Tran Phu V, Kennedy Bruce C, Pisansky Marc T, Won Kyoung-Jae, Gewirtz Jonathan C, Simmons Rebecca A, Georgieff Michael K
Department of Pediatrics,
Graduate Program in Neuroscience, and.
J Nutr. 2016 Mar;146(3):484-93. doi: 10.3945/jn.115.227561. Epub 2016 Feb 10.
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.
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.
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.
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.
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.
早年缺铁是全球常见的营养缺乏症。母体缺铁会增加后代患精神分裂症和自闭症的风险。幼儿期出生后缺铁，即使经过铁剂治疗，成年后也会导致认知和社会情感异常。饮食诱导的胎儿-新生儿缺铁大鼠模型再现了观察到的神经行为缺陷。
我们试图通过确定早年缺铁是否会永久性地重新编程海马转录组，来建立早年缺铁持续心理病理效应的分子基础。我们还评估了母体膳食补充胆碱对后代海马转录组的影响，以确定胆碱减轻长期认知缺陷出现的途径。
从妊娠第2天（G2）到出生后第7天（PND7），给怀孕和哺乳的母鼠提供缺铁（ID）饮食（4 g铁/千克），此后提供铁充足（IS）饮食（200 g铁/千克），使雄性幼鼠缺铁（ID）。对照幼鼠全程给予IS饮食。从G11到G18，每组中一半的怀孕母鼠给予胆碱（5 g/千克）。通过下一代测序（NGS）检测PND65海马转录组，并使用基于知识的 Ingenuity 通路分析进行分析。进行实时聚合酶链反应以验证一部分改变的基因。
通过NGS对超过10,000个基因位点进行测序，发现先前缺铁的大鼠海马中有619个基因表达发生改变，其中许多映射到与心理障碍相关的分子网络，包括焦虑症、自闭症和精神分裂症。铁状态和产前胆碱治疗在影响基因表达方面存在显著相互作用。补充胆碱可降低缺铁的影响，包括对与自闭症和精神分裂症相关基因网络的影响。
胎儿-新生儿缺铁会重新编程成年大鼠中与神经和心理疾病发病机制相关的分子网络。对产前胆碱的积极反应代表了对高危人群潜在的辅助治疗补充剂。
