Short- and Long-term Alterations of Congenital Iron Deficiency on Hematopoietic Cell Lineages in Rats

Narmin mukhtarova, University of Wisconsin-Madison, Madison, WI, United States; Anthony Babu, UW-Madison, Madison, WI, United States; Zachary R. Smith, UW-Madison, Madison, WI, United States; Ashajyothi Siddappa, University of Minnesota, Minnesota, MN, United States; Pamela J. Kling, University of Wisconsin-Madison, Madison, WI, United States

Background: Gestational iron deficiency (ID) is common and may limit fetal iron status, i.e., cause congenital ID that impairs red blood cell (RBC) production. When fetal iron is limited, iron is prioritized to the RBC over other tissues. Less is known about how gestational ID impacts other hematopoietic cell lineages. Limited data support that gestational ID may potentially alter immune cell responses at birth and then program atopic disease.

Objectives: To leverage an established model of gestational ID to study short- and long-term impact on hematopoietic lineages in neonatal rats.

Design/Methods: Gestational ID was created by ID diet to pregnant rats on pregnancy day 2 to postnatal (P)7, vs. iron sufficient (IS) control diet. We measured iron tests, complete cell count and differential cell counts in offspring at postnatal day (P)2-3 neonates, P15 suckling, and formerly ID P45 adolescence.

Results: ID P2-3 neonatal rats had 350% higher ZnPP/H ratios, 70% lower plasma ferritin, 30% lower hemoglobin, and RBC than IS, all p< 0.004. Additionally, ID P2-3 neonatal rats had 25% lower platelets and 36% lower white cell counts (WBC), and proportionately lower lymphocyte and granulocyte numbers, all p< 0.015. At P2-3, microscopic cell morphology differed in RBC, WBC, and platelets, including 37% larger mean platelet volume, p< 0.0001. P15 suckling rats had 98% higher ZnPP/H ratios, 70% lower plasma ferritin, 40% lower hemoglobin, 4% lower RBC than IS, all p< 0.006. In formerly ID P45 adolescent rats, ZnPP/H, plasma ferritin, RBC, WBC, and platelet counts did not differ, although lymphocyte numbers were 19% lower and granulocytes were 50% higher, p< 0.015 for both. Microscopic abnormalities in WBC and platelets remained, including 2.5% higher mean platelet volume, p< 0.024. At birth, the linear relationships between ZnPP/H ratios and hemoglobin, RBC, platelets, WBC, lymphocytes, and granulocytes were all significant, range p< 0.01-0.0001. The relationships between index of erythropoietic stimuli, reticulocytes, was only significant with hemoglobin and RBC, p< 0.03 for both.

Conclusion: At birth, gestational ID offspring exhibited marked abnormalities in RBC, WBC, and platelet lineages, but after normalization, differences in adolescents were also seen. These include microscopic cell morphological abnormalities, relative granulocytosis, and relative lymphopenia. The strong relationships of these measures with iron status suggest iron and not erythropoietic stimulus driving these changes. The long-term programming of hematopoietic and especially immune cell lineages may be clinically relevant warranting further study.