reduction of fetal weight and crown-rump length and elevated the incidence of IUGR. OCA decreased the incidence of IUGR during cholestasis. Interestingly, OCA attenuated reduction of blood sinusoid area in placental labyrinth layer and inhibited downregulation of placental sodium-coupled neutral amino acid transporter- (SNAT-) 2 during cholestasis. Additional experiment found that OCA attenuated glutathione depletion and lipid peroxidation in placenta and fetal liver and placental protein nitration during cholestasis. Moreover, OCA inhibited the upregulation of placental NADPH oxidase-4 and antioxidant genes during cholestasis. OCA activated antioxidant Nrf2 signaling during cholestasis. Overall, we demonstrated that OCA treatment protected against gestational cholestasis-induced placental dysfunction and IUGR through suppressing placental oxidative stress and maintaining bile acid homeostasis.

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The effects of Nrf2 deletion on placental morphology and exchange capacity in the mouse

Abstract: This data points out the necessity of functional Nrf2 for fetal and placental growth. A deficiency in Nrf2 signaling may negatively affect nutrient transfer capacity which is then no longer able to meet fetal growth demands.

Cited by 20 publications

References 29 publications

Aspirin pre-treatment modulates ozone-induced fetal growth restriction and alterations in uterine blood flow in rats

Aspirin pre-treatment modulates ozone-induced fetal growth restriction and alterations in uterine blood flow in rats

Nrf2 regulates gene-environment interactions in an animal model of intrauterine inflammation: Implications for preterm birth and prematurity

Obeticholic Acid Protects against Gestational Cholestasis-Induced Fetal Intrauterine Growth Restriction in Mice

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