title: Prenatal Choline Supplementation Diminishes Early-Life Iron Deficiency-Induced Reprogramming of Molecular Networks Associated with Behavioral Abnormalities in the Adult Rat Hippocampus.
abstract: BACKGROUND
  Early-life iron deficiency is a common nutrient deficiency worldwide. Maternal iron deficiency increases the risk of schizophrenia and autism in the offspring. Postnatal iron deficiency in young children results in cognitive and socioemotional abnormalities in adulthood despite iron treatment. The rat model of diet-induced fetal-neonatal iron deficiency recapitulates the observed neurobehavioral deficits.
  
  
  OBJECTIVE
  We sought to establish molecular underpinnings for the persistent psychopathologic effects of early-life iron deficiency by determining whether it permanently reprograms the hippocampal transcriptome. We also assessed the effects of maternal dietary choline supplementation on the offspring's hippocampal transcriptome to identify pathways through which choline mitigates the emergence of long-term cognitive deficits.
  
  
  METHODS
  Male rat pups were made iron deficient (ID) by providing pregnant and nursing dams an ID diet (4 g Fe/kg) from gestational day (G) 2 through postnatal day (PND) 7 and an iron-sufficient (IS) diet (200 g Fe/kg) thereafter. Control pups were provided IS diet throughout. Choline (5 g/kg) was given to half the pregnant dams in each group from G11 to G18. PND65 hippocampal transcriptomes were assayed by next generation sequencing (NGS) and analyzed with the use of knowledge-based Ingenuity Pathway Analysis. Real-time polymerase chain reaction was performed to validate a subset of altered genes.
  
  
  RESULTS
  Formerly ID rats had altered hippocampal expression of 619 from >10,000 gene loci sequenced by NGS, many of which map onto molecular networks implicated in psychological disorders, including anxiety, autism, and schizophrenia. There were significant interactions between iron status and prenatal choline treatment in influencing gene expression. Choline supplementation reduced the effects of iron deficiency, including those on gene networks associated with autism and schizophrenia.
  
  
  CONCLUSIONS
  Fetal-neonatal iron deficiency reprograms molecular networks associated with the pathogenesis of neurologic and psychological disorders in adult rats. The positive response to prenatal choline represents a potential adjunctive therapeutic supplement to the high-risk group.
authors: Department of Pediatrics, tranx271@umn.edu.
authors: Phu V
authors: PV
authors: Tran
authors: Graduate Program in Neuroscience, and.
authors: Bruce C
authors: BC
authors: Kennedy
authors: Graduate Program in Neuroscience, and.
authors: Marc T
authors: MT
authors: Pisansky
authors: Institute for Diabetes, Obesity and Metabolism, Department of Genetics, and.
authors: Kyoung-Jae
authors: KJ
authors: Won
authors: Graduate Program in Neuroscience, and Department of Psychology, University of Minnesota, Minneapolis, MN;
authors: Jonathan C
authors: JC
authors: Gewirtz
authors: Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA.
authors: Rebecca A
authors: RA
authors: Simmons
authors: Department of Pediatrics, Graduate Program in Neuroscience, and.
authors: Michael K
authors: MK
authors: Georgieff
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001522:Behavior, Animal / Q000187:drug effects; D002794:Choline / Q000494:pharmacology*; D019587:Dietary Supplements; D005260:Female; D005333:Fetus / Q000187:drug effects / Q000378:metabolism; D015870:Gene Expression; D056426:Genetic Loci; D059014:High-Throughput Nucleotide Sequencing; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D000090463:Iron Deficiencies; D008297:Male; D011247:Pregnancy; D011295:Prenatal Care; D011297:Prenatal Exposure Delayed Effects; D039401:Prenatal Nutritional Physiological Phenomena; D051381:Rats; D017207:Rats, Sprague-Dawley; D015203:Reproducibility of Results
chemical_list: D002794:Choline
keywords: choline supplementation; fetal iron deficiency; hippocampus; psychological disorders; transcriptome