Methylmercury (MeHg) elicits mitochondrial-dependent apoptosis in developing hippocampus and acts at low exposures


Sokolowski K <> , Falluel-Morel A <> , Zhou X <> , DiCicco-Bloom E <> .


Joint Graduate Program in Toxicology, Graduate School of Biomedical Sciences at Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA.


Neurotoxicology. 2011 Oct;32(5):535-44. Epub 2011 Jun 29.



The developing brain is particularly sensitive to environmental teratogens, such as methylmercury (MeHg), which may induce cell death. Although several mechanisms of MeHg-induced apoptosis have been defined in culture models, pathways mediating caspase-3 activation in vivo remain unclear, especially in the developing hippocampus. To explore apoptotic mechanisms, Sprague-Dawley rats were exposed to 5 μg/g MeHg or PBS vehicle on postnatal day 7 (P7) and the hippocampus was assessed at various times for levels of apoptotic proteins. MeHg induced a 38% increase in Bax protein and an increase in cytosolic cytochrome c at 4h, followed by later increases in caspase-9 (40% at 12h; 33% at 24h) and caspase-8 (33% at 24h), compared to controls. MeHg also induced an increase in executioner caspase-3, a protease activated by both mitochondrial-dependent caspase-9 and mitochondrial-independent caspase-8. To further define pathways, we used a forebrain culture model and found that the MeHg-induced increases in caspase-3 and caspase-8 were completely blocked by a caspase-9-specific inhibitor, while caspase-9 induction was unperturbed by the caspase-8 inhibitor. These observations suggest that MeHg acts primarily through the mitochondrial-dependent cascade to activate caspase-3 in forebrain precursors, a pathway that may contribute to previously documented neurotoxicity in developing hippocampus. In turn, using the endpoint protein, caspase-3, as a sensitive marker for neural injury, we were able to detect hippocampal cell death in vivo at ten-fold lower levels of MeHg exposure (0.6 μg/g) than previously reported. Thus mitochondrial-dependent cell death in the hippocampus may serve as a sensitive index for teratogenic insults to the developing brain.


PMCID: PMC3256128 Free PMC Article

     PMID: 21741406 [PubMed - indexed for MEDLINE] 

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