title: Methylmercury (MeHg) elicits mitochondrial-dependent apoptosis in developing hippocampus and acts at low exposures.
abstract: 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.
authors: Joint Graduate Program in Toxicology, Graduate School of Biomedical Sciences at Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA.
authors: Katie
authors: K
authors: Sokolowski
authors: Anthony
authors: A
authors: Falluel-Morel
authors: Xiaofeng
authors: X
authors: Zhou
authors: Emanuel
authors: E
authors: DiCicco-Bloom
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D005260:Female; D006624:Hippocampus / Q000187:drug effects / Q000254:growth & development*; D008297:Male; D008767:Methylmercury Compounds / Q000008:administration & dosage* / Q000633:toxicity*; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D008767:Methylmercury Compounds