CONICET | Buscador de Institutos y Recursos Humanos

Prenatal zinc deficiency resulting from insufficient dietary intake, absorption, or transport can compromise development of the central nervous system leading to a spectrum of defects ranging from severe congenital malformations to subtle neurological and cognitive impairments. We previously found that marginal zinc deficiency disrupts the ERK1/2 signaling pathway leading to disruption of neural progenitor cell proliferation. This study investigated if marginal zinc deficiency during gestation in rats could affect fetal neurogenesis. Rats were fed a marginally zinc-deficient or adequate diet through gestation and offspring were analyzed at embryonic day (E)14, E19, postnatal day (P)2, and P56. ERK1/2 phosphorylation measured by Western blot in the cerebral cortex was decreased in the marginal zinc fetuses at E19. Immunofluorescence staining showed the pattern of ERK1/2 phosphorylation was specifically decreased in the ventricular zone ofthe frontal cortex at E19 and this was associated with decreased labile zinc levels measured by zinquin staining. Marginal zinc deficiency decreased neural progenitor cell proliferation measured by Western blot and immunofluorescence for the mitotic marker phosphorylated-vimentin. Decreased proliferation led to decreased expression of the neural progenitor cell marker Sox2 and the neuronal marker (NeuN) at E19. However, the density of Tbr1 expressing glutamatergic neurons was increased in the superficial layers of the frontal cortex at E19. At P56 the density of cells expressing NeuN was decreased, demonstrating that disruption of fetal neurogenesis had lasting effects on the density of neurons in the frontal cortex following dietary repletion with adequate zinc levels. Disruption of neurogenesis could underlie irreversible neurobehavioralimpairments observed after marginal zinc deficiency during fetal development.