During the first weeks of pregnancy, developing cells are already laying the foundation for the brain. Iron plays a major role in the organization and shaping of cells during this stage of gestation. Epidemiological studies suggest that mothers with low iron levels during the first trimester of pregnancy have a higher risk of giving birth to a child who develops cognitive impairments like autism, ADHD, and learning disabilities.
"We know pregnancy as a critical window for iron-dependent brain development, and current clinical measures may underestimate the long-term impact of prenatal iron deficiency," said Margot Mayer-Proschel, PhD, professor of Biomedical Genetics and Neuroscience at the University of Rochester School of Medicine & Dentistry , and lead author of a study published in The Journal of Nutrition . The Mayer-Proschel team used a nutrition-based mouse model to understand how deficiency in iron during pregnancy leads to long-term functional changes in the brain of offspring."
The Blood Recovers, Not the Brain
Researchers fed mice iron-sufficient and iron-deficient diets prior to conception and continued those diets through pregnancy. At birth, all mice received iron-sufficient diets to determine whether known cellular changes could be rescued. They first found that iron levels normalized in the blood after supplementation, but iron levels were still impaired in the brain, with some regions remaining deficient while other regions accumulating iron above the normal level.
"These effects of tissue specific changes in the brain went beyond iron," said Mayer-Proschel. They found an imbalance of several other minerals that support development and function, including essential macro minerals like calcium and magnesium and essential trace minerals like manganese, copper, and zinc in the mice that were iron-deficient in utero. Working with a mouse model provided URochester researchers the opportunity to follow changes from early life into young adulthood. "Changes in these minerals were more profound in the brain compared to the blood, suggesting that a prenatal or postnatal blood analysis may not tell the full story of long-term changes that occur in the brain of offspring."
Lasting Brain Changes
These mineral imbalances were accompanied by lasting changes in networks associated with genes involved in brain development and communication between brain cells. These included changes in myelin formation, an important structure that insulates nerve fibers, allowing signals between neurons to travel efficiently. When myelin is damaged or underdeveloped, communication between neurons can be affected.
Researchers also discovered changes in expression levels of genes associated with neurodevelopment and autism spectrum disorder. These changes varied across the brain. In the cortex, hippocampus, and thalamus, genes were less active, whereas posterior cortex genes were more active. This novel discovery highlights how gestational iron deficiency can affect multiple brain regions in different ways.
Some of the most extensive gene expression changes were found in the superior colliculus, a brain region involved in processing sensory information and directing attention. "This sensory-processing brain region emerged as a key area of vulnerability," said Mayer-Proschel. "This finding underscores the urgent need for brain-specific biomarkers that allow earlier intervention to protect the developing brain from the hidden consequences of gestational iron deficiency, as recovery of blood iron levels alone may not reflect recovery of the developing brain."
Janine Cubello, PhD, and Aslihan Ambeskovic, PhD, were the first authors on this paper. Other authors include Garrick Salois, PhD, Lu Wang, Derick Peterson, PhD, and Christoph Proschel, PhD, of the University of Rochester. This research was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, a Schmitt Program in Integrative Neuroscience pilot grant through University of Rochester Medicine Del Monte Institute for Neuroscience , and the National Institute of Environmental Health Sciences.
