Sex-Specific Effects of Early-Life Iron Deficiency and Prenatal Choline Treatment on Adult Rat Hippocampal Transcriptome

Abstract

Background: Fetal-neonatal iron deficiency (ID) causes long-term neurocognitive and affective dysfunctions. Clinical and preclinical studies showed that early-life ID produced sex-specific effects. However, little is known about molecular mechanisms behind the sex-specific effects of early-life ID on neural gene regulation. Objective: To illustrate sex-specific transcriptome alteration in adult rat hippocampus induced by fetal-neonatal ID and prenatal choline treatment. Methods: Pregnant rats were fed iron-deficient (4 mg/kg Fe) or iron-sufficient (200 mg/kg Fe) diet from gestational day (G) 2 to postnatal day (P) 7 with or without choline supplementation (5 g/kg choline) from G11-18. Hippocampi were collected from P65 offspring of both sexes and analyzed for changes in gene expression. Results: Both early-life ID and choline treatment induced more transcriptional changes in female rat hippocampus than males with a less than 10 percent overlap between sexes. While both sexes showed alterations in gene networks related to increased risks of neurocognitive disorders, males also showed enhanced anti-inflammatory activities in response to ID, contrary to activated pro-inflammatory responses in females. Prenatal choline treatment to ID animals partially rescued ID-induced dysregulations in males but showed less effects in females. However, choline treatment to iron-sufficient rats showed more negative effects on the regulation of genes associated with cognition and affective behaviors, especially in females. Conclusions: This study provided unbiased global assessments of gene expression regulated by iron and choline in a sex-specific manner, with greater negative effects in female than male rats. Our new findings highlight potential sex-specific gene networks for further investigation.