Fetal anemia and elevated hepcidin in a mouse model of fetal alcohol spectrum disorder

Helfrich, Kaylee K.; Saini, Nipun; Kwan, Sze Ting Cecilia; Rivera, Olivia C.; Mooney, Sandra M.; Smith, Susan

doi:10.1038/s41390-023-02469-6

Cited by 5 publications

(7 citation statements)

References 45 publications

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“…However, the gene expression levels of Bmp pathway components were contradictory with one study (Gerjevic et al, 2012) showed ethanol-induced increased gene expression of Bmp2, Bmp4 and Bmp6 (54), while the other study (Helfrich et al, 2023) showed ethanol-induced decreased gene expression of Bmp2 and Bmp6 (55). While our work and the mouse studies reveal that ethanol attenuates Bmp signaling, at what level and how ethanol disrupts Bmp signaling remains a major open question.…”

Section: Discussionmentioning

confidence: 97%

“…Exacerbation of facial phenotypes in bmp4 -/- ;smad5 -/- larvae demonstrates that dose-dependent reduction in Bmp signaling drives ethanol-induced phenotypes, indicating that ethanol reduces signaling in the Bmp pathway. Work in mouse models of ethanol-induced iron deficiency found that ethanol decreases Bmp signaling (54,55). In these studies, ethanol exposure decreases phosphorylation levels of BmpR1 and Smad1,5 in the adult mouse liver.…”

Section: Discussionmentioning

confidence: 99%

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Mutations in the Bone Morphogenetic Protein signaling pathway sensitize zebrafish and humans to ethanol-induced jaw malformations

Klem

Schwantes‐An

Abreu

et al. 2023

Preprint

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Background: Fetal Alcohol Spectrum Disorders (FASD) describe a continuum of ethanol-induced developmental defects including commonly observed craniofacial malformations. While ethanol-sensitive genetic mutations are a major contributor to facial malformations, the impacted cellular mechanisms underlying these facial anomalies remain unknown. The Bone Morphogenetic Protein (Bmp) signaling pathway is a key regulator of epithelial morphogenesis driving facial development, providing a possible ethanol-sensitive mechanism to malformations to the facial skeleton. Methods: Using zebrafish, we tested several mutants for Bmp pathway components for ethanol-induced facial malformations. Mutant embryos were exposed to ethanol in the media from 10-18 hours post-fertilization (hpf). Exposed zebrafish were fixed at 36 hpf to analyze anterior pharyngeal endoderm size and shape by immunofluorescence or at 5 days post-fertilization (dpf) to quantitatively examine shape of the facial skeleton stained with Alcian Blue/Alizarin Red staining. Integrating human genetic data, we screened for Bmp-ethanol associations in jaw volume of ethanol-exposed children. Results: We found that mutations in the Bmp pathway sensitize zebrafish embryos to ethanol-induced malformations to anterior pharyngeal endoderm shape, leading to altered expression of fgf8a in the oral ectoderm. These changes correlate with shape changes in the viscerocranium, suggesting that ethanol-induced malformations of the anterior pharyngeal endoderm lead to facial malformations. Variants in the Bmp receptor gene, BMPR1B were associated with ethanol-related differences in jaw volume in humans. Conclusions: For the first time, we show that ethanol exposure disrupts proper morphogenesis of, and tissue interactions between, the facial epithelia. These shape changes in the anterior pharyngeal endoderm-oral ectoderm-signaling axis during early zebrafish development mirror the overall shape changes observed in the viscerocranium and were predictive for Bmp-ethanol associations in jaw development in human. Collectively, our work provides a mechanistic paradigm linking the impact of ethanol to the epithelial cell behaviors that underlie facial defects in FASD.

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Mutations in the Bone Morphogenetic Protein signaling pathway sensitize zebrafish and humans to ethanol-induced jaw malformations

Klem

Schwantes‐An

Abreu

et al. 2023

Preprint

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“…The gene expression data for the fetal gluconeogenic genes is a subset of data from RNASeq analysis on fetal livers 34 . These tissues and maternal–fetal dyads are the same as those also sampled for the untargeted metabolome analysis above 29 .…”

Section: Methodsmentioning

confidence: 99%

“…The gene expression data for the fetal gluconeogenic genes is a subset of data from RNASeq analysis on fetal livers. 34 These tissues and maternal-fetal dyads are the same as those also sampled for the untargeted metabolome analysis above. 29 Briefly, RNA was isolated from pooled fetal livers (n = 4/litter, 8 litters per exposure) using Trizol, according to the manufacturer's instructions.…”

Section: Fetal Gluconeogenic Gene Expressionmentioning

confidence: 99%

Alcohol blunts pregnancy‐mediated insulin resistance and reduces fetal brain glucose despite elevated fetal gluconeogenesis, and these changes associate with fetal weight outcomes

Saini,

Mooney,

Smith

2023

The FASEB Journal

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Prenatal alcohol exposure (PAE) impairs fetal growth and neurodevelopment. Although alcohol is well known to alter metabolism, its impact on these processes during pregnancy is largely unexplored. Here, we investigate how alcohol affects maternal–fetal glucose metabolism using our established mouse binge model of PAE. In the dam, alcohol reduces the hepatic abundance of glucose and glycolytic intermediates, and the gluconeogenic enzymes glucose‐6‐phosphtase and phosphoenolpyruvate carboxykinase. Fasting blood glucose is also reduced. In a healthy pregnancy, elevated maternal gluconeogenesis and insulin resistance ensures glucose availability for the fetus. Glucose and insulin tolerance tests reveal that alcohol impairs the dam's ability to acquire insulin resistance. Alcohol‐exposed dams have enhanced glucose clearance (p < .05) in early gestation, after just two days of alcohol, and this persists through late term when fetal glucose needs are maximal. However, maternal plasma insulin levels, hepatic insulin signaling, and the abundance of glucose transporter proteins remain unchanged. In the PAE fetus, the expression of hepatic gluconeogenic genes is elevated, and there is a trend for elevated blood and liver glucose levels. In contrast, fetal brain and placental glucose levels remain low. This reduced maternal fasting glucose, reduced hepatic glucose, and elevated glucose clearance inversely correlated with fetal body and brain weight. Taken together, these data suggest that alcohol blunts the adaptive changes in maternal glucose metabolism that otherwise enhance fetal glucose availability. Compensatory attempts by the fetus to increase glucose pools via gluconeogenesis do not normalize brain glucose. These metabolic changes may contribute to the impaired fetal growth and brain development that typifies PAE.

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“…With iron supplementation, PAE animals had no fetal anemia, normalized red blood cell counts, and increased brain weight, although only males experienced a recovery equivalent to non-exposed controls. These effects are conserved across species, as this group recently found that iron deficiency with concomitant PAE also reduces hemoglobin and red blood cells in a PAE mouse model ( Helfrich et al, 2023 ). In this study, they further found that the underlying mechanisms for this change in hemoglobin are likely, surprisingly, changes in ribosome biogenesis and not hemoglobin synthesis or iron metabolism.…”

Section: Nutrition As a Driver And Consequence Of Pae-altered Microbiotamentioning

confidence: 98%

Microbiota and nutrition as risk and resiliency factors following prenatal alcohol exposure

Upreti,

Rouzer,

Bowring

et al. 2023

Front. Neurosci.

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Alcohol exposure in adulthood can result in inflammation, malnutrition, and altered gastroenteric microbiota, which may disrupt efficient nutrient extraction. Clinical and preclinical studies have documented convincingly that prenatal alcohol exposure (PAE) also results in persistent inflammation and nutrition deficiencies, though research on the impact of PAE on the enteric microbiota is in its infancy. Importantly, other neurodevelopmental disorders, including autism spectrum and attention deficit/hyperactivity disorders, have been linked to gut microbiota dysbiosis. The combined evidence from alcohol exposure in adulthood and from other neurodevelopmental disorders supports the hypothesis that gut microbiota dysbiosis is likely an etiological feature that contributes to negative developmental, including neurodevelopmental, consequences of PAE and results in fetal alcohol spectrum disorders. Here, we highlight published data that support a role for gut microbiota in healthy development and explore the implication of these studies for the role of altered microbiota in the lifelong health consequences of PAE.

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Fetal anemia and elevated hepcidin in a mouse model of fetal alcohol spectrum disorder

Cited by 5 publications

References 45 publications

Mutations in the Bone Morphogenetic Protein signaling pathway sensitize zebrafish and humans to ethanol-induced jaw malformations

Mutations in the Bone Morphogenetic Protein signaling pathway sensitize zebrafish and humans to ethanol-induced jaw malformations

Alcohol blunts pregnancy‐mediated insulin resistance and reduces fetal brain glucose despite elevated fetal gluconeogenesis, and these changes associate with fetal weight outcomes

Microbiota and nutrition as risk and resiliency factors following prenatal alcohol exposure

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