Hippocampal Neurogenesis as a Critical Target of Neurotoxicants Contained in Foods

Abstract

Evidence has been accumulating that environmental chemicals contained in foods can cause neurodevelopmental disabilities. However, regular developmental neurotoxicity (DNT) studies require large numbers of animals for detection of subtle dose-response changes, and it is urgent concern to establish a rapid and efficient evaluation system of DNT. Evidence from our recent studies points to the notion that adult neurogenesis in the hippocampus may represent vulnerable endpoint to cause DNT. Adult neurogenesis is the postnatal process of continued production of new neurons through the adult stage in the brain. Monitoring of granule cell lineage in the subgranular zone (SGZ) and γ-aminobutyric acid (GABA)-ergic interneurons in the dentate hilus is effective for detection of target cell populations of DNT as manifested by disruption of neurogenesis. Especially, reelin-expressing GABAergic interneurons are a useful marker to detect disruption of the migration and correct positioning of developing neurons following impairment of neurogenesis. Because axon terminal toxicants target granule cell lineage population growing dendritic processes, there may be common target mechanisms between the DNT and adult-type neurotoxicity affecting mature nervous system. Adult neurogenesis may also be a suitable endpoint for detection of DNT in a scheme of standard regular 28-day toxicity study. In other words, adult-type neurotoxicity could be detected by measuring the cellular responses in adult neurogenesis. Moreover, it should be stressed that there may be epigenome toxicity mechanisms to affect the process of hippocampal neurogenesis involving both neuronal stem cells and interneuron subpopulations, with continued disruption through the adult stage. These findings suggest that hippocampal neurogenesis is considered to be a critical target of environmental neurotoxicants contained in foods.

Figures

Fig. 1.

Neurogenesis in the dentate gyrus of the rat hippocampus.

Fig. 2.

Schematic presentation of adult neurogenesis in the hippocampal dentate gyrus.

Fig. 3.

Generation of granule cell lineages in the hippocampal dentate gyrus.

Fig. 4.

Detection of aberrations in the hippocampal neurogenesis of rodent animals. Distribution of granule cell lineages can be immunohistochemically analyzed employing cellular markers, such as paired box 6 (Pax6), T box brain 2 (Tbr2), NeuroD1 (Nd1), doublecortin (Dcx), dihydropyrimidinase-like 3 (Dpysl3) and neuron-specific nuclear protein (NeuN) in the subgranular zone (SGZ) and granule cell layer (GCL). Apoptosis and cell proliferation activity in the SGZ can also be measured. Distribution of neuronal inputs from the outside of the SGZ, such as reelin-producing cells and GABAergic interneurons can be immunohistochemically detected in the hilus of the dentate gyrus.

Fig. 5.

Summary of developmental exposure effects of anti-thyroid agents (ATAs) and brominated flame retardants (BFRs) in rats.

Fig. 6.

Hypothetical relationship between developmental neurotoxicants and adult-type neurotoxicants on toxicity targets during the process of neuronal development.

Fig. 7.

Developmental neurotoxic target of acrylamide in the process of hippocampal neurogenesis in rats.

Fig. 8.

Comparison of the effect on hippocampal neurogenesis between developmental exposure study and 28-day exposure study of glycidol in rats.

Fig. 9.

Comparison of the effect on hippocampal neurogenesis between developmental exposure study and adult-stage exposure study of methimazole (MMI) in rats.

Fig. 10.

Epigenome toxicity in the hippocampal neurogenesis after developmental exposure to manganese (Mn) in mice.

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