UC Davis

Adequate zinc intake during prenatal and postnatal period is important for brain development. During development, severe zinc deficiency can cause teratogenic effects including neuronal tube defects and multiple organ malformations. Marginal zinc deficiency during pregnancy and in the early postnatal period can have irreversible adverse effects on offspring neurodevelopment which can persist into adulthood. This can result in behavioral abnormalities including cognitive function, mood disorders, and motor dysfunctions. This thesis focused on investigating the effects of a decreased availability of zinc, primarily due to low zinc intake or secondarily to di-2-ethylhexyl phthalate (DEHP)-induced alterations in zinc homeostasis, during early development in rats on the genesis of the neuronal and/or oligodendroglial lineages. Cell signaling pathways that are involved in these processes were investigated. The impact of maternal marginal zinc deficiency on neurogenesis was evaluated in chapter one of the thesis. The progression of neurogenesis was evaluated at different developmental stages: embryonic day (E) 14, E19, postnatal day (P) 2, and P56. Results showed that the expression of protein markers neural stem cells (NSCs) (SOX2, PAX6), neuronal differentiation (TBR1, TBR2), mature neurons (NeuN), neuronal subtype glutamatergic neuron (VGLUT1) were significantly decreased due to maternal marginal zinc intake, whereas GABAergic neurons (GAD65) were not affected. This was associated with the downregulation of ERK1/2 signaling pathway, which participates in the regulation of NSCs self-renewal, proliferation, and differentiation. In chapter two we investigated the effects of maternal exposure to the environmental toxicant DEHP on neurogenesis. DEHP altered zinc homeostasis, decreasing zinc availability to the fetus in the developing E19 brain. Results indicated that DEHP had similar adverse effects on neurogenesis as the nutritional marginal zinc deficiency, causing decreased NSCs proliferation and differentiation into neurons and particularly affecting the glutamatergic neuron subtype but not markers of GABAergic neurons. In vivo and vitro mechanistic studies showed that the ERK1/2 signaling pathway was inhibited (decreased phosphorylation) in part through the activation of protein phosphatase 2A. Finally, chapter three investigated the effects of maternal marginal zinc deficiency on oligodendrogenesis and myelination and the consequences on behaviors in the offspring rat. The progression of oligodendrogenesis was evaluated at different developmental stages: P2, P5, P10, P20 and P60. Results showed that the expression of markers for oligodendrocytes progenitor cells (OPCs) (NG2, PDGFRα), OPCs differentiation (CNPase), mature oligodendrocytes (MBP, MAG, MOG, PLP) and transcription factors (Olig2, SOX10) were significantly decreased in the marginal zinc deficient offspring rat brain at certain stages of oligodendroglial development. Behavioral assessment results showed that early stages maternal marginal zinc nutrition had long-term impact on neuromuscular functions, locomotor activity and anxiety in the offspring rat. In summary, results from this thesis stress the need of an adequate zinc availability during early development to prevent alterations in neurogenesis and oligodendrogenesis and the long-lasting consequences on brain structure and function.