Session: 102. Iron Homeostasis and Biology: Poster III
Hematology Disease Topics & Pathways:
Research, Fundamental Science, Translational Research, metabolism, Biological Processes, Maternal Health
Methods: We investigated the effect of lobe specificity of iron binding to transferrin (Tf) with wild-type (wt), N-blocked and C-blocked Tf mutant maternal mice fed a standard iron diet during their pregnancy. We compared erythropoietic parameters, serum hepcidin levels, renal erythropoietin, placental weight and fetal weight assessed at ~E18.
Results: Compared to wt maternal mice, N-blocked and C-blocked monoferric mice had lower hemoglobin concentrations (12.4 + 0.9 vs 10.1 + 0.5 and 9.9 + 0.65 g/dL; p <0.0001). Despite similar hemoglobin concentrations between the monoferric strains, renal erythropoietin expression was higher in the N-blocked dams than in the C-blocked dams (-11.46 +.24 vs -12.71 + 0.63 -delta Cq relative to beta-actin; p < 0.01). Each of the monoferric strains had higher serum iron than wt, (198.3 + 22.9, 170.4 + 13.3 and 118.4 + 33 for the N-blocked, C-blocked and wt respectively, p < 0.05). Liver iron concentrations were likewise higher in each of the monoferric mutant dams compared to wt, with the N-blocked dams being the highest (2950 + 1209, 1856 + 476.8 and 635.2 + 698.5 ug Fe/g dry weight for N-blocked, C-blocked, and wt; p < 0.01). By contrast, the N-blocked mice had a greater decrease in splenic iron during pregnancy compared with C-blocked. Serum hepcidin levels were decreased relative to non-pregnant mice in all three strains, and similar in N-blocked and C-blocked mice. N-blocked dams had fewer fetuses than wt dams (6.3 + 1.6 vs 8.7 + 0.8 pups/litter). Compared to C-blocked mice, N-blocked mice had lower fetal weights (0.87 + 0.2 vs 0.99 + 0.16 g; p < 0.01) but greater placental weights (0.091 + 0.02 vs 0.079 + 0.02 g; p < 0.01).
Conclusions: N-blocked dams demonstrate a higher serum erythropoietin level compared with C-blocked dams despite a similar hemoglobin, consistent with previous reports of relative erythropoietin resistance in these mice. N-blocked dams moreover demonstrate iron overload without a compensatory increase in serum hepcidin, consistent with dampened signaling of iron status in hepcidin regulation. The increased placental and decreased fetal weights in N-blocked dams suggest a deleterious effect on placental efficiency. We speculate that lack of iron occupancy in the Tf N-lobe confers an iron-depletion signal in the regulation of maternal iron metabolism and erythropoiesis in pregnancy.
Disclosures: Parrow: Protagonist: Consultancy. Fleming: Silence Therapeutics: Consultancy; Ultragenyx: Research Funding; Protagonist Therapeutics: Consultancy.
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