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Fetal anemia and elevated hepcidin in a mouse model of fetal alcohol spectrum disorder
Kaylee K Helfrich1,2, Nipun Saini1, Sze Ting Cecilia Kwan1
1Nutrition Research Institute, University of North Carolina at Chapel Hill, Kannapolis, NC, 28081, USA.
Insights
Prenatal alcohol exposure (PAE) causes fetal anemia and iron deficiency by disrupting iron metabolism. This study reveals mechanisms of dysregulated iron status in a mouse model, highlighting increased gestational iron needs.
Area of Science:
- Developmental Biology
- Maternal-Fetal Medicine
- Nutritional Neuroscience
Background:
- Prenatal alcohol exposure (PAE) is a leading cause of preventable birth defects, including cognitive impairments and growth deficits.
- PAE exacerbates these issues through concurrent iron deficiency, disrupting fetal iron metabolism and leading to functional iron deficiency even with adequate maternal iron.
- Understanding the mechanisms of dysregulated iron status during PAE is crucial for developing targeted interventions.
Purpose of the Study:
- To investigate the mechanisms by which moderate PAE disrupts fetal iron metabolism and iron status in a mouse model.
- To elucidate the impact of PAE on maternal and fetal iron regulatory pathways, including hepcidin and erythropoietin.
- To identify potential molecular effectors contributing to fetal anemia associated with PAE.
Main Methods:
- A mouse model was utilized, administering 3 g/kg of alcohol daily to pregnant C57BL/6J female mice from embryonic day 8.5 to 17.5.
- Fetal iron status, hemoglobin, hematocrit, and red blood cell counts were assessed at embryonic day 17.5.
- Expression levels of key iron metabolism regulators (hepcidin, BMP/SMAD, IL-6/STAT3 pathways) and hepatic genes were analyzed.
Main Results:
- PAE significantly reduced fetal hemoglobin, hematocrit, and red blood cell counts, indicating fetal anemia, despite elevated erythropoietin.
- Maternal hepcidin expression and the BMP/SMAD pathway were suppressed by alcohol, while fetal hepcidin was elevated without corresponding pathway activation.
- Alcohol exposure suppressed fetal hepatic genes involved in ribosome biogenesis, suggesting a novel mechanism for PAE-induced anemia.
Conclusions:
- These findings confirm that PAE disrupts maternal and fetal iron metabolism, impairing the fetus's ability to regulate iron status.
- The observed dysregulation increases gestational iron requirements, representing a conserved response to PAE.
- PAE-induced fetal anemia is linked to elevated hepcidin and erythropoietin, underscoring the complex interplay of iron regulation during development.
Introduction:
Prenatal alcohol exposure (PAE) impairs offspring growth and cognition, and this is worsened by concurrent iron deficiency. Alcohol disrupts fetal iron metabolism and produces functional iron deficiency, even when maternal iron status is adequate. We used a mouse model of moderate PAE to investigate the mechanisms underlying this dysregulated iron status.
Methods:
C57BL/6J female mice received 3 g/kg alcohol daily from embryonic day (E) 8.5-17.5 and were assessed at E17.5.
Results:
Alcohol reduced fetal hemoglobin, hematocrit, and red blood cell counts, despite elevated erythropoietin production. Alcohol suppressed maternal hepcidin expression and the upstream iron-sensing BMP/SMAD pathway, consistent with its effects in the nonpregnant state. In contrast, alcohol elevated fetal hepcidin, although this was not accompanied by an upregulation of the BMP/SMAD or proinflammatory IL-6/STAT3 pathways. Fetal expression of hepatic genes contributing to hemoglobin synthesis and iron metabolism were unaffected by alcohol, whereas those affecting ribosome biogenesis were suppressed, suggesting a novel candidate effector for this fetal anemia.
Conclusion:
These data confirm and extend prior observations that PAE disrupts maternal and fetal iron metabolism and impairs the fetus's ability to regulate iron status. We propose this dysregulation increases gestational iron needs and represents a conserved response to PAE.
Impact:
Prenatal alcohol exposure causes a functional iron deficiency in a model that also impairs cognition in later life. Prenatal alcohol exposure causes fetal anemia. This fetal anemia is accompanied by elevated hepcidin and erythropoietin. Findings are consistent with prior observations that prenatal alcohol exposure increases maternal-fetal iron requirements during pregnancy.
