Fetal and Maternal Hepcidin Respond Inversely to Prenatal Alcohol Exposure in a C57BL/6J Mouse Model (P09-010-19)

Abstract

ObjectivesPrenatal alcohol exposure (PAE) dysregulates iron metabolism and causes fetal iron deficiency in rats, even when mothers consume sufficient iron. This dysregulation is partly due to PAE-mediated induction of hepcidin, which routes iron to hepatic storage, where it is unavailable for fetal use. It is unclear how PAE upregulates hepcidin; our rat model suggests dysregulation may be via the IL6/STAT3 pathway. The objective of this study is to quantify hepcidin in a mouse PAE model and ascertain via which pathway(s) PAE disrupts hepcidin. MethodsC57BL/6J female mice consumed AIN93G diet prior to and throughout pregnancy. Pregnant females received 3g/Kg alcohol or isocaloric maltodextrin (MD) by gavage from gestational day (GD) 8.5-17.5. We analyzed mothers and fetuses at GD17.5. ResultsAlthough PAE fetuses had an increased incidence of malformations, fetal weight at GD17.5 did not differ from MD controls (p = 0.800). As in our rat model, PAE upregulated fetal hepatic hepcidin expression (191% increase, p = 0.010). Supporting other studies of chronic alcohol consumption in mice, PAE reduced maternal hepcidin expression, although not significantly (45% decrease, p = 0.055). At a higher alcohol dose (4.5g/Kg, GD13.5-17.5), maternal hepcidin expression was significantly lower than MD controls (59% decrease, p = 0.044). Potential sources of this hepcidin dysregulation include PAE-induced reductions in fetal (24% decrease, p = 0.035) and maternal (61% decrease, p = 0.0004) hepatic Bmp6 expression and elevated fetal hepatic erythropoietin expression (61% increase, p = 0.033). Although decreased BMP6 may contribute to the reduced maternal hepcidin, decreased BMP6 is inconsistent with the elevated fetal hepcidin, and, along with the elevated Epo, may reflect an attempt to increase iron availability in response to PAE. We quantified pro-inflammatory cytokines and found unaltered (Il-6, Ifn-gamma) or decreased (Tnf-alpha) expression in maternal and fetal liver, suggesting a lack of generalized hepatic inflammation in this model. ConclusionsPAE exerts different effects on maternal and fetal hepcidin, which may reflect differences in iron status, time of development, or ethanol processing. PAE also dysregulates hepcidin regulatory pathways. Funding SourcesT32-DK, R01-AA.