Cellular Iron Deficiency Disrupts Thyroid Hormone Regulated Gene Expression in Developing Hippocampal Neurons.

BACKGROUND

Developing neurons have high thyroid hormone and iron requirements to support their metabolism and growth. Early-life iron and thyroid hormone deficiencies are prevalent, often coexist, and increase the risk of permanently impaired neurobehavioral function in children. Early-life dietary iron deficiency reduces thyroid hormone levels and impairs thyroid hormone-responsive gene expression in the neonatal rat brain.

OBJECTIVE

This study determined whether neuronal-specific iron deficiency alters thyroid hormone-regulated gene expression in developing neurons.

METHODS

Iron deficiency was induced in primary mouse embryonic hippocampal neuron cultures with the iron chelator deferoxamine (DFO) beginning at 3 days in vitro (DIV). At 11DIV and 18DIV, mRNA levels for thyroid hormone-regulated genes indexing thyroid hormone homeostasis () and neurodevelopment () were quantified. To assess the effect of iron repletion, DFO was removed at 14DIV from a subset of DFO-treated cultures and gene expression and ATP levels were quantified at 21DIV.

RESULTS

At 11DIV and 18DIV, neuronal iron deficiency decreased , and , and by 18DIV, , and were increased; collectively suggesting cellular sensing of a functionally abnormal thyroid hormone state. Dimensionality reduction with Principal Component Analysis (PCA) reveals that thyroid hormone homeostatic genes strongly correlate with and predict iron status ( mRNA). Iron repletion from 14-21DIV restored neurodevelopmental genes, but not all thyroid hormone homeostatic genes, and ATP concentrations remained significantly altered. PCA clustering suggests that cultures replete with iron maintain a gene expression signature indicative of previous iron deficiency.

CONCLUSIONS

These novel findings suggest there is an intracellular mechanism coordinating cellular iron/thyroid hormone activities. We speculate this is a part of homeostatic response to match neuronal energy production and growth signaling for these important metabolic regulators. However, iron deficiency may cause permanent deficits in thyroid hormone-dependent neurodevelopmental processes even after recovery from iron deficiency.