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.
C57BL/6J female mice received 3 g/kg alcohol daily from embryonic day (E) 8.5–17.5 and were assessed at E17.5.
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.
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.
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.
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We thank Brandon Presswood and Dane Ricketts for technical support, and Pamela Kling for helpful suggestions during this study.
This study was supported by R01 AA022999 and R01 AA011085 to S.M.S., T32 DK007686 to K.K.H., K99 AA028291 to N.S., F32 AA028684 to O.C.R., and F32 AA027121 to S.T.C.K.
The authors declare no competing interests.
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Helfrich, K.K., Saini, N., Kwan, S.T.(. et al. Fetal anemia and elevated hepcidin in a mouse model of fetal alcohol spectrum disorder. Pediatr Res (2023). https://doi.org/10.1038/s41390-023-02469-6