Department of Pediatrics, University of Minnesota, Minneapolis, MN.
Department of Biology, Luther College, Decorah, IA.
J Nutr. 2018 Oct 1;148(10):1521-1528. doi: 10.1093/jn/nxy125.
Iron deficiency (ID) compromises the developing nervous system, including the hippocampus, resulting in later-life deficits despite iron repletion. The iron-dependent molecular changes driving these lasting deficits, and the effect of early iron repletion, are incompletely understood. Previous studies have utilized dietary models of maternal-fetal ID anemia (IDA) to address these questions; however, concurrent anemia prevents delineation of the specific role of iron.
The aim of the study was to isolate the effects of developmental ID on adult hippocampal gene expression and to determine if iron repletion reverses these effects in a mouse model of nonanemic hippocampal neuronal ID.
Nonanemic, hippocampus-specific neuronal ID was generated by using a Tet-OFF dominant negative transferrin receptor (DN-TFR1) mouse model that impairs cellular iron uptake. Hippocampal ID was reversed with doxycycline at postnatal day 21 (P21) in a subset of mice to create 2 experimental groups, chronically iron-deficient and formerly iron-deficient mice, which were compared with their respective doxycycline-treated and untreated iron-sufficient controls. RNA from adult male hippocampi was sequenced. Paired-end reads were analyzed for differential expression. Differentially expressed genes were analyzed in Ingenuity Pathway Analysis.
A total of 346 genes were differentially expressed in adult, chronically iron-deficient hippocampi compared with controls. ID dysregulated genes in critical neurodevelopmental pathways, including axonal guidance, CDK5, Ephrin receptor, Rac, and Neurotrophin/Trk signaling. Iron repletion at P21 normalized adult hippocampal expression of 198 genes; however, genes involved in cAMP response element-binding protein (CREB) signaling, neurocognition, and neurologic disease remained dysregulated in adulthood.
Chronic ID during development, independent of anemia, alters the adult mouse hippocampal transcriptome. Restoring iron status during a known critical period of hippocampal neurodevelopment incompletely normalized these changes, suggesting a need for additional studies to identify the most effective timeline for iron therapy, and adjunctive treatments that can fully restore ID-induced molecular changes, particularly in human populations in whom chronic ID is endemic.
铁缺乏（ID）会损害发育中的神经系统，包括海马体，尽管补充了铁，但仍会导致以后的生活出现缺陷。导致这些持久缺陷的铁依赖性分子变化以及早期铁补充的效果尚不完全清楚。先前的研究利用母体-胎儿 ID 贫血（IDA）的饮食模型来解决这些问题；然而，同时存在的贫血会妨碍明确铁的具体作用。
本研究的目的是分离发育性 ID 对成年海马体基因表达的影响，并确定在非贫血性海马神经元 ID 的小鼠模型中，铁补充是否可以逆转这些影响。
使用 Tet-OFF 显性负性转铁蛋白受体（DN-TFR1）小鼠模型产生非贫血性、海马体特异性神经元 ID，该模型会损害细胞铁摄取。在一组小鼠中，于出生后第 21 天（P21）用强力霉素逆转海马体 ID，以创建 2 个实验组，即慢性铁缺乏组和曾经铁缺乏组，并将其与各自的强力霉素处理和未处理的铁充足对照组进行比较。从成年雄性海马体中提取 RNA，进行测序。对配对末端读数进行差异表达分析。在 Ingenuity Pathway Analysis 中对差异表达基因进行分析。
与对照组相比，成年慢性铁缺乏海马体中共有 346 个基因差异表达。ID 失调了关键神经发育途径中的基因，包括轴突导向、CDK5、Ephrin 受体、Rac 和神经营养素/Trk 信号。在 P21 时进行铁补充可使 198 个成年海马体基因的表达正常化；然而，在成年期，与 cAMP 反应元件结合蛋白（CREB）信号、神经认知和神经疾病相关的基因仍存在失调。
在发育过程中，慢性 ID 独立于贫血会改变成年小鼠海马体的转录组。在已知的海马体神经发育关键时期恢复铁状态并不能完全使这些变化正常化，这表明需要进一步研究以确定铁治疗的最佳时间框架，以及可以完全恢复 ID 诱导的分子变化的辅助治疗方法，特别是在慢性 ID 流行的人群中。
