Nutritional and Toxic Insults During Gestation

This line of work is motivated by the concept that complex neural developmental disorders originate in the embryonic brain and, in essence, are progenitor cell diseases. The rational originated with the discovery of CNS embryonic progenitor cells, capable of giving rise to mature neurons and glial cells. We found that these cells are highly sensitive to alterations in their environment, with even small initial changes having a large impact on brain maturation. Among the environmental insults that affect embryonic progenitor cell pools during pregnancy, nutritional iron deficiency and exposure to environmental toxicants like lead (Pb) are particularly relevant due to its prevalence and its associated developmental pathologies. While many studies describe the negative consequences of iron deficiency or Pb exposure for the cognitive development in children, the cellular targets and the response of an iron deficient brain to environmental Pb are not clear. We established relevant mouse models and human brain organoid systems to test the hypothesis that gestational iron deficiency and Pb exposure impairs embryonic neural progenitor cells and results in long lasting consequences for postnatal brain development. One of the highlights of this work is the discovery that iron deficiency during gestation is associated with altered metal homeostasis in the brain later in life and results in an alteration of the excitatory/inhibitory balance, which is associated with complex disorders like autism spectrum disorders and ADHD. Using our in vivo animal model and in vitro human organoid model we are currently investigating the consequences of postnatal iron supplementation on metal homeostasis and the vulnerability of embryonic human cells to iron deficiency and Pb exposure.