Perinatal Iron Deficiency-Induced Hypothyroxinemia Impairs Early Brain Development Regardless of Normal Iron Levels in the Neonatal Brain.

Abstract

Both perinatal hypothyroxinemia and perinatal iron deficiency (ID) are associated with poor neurodevelopment in offspring. Iron is an important component of thyroid peroxidase, a key enzyme in the synthesis of thyroid hormone. The authors' previous study demonstrated that perinatal ID can lead to maternal hypothyroxinemia during pregnancy. The goal of this study was to determine whether perinatal ID-associated hypothyroxinemia can cause brain defects prior to neonatal brain iron depletion. Two rat models were established to imitate the two common types of maternal ID (mild ID with anemia [ID + A] and ID without anemia [ID - A]), and iron limitation was initiated two weeks before pregnancy. Maternal and neonatal thyroid hormones in serum were analyzed at postnatal day (P) 0 and P10. Neonatal thyroid hormone, as well as mRNA expression of some thyroid hormone-responsive genes in the cerebral cortex and hippocampus, were measured at P10. Serum iron and brain iron concentrations were analyzed by inductively coupled plasma mass spectrometry. Liver iron concentration was determined using graphite furnace atomic absorption spectroscopy. Hemoglobin was analyzed with an automated blood coagulation analyzer. Surface righting reflex and vibrissae-evoked forelimb placing were measured to assess the sensorimotor behaviors. It was found that pre-pregnant mild ID resulted in maternal hypothyroxinemia, which lasted from gestation day 13 to P10. Pre-pregnant mild ID decreased the neonatal brain total triiodothyronine level at P10. Consistent with a low total triiodothyronine level, the mRNA expression of some thyroid hormone-responsive genes (Mbp, RC3, and Srg1) were significantly reduced in the neonatal cerebral cortex and hippocampus in both ID rat models at P10. Furthermore, ID rat pups at P10 showed retarded sensorimotor skills. No significant difference was found between the control and the ID pups in terms of iron concentrations in the neonatal brain at P10. This study demonstrates that perinatal ID-associated hypothyroxinemia is sufficient to impair early brain development, regardless of whether the neonatal brain iron level is normal, and monitoring thyroid hormone level is indicated in ID pregnant women.