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Nrf2-mediated transcriptional induction of antioxidant response in mouse embryos exposed to ethanol in vivo: implications for the prevention of fetal alcohol spectrum disorders.

ABSTRACT: Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that is important in protection against oxidative stress. This study was designed to determine the role of Nrf2 signaling in transcriptional activation of detoxifying and antioxidant genes in an in vivo mouse fetal alcohol syndrome model. Maternal ethanol treatment was found to increase both Nrf2 protein levels and Nrf2-ARE binding in mouse embryos. It also resulted in a moderate increase in the mRNA expression of Nrf2 downstream target detoxifying and antioxidant genes as well as an increase in the expression of antioxidant proteins. Pretreatment with the Nrf2 inducer, 3H-1,2 dithiole-3-thione (D3T), significantly increased Nrf2 protein levels and Nrf2-ARE binding, and strongly induced the mRNA expression of Nrf2 downstream target genes. It also increased the expression of antioxidant proteins and the activities of the antioxidant enzymes. Additionally, D3T pretreatment resulted in a significant decrease in ethanol-induced reactive oxygen species generation and apoptosis in mouse embryos. These results demonstrate that Nrf2 signaling is involved in the induction of antioxidant response in ethanol-exposed embryos. In addition, the potency of D3T in inducing antioxidants as well as in diminishing ethanol-induced apoptosis suggests that further exploration of the antiteratogenic effect of this compound will be fruitful.

SUBMITTER: Dong J

PROVIDER: S-EPMC2933156 | biostudies-literature | 2008 Dec

REPOSITORIES: biostudies-literature

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Nrf2-mediated transcriptional induction of antioxidant response in mouse embryos exposed to ethanol in vivo: implications for the prevention of fetal alcohol spectrum disorders.

Dong Jian J Sulik Kathleen K KK Chen Shao-Yu SY

Antioxidants & redox signaling 20081201 12

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that is important in protection against oxidative stress. This study was designed to determine the role of Nrf2 signaling in transcriptional activation of detoxifying and antioxidant genes in an in vivo mouse fetal alcohol syndrome model. Maternal ethanol treatment was found to increase both Nrf2 protein levels and Nrf2-ARE binding in mouse embryos. It also resulted in a moderate increase in the mRNA expression of Nrf2 ...[more]

PMID: 18759561

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Project description:BackgroundInflammation during brain development participates in the pathogenesis of early brain injury and cognitive dysfunctions. Prenatal ethanol exposure affects the developing brain and causes neural impairment, cognitive and behavioral effects, collectively known as fetal alcohol spectrum disorders (FASD). Our previous studies demonstrate that ethanol activates the innate immune response and TLR4 receptor and causes neuroinflammation, brain damage, and cognitive defects in the developmental brain stage of adolescents. We hypothesize that by activating the TLR4 response, maternal alcohol consumption during pregnancy triggers the release of cytokines and chemokines in both the maternal sera and brains of fetuses/offspring, which impairs brain ontogeny and causes cognitive dysfunction.MethodsWT and TLR4-KO female mice treated with or without 10% ethanol in the drinking water during gestation and lactation were used. Cytokine/chemokine levels were determined by ELISA in the amniotic fluid, maternal serum, and cerebral cortex, as well as in the offspring cerebral cortex. Microglial and neuronal markers (evaluated by western blotting), myelin proteins (immunohistochemical and western blotting) and synaptic parameters (western blotting and electron microscopy) were assessed in the cortices of the WT and TLR4-KO pups on PND 0, 20, and 66. Behavioral tests (elevated plus maze and passive avoidance) were performed in the WT and TLR4-KO mice on PND 66 exposed or not to ethanol.ResultsWe show that alcohol intake during gestation and lactation increases the levels of several cytokines/chemokines (IL-1β, IL-17, MIP-1α, and fractalkine) in the maternal sera, amniotic fluid, and brains of fetuses and offspring. The upregulation of cytokines/chemokines is associated with an increase in activated microglia markers (CD11b and MHC-II), and with a reduction in some synaptic (synaptotagmin, synapsin IIa) and myelin (MBP, PLP) proteins in the brains of offspring on days 0, 20, and 66 (long-term effects). These changes are associated with long-term behavioral impairments, in the 66-day-old alcohol-exposed pups. TLR4-deficient mice are protected against ethanol-induced cytokine/chemokine production in alcohol-treated dams and offspring, along with synaptic and myelin alterations, and the log-term behavioral dysfunction induced by ethanol in offspring.ConclusionsThese results suggest that the immune system activation, through the TLR4 response, might play an important role in the neurodevelopmental defects in FASD.

Project description:BACKGROUND:Fetal Alcohol Spectrum Disorder (FASD) is a public health problem globally, with South Africa having the highest recorded prevalence of all countries. Government programmes to prevent and manage FASD remain limited because of the lack of a specific policy. Herein, we developed a guideline to inform policy on the prevention and management of FASD in South Africa. METHODS:We applied a modified version of the World Health Organization's approach to guideline development in three phases. In the first phase, we designed the initial guideline prototype. To do this, we conducted an in-depth interview with policymakers and a focus group with relevant service providers on policy requirements for FASD, a document review of policies on FASD and a scoping review of various interventions for FASD. In phase 2, we refined the initially formulated guideline prototype through a discursive approach with seven local and international experts on FASD. Phase 3 involved refining the prototype using a modified Delphi approach. Forty-three and forty-one experts participated in rounds 1 and 2 of the Delphi approach, respectively. The acceptable consensus for each included policy statement was 85%. RESULTS:We identified three aspects of the proposed guideline, which are the approaches and guiding principles, the prevention measures and the management measures. The guideline proposes that a FASD policy should consider lifespan needs, be culturally diverse, collaborative, evidence-based, multi-sectoral and address social determinants of health contributing to FASD. The essential components of FASD prevention policy consist of awareness and education of the dangers of drinking alcohol, access to treatment for alcohol problems and training of service providers. The management components include capacity building related to diagnosis, educating parents regarding the needs and management, appropriate referral pathways, training of teachers regarding classroom management and support for parents and individuals with FASD. CONCLUSION:FASD in South Africa deserves urgent attention. Developing a specific policy to guide programmes could enhance and coordinate the efforts towards preventing and managing FASD. The guideline has the potential to assist policymakers in the development of a comprehensive and multi-sectoral policy for prevention and management of FASD, considering the consensus obtained from the experts.

Project description:BackgroundFetal alcohol spectrum disorder (FASD) is a preventable, lifelong neurodevelopmental disorder caused by prenatal alcohol exposure. FASD negatively impacts individual Indigenous communities around the world. Although many prevention interventions have been developed and implemented, they have not been adequately evaluated. This systematic review updates the evidence for the effectiveness of FASD prevention interventions in Indigenous/Aboriginal populations internationally, and in specific populations in North America and New Zealand, and offers recommendations for future work.MethodThe MEDLINE, Embase, CINAHL Plus, Web of Science, PsycINFO, SocINDEX, and Informit databases were searched from inception to 22/08/2017 for all prevention and intervention papers published in peer-reviewed scientific journals, with results, targeting prenatal alcohol exposure and FASD in Indigenous populations. This review was limited to studies published in English and excluded interventions focusing on the workforce. All steps were completed independently by two reviewers with discrepancies resolved via consensus with the senior author.ResultsThere was significant heterogeneity in the ten included studies. Populations targeted included non-pregnant women of child-bearing age, pregnant women, school children and the general public. Study designs included one randomised controlled trial, five cohort studies with pre-post design, one cross-sectional study with different pre- and post-intervention groups, and four studies collected post-intervention data. Studies assessed changes in knowledge, and/or changes in risk for prenatal alcohol exposure including self-reported alcohol consumption, use of birth control or a combination of both. One study was conducted in Australia and nine in the US. The methodological quality of all studies was rated as 'Poor' using the systematic review assessment tools developed by The National Heart, Lung and Blood Institute. Studies were subject to substantial bias due to issues such as high loss to follow-up, lack of control groups and the reliance on self-report measures to assess the main outcome.ConclusionOverall, there is little evidence that previous interventions aiming to reduce the risk of prenatal alcohol exposure or FASD in Indigenous populations have been effective. Future intervention studies should address the cultural factors and historical context that are fundamental to successful work with Indigenous populations, and be designed, implemented and evaluated using rigorous methods. This systematic review was registered with PROSPERO, CRD42018086212.

Dataset Information

Nrf2-mediated transcriptional induction of antioxidant response in mouse embryos exposed to ethanol in vivo: implications for the prevention of fetal alcohol spectrum disorders.

Publications

Nrf2-mediated transcriptional induction of antioxidant response in mouse embryos exposed to ethanol in vivo: implications for the prevention of fetal alcohol spectrum disorders.

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