title: 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.
authors.affiliation: 1 Department of Endocrinology and Metabolism, Institute of Endocrinology, Liaoning Provincial Key Laboratory of Endocrine Diseases, The First Affiliated Hospital of China Medical University , Shenyang, China .|2 Department of Endocrinology, The People's Hospital of Liaoning Province , Shenyang, China .
authors.forename: Xiaona
authors.initials: X
authors.lastname: Hu
authors.affiliation: 1 Department of Endocrinology and Metabolism, Institute of Endocrinology, Liaoning Provincial Key Laboratory of Endocrine Diseases, The First Affiliated Hospital of China Medical University , Shenyang, China .
authors.forename: Ranran
authors.initials: R
authors.lastname: Wang
authors.affiliation: 1 Department of Endocrinology and Metabolism, Institute of Endocrinology, Liaoning Provincial Key Laboratory of Endocrine Diseases, The First Affiliated Hospital of China Medical University , Shenyang, China .
authors.forename: Zhongyan
authors.initials: Z
authors.lastname: Shan
authors.affiliation: 3 Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University , Shanghai, China .
authors.forename: Yujie
authors.initials: Y
authors.lastname: Dong
authors.affiliation: 1 Department of Endocrinology and Metabolism, Institute of Endocrinology, Liaoning Provincial Key Laboratory of Endocrine Diseases, The First Affiliated Hospital of China Medical University , Shenyang, China .
authors.forename: Hongzhi
authors.initials: H
authors.lastname: Zheng
authors.affiliation: 3 Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University , Shanghai, China .
authors.forename: Forrest Fabian
authors.initials: FF
authors.lastname: Jesse
authors.affiliation: 3 Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University , Shanghai, China .
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Rao
authors.affiliation: 4 RIKEN Brain Science Institute , Research Resources Center, Support Unit for Animal Resources Development, Wako, Japan .
authors.forename: Eiki
authors.initials: E
authors.lastname: Takahashi
authors.affiliation: 3 Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University , Shanghai, China .
authors.forename: Weidong
authors.initials: W
authors.lastname: Li
authors.affiliation: 1 Department of Endocrinology and Metabolism, Institute of Endocrinology, Liaoning Provincial Key Laboratory of Endocrine Diseases, The First Affiliated Hospital of China Medical University , Shenyang, China .
authors.forename: Weiping
authors.initials: W
authors.lastname: Teng
authors.affiliation: 1 Department of Endocrinology and Metabolism, Institute of Endocrinology, Liaoning Provincial Key Laboratory of Endocrine Diseases, The First Affiliated Hospital of China Medical University , Shenyang, China .
authors.forename: Xiaochun
authors.initials: X
authors.lastname: Teng
mesh_terms: D018798:Anemia, Iron-Deficiency / Q000378:metabolism* / Q000503:physiopathology; D000818:Animals; D000831:Animals, Newborn; D001522:Behavior, Animal; D001921:Brain / Q000254:growth & development* / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006624:Hippocampus / Q000378:metabolism; D007037:Hypothyroidism / Q000378:metabolism* / Q000503:physiopathology; D007453:Iodide Peroxidase; D007501:Iron / Q000378:metabolism*; D000090463:Iron Deficiencies; D008099:Liver / Q000378:metabolism; D011247:Pregnancy; D011248:Pregnancy Complications / Q000378:metabolism / Q000503:physiopathology; D011250:Pregnancy Complications, Hematologic / Q000378:metabolism* / Q000503:physiopathology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D012018:Reflex; D013054:Spectrophotometry, Atomic; D013974:Thyroxine / Q000378:metabolism*; D059467:Transcriptome
chemical_list: D012333:RNA, Messenger; D007501:Iron; D007453:Iodide Peroxidase; D013974:Thyroxine