Mercury Toxicity and Neurogenesis in the Mammalian Brain

Abstract

The mammalian brain is formed from billions of cells that include a wide array of neuronal and glial subtypes. Neural progenitor cells give rise to the vast majority of these cells during embryonic, fetal, and early postnatal developmental periods. The process of embryonic neurogenesis includes proliferation, differentiation, migration, the programmed death of some newly formed cells, and the final integration of differentiated neurons into neural networks. Adult neurogenesis also occurs in the mammalian brain, but adult neurogenesis is beyond the scope of this review. Developing embryonic neurons are particularly susceptible to neurotoxicants and especially mercury toxicity. This review focused on observations concerning how mercury, and in particular, methylmercury, affects neurogenesis in the developing mammalian brain. We summarized information on models used to study developmental mercury toxicity, theories of pathogenesis, and treatments that could be used to reduce the toxic effects of mercury on developing neurons.

Keywords: developing neurons; developmental neurotoxicology; differentiation; methylmercury; migration; neural progenitor cell; neural stem cell; proliferation.

Figure 1

Summary of neurogenesis. (A) Schematic diagram of neural tube formation in a cross section of a mammalian embryo. The neural tube forms between paired somites. Below the neural tube is the notochord (N). During neural tube formation, neural crest cells migrate away from the neural plate to form numerous structures, including spinal ganglia (SG). The green box shows the area of the neural tube that is enlarged in diagrams B through E. (B) Early cell divisions in the developing neural tube. Neuroepithelial cells undergo symmetrical cell divisions to form more neuroepithelial cells. Cell divisions occur in the ventricular zone (VZ) located next to the neural canal. The mantle zone (MZ) or mantle layer is the layer of the neural tube next to the surface of the neural tube. In between the VZ and the MZ is the intermediate zone (IZ) or intermediate layer. (C) Neuroepithelial cells also give rise to apical radial glial cells that undergo symmetrical divisions to produce more apical radial glial cells. (D) Apical radial glial cells also undergo asymmetrical cell divisions to produce a range of cell types, including basal radial glial cells, intermediate progenitor cells, and early neurons. (E) Intermediate progenitor cells are located in a second germinal layer called the subventricular zone (SVZ) and undergo additional cell divisions. Intermediate progenitor cells give rise to neurons that migrate to their final locations in the developing central nervous system. The key seen in the bottom right corner of Figure 1 shows the different cell types described in the figure.

Figure 2

Development of the six layers of the mammalian neocortex. Figure 2 is a set of diagrams that show four different points during the development of the mammalian neocortex. The first diagram on the left is the earliest, and the last diagram on the right is the oldest. Neurons are initially formed in the ventricular zone (VZ) and then in the subventricular zone (SVZ). The earliest layers of the developing neural tube that gives rise to the central nervous system, which consists of the brain and spinal cord, are the VZ, intermediate zone (IZ), or intermediate layer, and the mantle zone (MZ) or mantle layer. Newly formed neurons migrate along radial glial cells to form Layers VI and V (L-VI, L-V) in an inside-to-outside pattern. Layer I (L-I) is an exception and forms separately. Subsequently, Layer IV (L-IV) is formed, and then Layers II and III (L-II/III). The different colors of neurons merely denote the different layers of neurons that form. Deep in L-VI, a region called the subplate (SP) forms, and the region of the SVZ develops into a layer of myelinated axons (white matter, WM). Note, this diagram does not show gliogenesis, which is initiated during the later stages of layer formation in the neocortex.

Figure 3

Summary of the neurotoxic effects of methylmercury during neurogenesis. This diagram summarizes the neurotoxic effects of methylmercury after it enters into developing cells, including neuroepithelial cells, intermediate progenitor cells, and migrating and differentiating neurons. Abbreviations: MeHg, methylmercury; NMDA-R, NMDA receptors; Ca²⁺, calcium ion; ROS, reactive oxygen species; mtDNA, mitochondrial DNA. Sources used to create this summary include references [38,42,59,64,84,106].