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

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.