Neural stem cell apoptosis after low‐methylmercury exposures in postnatal hippocampus produce persistent cell loss and adolescent memory deficits

Abstract

The developing brain is particularly sensitive to exposures to environmental contaminants. In contrast to the adult, the developing brain contains large numbers of dividing neuronal precursors, suggesting that they may be vulnerable targets. The postnatal day 7 (P7) rat hippocampus has populations of both mature neurons in the CA1-3 region as well as neural stem cells (NSC) in the dentate gyrus (DG) hilus, that actively produce new neurons that migrate to the granule cell layer (GCL). Using this well-characterized NSC population, we examined the impact of low levels of MeHg on proliferation, neurogenesis, and subsequent adolescent learning and memory behavior. Assessing a range of exposures, we found that a single subcutaneous injection of 0.6μg/g MeHg in P7 rats induced caspase activation in proliferating NSC of the hilus and GCL. This acute NSC death had lasting impact on the DG at P21, reducing cell numbers in the hilus by 22% and the GCL by 27%, as well as reductions in neural precursor proliferation by 25%. In contrast, non-proliferative CA1-3 pyramidal neuron cell number was unchanged. Furthermore, animals exposed to P7 MeHg exhibited an adolescent spatial memory deficit as assessed by Morris water maze. These results suggest that environmentally relevant levels of MeHg exposure may decrease NSC populations and, despite ongoing neurogenesis, the brain may not restore the hippocampal cell deficits, which may contribute to hippocampal-dependent memory deficits during adolescence.

Low-Dose Methylmercury-Induced Genes Regulate Mitochondrial Biogenesis via miR-25 in Immortalized Human Embryonic Neural Progenitor Cells

“…Similar results have been reported in animal models of brain development after exposure to MeHg in utero [8,9]. Moreover, extensive evidence has demonstrated that MeHg can lead to neural cell death, as well as to cytoarchitectural alterations in the nervous system [10,11,12,13,14]. There is an abundance of knowledge regarding reactive oxygen species (ROS) and especially effects of low-level MeHg exposure on cell cycle regulators in neural stem cells in vitro and in vivo [15,16,17].…”

Methylmercury exposure during early Xenopus laevis development affects cell proliferation and death but not neural progenitor specification

“…Likewise, microarray analysis of adult zebrafish brain tissue after intraperitoneal injection of MeHg found significant alteration of gene pathways regulating cell survival and apoptosis in favor of cell death (Richter et al 2011). And a decreased neural proliferation and increased cell death in the hippocampus of rats exposed perinatally to MeHg lead to impairment in memory function lasting through adolescence (Falluel-Morel et al 2007; Sokolowski et al 2013). In our stage 12 embryos, microarray results displayed a strong upregulation of mitochondrial associated apoptotic genes such as cytochrome c (p < 0.005) and caspase 9 (p < 0.03), but found a downregulation of bax (p < 0.012) and no significant change in caspase 8 (p > 0.08), caspase 3 (p > 0.07), or p53 (p > 0.5).…”

Methylmercury and brain development: A review of recent literature

“…Rats exposed to a single injection of 5μg/g MeHg at P7 showed profound juvenile spatial learning impairment and decreases in cell number in P21 hippocampus, that correlated with acute caspase-dependent apoptosis [27]. Furthermore, acute exposure to an environmentally relevant dose of MeHg (0.6μg/g, 24h) in P7 rats, induced caspase-3 activation in neural stem cells (NSCs) of the dentate gyrus (DG), and caused hippocampal-dependent memory deficits during adolescence, assessed by Morris water maze [123]. In addition, a significant degeneration of neuritic processes, and either apoptotic or necrotic death was observed in cortical cultures obtained from pups born to 8 mg/kg MeHg-exposed dams, which was correlated with long term memory impairment of adult offspring subjected to a memory task [73].…”