Developmental Exposure to Aluminum Chloride Irreversibly Affects Postnatal Hippocampal Neurogenesis Involving Multiple Functions in Mice

Aluminum (Al) is neurotoxic to adults and also to infants. In this study, we investigated the developmental exposure effect of AlCl(3) on postnatal hippocampal neurogenesis. Pregnant mice were administered 0-, 900-, or 1800-ppm AlCl(3) via drinking water from gestational day 6 to postnatal day (PND) 21, with their offspring examined on PND 21 and PND 77. On PND 21, GFAP-immunoreactive ((+)) neural stem cells (NSCs) and p21(Cip1/Waf1+) cells were decreased in number in the subgranular zone at 900 and ≥900 ppm, respectively. Pcna transcript level examined at 1800 ppm was decreased in the dentate gyrus. These results suggest induction of compromised cell quiescence that caused impaired self-renewal capacity of NSCs accompanying slowing down of cell cycling, which ultimately resulted in exhaustion of the NSC pool. At 1800 ppm, Reelin(+) hilar GABAergic interneurons were also decreased, suggesting a contribution to the NSC reduction. At this dose, TBR2(+) or DCX(+) progenitor and immature granule cells and PVALB(+) interneurons were increased. Moreover, COX-2(+) granule cells were increased at ≥900 ppm. These results suggest facilitation of transient progenitor cell proliferation and differentiation during exposure. Moreover, TUNEL(+) or Morin-stained granule cells were increased, together with Casp12 transcript upregulation, suggesting induction of Al accumulation-related endoplasmic reticulum stress-mediated granule cell apoptosis. Transcript expression changes on cholinergic and glutamatergic signals and synaptic plasticity suggested contribution to disruptive neurogenesis. The NSC-targeting effects sustained through the adult stage despite no sustained Al-accumulation. These results suggest that developmental AlCl(3)-exposure irreversibly affects postnatal hippocampal neurogenesis involving multiple functions in mice.