Brain Structure and Function

, Volume 223, Issue 3, pp 1519–1536 | Cite as

Dietary lipophilic iron accelerates regional brain iron-load in C57BL6 mice

  • Douglas G. Peters
  • Carson J. Purnell
  • Michael P. Haaf
  • Qing X. Yang
  • James R. Connor
  • Mark D. Meadowcroft
Original Article


Impaired brain iron homeostatic mechanisms, independent of pathological hallmarks, are harmful to the brain because excess free iron can cause DNA, protein, and lipid damage via oxidative stress. The goal of this study was to evaluate the longitudinal effect of chronic iron overload and deficiency in the vertebrate brain. Ten-week-old C57BL6 male mice were randomly assigned to one of four unique dietary regiments for 1 year: iron-deficient, normal iron, and two different concentrations of lipophilic iron diet containing 3,5,5-trimethylhexanoyl ferrocene (TMHF). Longitudinal MRI parametrics were used to assess the location and extent of ferric iron distribution. Tissue collected at 12 months was used to directly measure iron-load, protein alterations, and histological metrics. While the iron-deficient diet did not alter brain iron stores, 0.11% TMHF and early exposure with 0.5% TMHF elevated brain iron by roughly 40 and 100%, respectively. R 2 rate increased more in the TMHF groups within iron rich brain regions. Increased brain iron concentration was linearly correlated with an increase in L-ferritin expression, and TMHF diet was found to increase L-ferritin within the olfactory bulb, neocortex, pallidum, thalamus, corpus callosum, CA3 regions of the hippocampus, and substantia nigra. Moreover, gliosis and oxidative stress were detected in the TMHF groups in the regions associated with iron-load. Spatial memory impairment was evident in the iron-loaded mice. This work illustrates that lipophilic iron elevates brain iron in a regionally specific fashion and positions dietary TMHF administration as a model for brain iron overloading.


Iron Iron loading Ferrocene MRI Histology 



The authors would like to acknowledge the following funding sources: The George M. and Mary Jane Leader Foundation and NIH-R03 AG047461-02. We would like to acknowledge the help of Charles DeGanga, B. S. and Deandra Bolton, B. S. in the synthesis of the TMHF compound.


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2017

Authors and Affiliations

  1. 1.Department of NeurosurgeryThe Pennsylvania State University - College of Medicine, Milton S. Hershey Medical CenterHersheyUSA
  2. 2.Department of Neural and Behavioral ScienceThe Pennsylvania State University - College of Medicine, Milton S. Hershey Medical CenterHersheyUSA
  3. 3.Department of Radiology, Center for NMR ResearchThe Pennsylvania State University - College of Medicine, Milton S. Hershey Medical CenterHersheyUSA
  4. 4.Department of ChemistryIthaca CollegeIthacaUSA

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