Transgenic Mouse Models for Alcohol Metabolism, Toxicity, and Cancer

Heit, Claire; Dong, Hongbin; Chen, Ying; Shah, Yatrik M.; Thompson, David C.; Vasiliou, Vasilis

doi:10.1007/978-3-319-09614-8_22

Cited by 23 publications

(21 citation statements)

References 81 publications

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“…1 and 2). Therefore, we examined the effect of PXR deficiency, binge EtOH, and their interaction on mRNAs of Adh1, Adh4, Aldh2, and Aldh1a1 as well as the protein levels of ADH1, CYP2E1, and ALDH1A1, which are known to be involved in EtOH metabolism (Heit et al, 2015). The EtOH treatment had a significant effect on mRNA levels of hepatic Adh1, Adh4, and Aldh2 (P 5 0.001) but not the genotype or their interaction.…”

Section: Resultsmentioning

confidence: 99%

Role of the Pregnane X Receptor in Binge Ethanol-Induced Steatosis and Hepatotoxicity

Choi

Gyamfi

Neequaye

et al. 2018

J Pharmacol Exp Ther

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The pregnane X receptor (PXR, NR1I2) is a xenobiotic-sensing nuclear receptor that defends against toxic agents. We have shown that PXR promotes chronic ethanol (EtOH)-induced steatosis. Therefore, we examined the role of PXR in binge EtOH-induced hepatotoxicity. Male wild type (WT) and Pxr-null mice were orally administered three binge doses of EtOH (4.5 g/kg, every 12 hours) and euthanized four hours after the final dose. Pxr-null mice displayed higher basal mRNA levels of hepatic lipogenic transcription factor sterol regulatory element binding protein 1c (Srebp-1c) and its target stearoyl-CoA desaturase 1 (Scd1) and the lipid peroxide detoxifying aldo-keto reductase 1b7 (Akr1b7) and higher protein levels of EtOH-metabolizing alcohol dehydrogenase 1 (ADH1). In both genotypes, binge EtOH-induced triglyceride accumulation was associated with inhibition of fatty acid β-oxidation and upregulation of Srebp-1c- regulated lipogenic genes and hepatic CYP2E1 protein. Unexpectedly, gene expression of Cyp2b10, a constitutive androstane receptor target gene, implicated in EtOH hepatotoxicity, was PXR-dependent upregulated by binge EtOH. Also, PXR-dependent was the binge EtOH-induced inhibition of hepatic Akr1b8 mRNA, and protein levels of aldehyde dehydrogenase (ALDH) 1A1 and anti-apoptotic Bcl-2, but increased pro-apoptotic Bax protein expression, leading to increases in residual EtOH concentration and the cellular oxidative stress marker, malondialdehyde. In contrast, Pxr-null mice displayed increased Akr1b7 gene and ADH1 protein expression and hypertriglyceridemia following binge EtOH exposure. Taken together, this study demonstrates that PXR ablation prevents EtOH induced upregulation of Cyp2b10 and that PXR potentiates binge EtOH-induced oxidative stress and inhibition of EtOH catabolism, but protects against alcoholic hyperlipidemia.

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Section: Resultsmentioning

confidence: 99%

Role of the Pregnane X Receptor in Binge Ethanol-Induced Steatosis and Hepatotoxicity

Choi

Gyamfi

Neequaye

et al. 2018

J Pharmacol Exp Ther

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“…For example, studies in mouse models and non-human primates suggest that alcohol consumption in young adult females adversely affects oocyte quality and early stages of embryogenesis, even when alcohol consumption ceases before the completion of fertilisation and pregnancy42,43. Experimental evidence from animal models and on oocytes from women treated for infertility also suggest that maternal obesity may affect oocyte quality44.…”

Section: Mendelian Randomization Assumptions and Assessing Causal Intmentioning

confidence: 99%

Using Mendelian randomization to determine causal effects of maternal pregnancy (intrauterine) exposures on offspring outcomes: Sources of bias and methods for assessing them

Lawlor¹,

Richmond²,

Warrington³

et al. 2017

Wellcome Open Res

122

175

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Mendelian randomization (MR), the use of genetic variants as instrumental variables (IVs) to test causal effects, is increasingly used in aetiological epidemiology. Few of the methodological developments in MR have considered the specific situation of using genetic IVs to test the causal effect of exposures in pregnant women on postnatal offspring outcomes. In this paper, we describe specific ways in which the IV assumptions might be violated when MR is used to test such intrauterine effects. We highlight the importance of considering the extent to which there is overlap between genetic variants in offspring that influence their outcome with genetic variants used as IVs in their mothers. Where there is overlap, and particularly if it generates a strong association of maternal genetic IVs with offspring outcome via the offspring genotype, the exclusion restriction assumption of IV analyses will be violated. We recommend a set of analyses that ought to be considered when MR is used to address research questions concerned with intrauterine effects on post-natal offspring outcomes, and provide details of how these can be undertaken and interpreted. These additional analyses include the use of genetic data from offspring and fathers, examining associations using maternal non-transmitted alleles, and using simulated data in sensitivity analyses (for which we provide code). We explore the extent to which new methods that have been developed for exploring violation of the exclusion restriction assumption in the two-sample setting (MR-Egger and median based methods) might be used when exploring intrauterine effects in one-sample MR. We provide a list of recommendations that researchers should use when applying MR to test the effects of intrauterine exposures on postnatal offspring outcomes and use an illustrative example with real data to demonstrate how our recommendations can be applied and subsequent results appropriately interpreted.

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“…The studies available suggest that ethanol increases ROS through two parallel and reinforcing mechanisms. Normal alcohol metabolism is known to generate ROS as a result of ethanol oxidation (Figure ) (Ceni, Mello, & Galli, ; Dennery, ; Heit et al, ; Mello, Ceni, Surrenti, & Galli, ). In support of these observations, Reinke and collaborators showed that in vivo exposure to ethanol increased the formation of free radicals (Reinke, Lai, DuBose, & McCay, ).…”

Section: The Etiology Of Fasdmentioning

confidence: 99%

Insights into retinoic acid deficiency and the induction of craniofacial malformations and microcephaly in fetal alcohol spectrum disorder

Petrelli

Bendelac

Hicks

et al. 2019

Genesis

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Summary Fetal Alcohol Spectrum Disorder (FASD) is a set of neurodevelopmental malformations caused by maternal consumption of alcohol during pregnancy. FASD sentinel facial features are unique to the disorder, and microcephaly is common in severe forms of FASD. Retinoic acid deficiency has been shown to cause craniofacial malformations and microcephaly in animal models reminiscent of those caused by prenatal alcohol exposure. Alcohol exposure affects the migration and survival of cranial neural crest cells, which are required for proper frontonasal prominence and pharyngeal arch development. Defects in craniofacial development are further amplified by the many downstream pathways that are transcriptionally controlled retinoic acid target genes, including Shh signaling. Recent evidence shows that alcohol exposure itself is sufficient to induce retinoic acid deficiency in the embryo. These data suggest that retinoic acid deficiency is an important underlying etiology of FASD. In disorders like Vitamin A Deficiency, FASD, DiGeorge (22q11.2 Deletion Syndrome), CHARGE, Smith‐Magenis, Matthew‐Wood, and Congenital Zika Syndromes, evidence is accumulating to link reduced retinoic acid signaling with developmental defects like craniofacial malformations and microcephaly. Research focus on characterizing the effects of retinoic acid deficiency during early development and on understanding the downstream signaling pathways involved in aberrant head, and craniofacial development will reveal underlying etiologies of these disorders.

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Transgenic Mouse Models for Alcohol Metabolism, Toxicity, and Cancer

Cited by 23 publications

References 81 publications

Role of the Pregnane X Receptor in Binge Ethanol-Induced Steatosis and Hepatotoxicity

Role of the Pregnane X Receptor in Binge Ethanol-Induced Steatosis and Hepatotoxicity

Using Mendelian randomization to determine causal effects of maternal pregnancy (intrauterine) exposures on offspring outcomes: Sources of bias and methods for assessing them

Insights into retinoic acid deficiency and the induction of craniofacial malformations and microcephaly in fetal alcohol spectrum disorder

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