Chemical-induced hippocampal neurodegeneration and elevations in TNFalpha, TNFbeta, IL-1alpha, IP-10, and MCP-1 mRNA in osteopetrotic (op/op) mice.
The osteopetrotic (op/op) mouse, deficient in biologically active colony stimulating factor 1 (CSF-1), was used to examine the role of microglia in chemical-induced trauma. Op/op mice and normal phenotype littermates (non-op/op) received an acute i.p. injection of the hippocampal toxicant, trimethyltin hydroxide (TMT; 1.5 or 2.0 mg/kg). At 2.0 mg/kg, both mice displayed severe degeneration of dentate granule neurons. At 1.5 mg/kg, non-op/op mice showed a limited punctate pattern of neuronal death while op/op mice showed prominent neuronal death. TMT-induced astrocyte reactivity was similar in both groups. RNase protection assays were conducted on hippocampal tissue at 24 hr post-TMT. Elevations were seen in mRNA levels for the host response genes: intercellular cell adhesion molecule (ICAM-1; non-op/op 80%, op/op 85%), the protease inhibitor EB22 (non-op/op 60%, op/op 300%), and glial fibrillary acidic protein (GFAP; non-op/op 300%, op/op 480%) within 24 hr. Macrophage-1 antigen (Mac-1) mRNA levels were lower in all op/op mice and were not induced by TMT exposure. Macrophage inflammatory protein (MIP)-1alpha and MIP-1beta mRNA levels were elevated in non-op/op mice while mRNA levels for interferon inducible protein (IP-10) and monocyte chemoattractant protein (MCP-1) were elevated in op/op mice. Tumor necrosis factor alpha (TNFalpha) mRNA levels were significantly elevated in both non-op/op (100%) and op/op (600%) mice. TNFbeta mRNA levels in op/op mice were elevated 200% and interleukin 1alpha (IL-1alpha) 150%. Reverse transcriptase polymerase chain reaction (RT-PCR) showed a TMT-induced elevation in INFalpha and INFbeta mRNA levels and no elevation of INFgamma. mRNA levels of the CSF-1 receptor, c-fms, were unaltered.
Bruccoleri
A
A
Neurotoxicology Group, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA.
Harry
G J
GJ
D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D054357:Chemokine CXCL10; D019743:Chemokines, CXC / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000737:chemistry*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D007375:Interleukin-1 / Q000235:genetics / Q000378:metabolism; D008233:Lymphotoxin-alpha / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D017628:Microglia / Q000378:metabolism*; D019636:Neurodegenerative Diseases / Q000139:chemically induced / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D010022:Osteopetrosis / Q000150:complications / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism*; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012260:Ribonucleases / Q000378:metabolism; D014298:Trimethyltin Compounds; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
D018932:Chemokine CCL2; D054357:Chemokine CXCL10; D019743:Chemokines, CXC; D016207:Cytokines; D005904:Glial Fibrillary Acidic Protein; D007375:Interleukin-1; D008233:Lymphotoxin-alpha; D012333:RNA, Messenger; D014298:Trimethyltin Compounds; D014409:Tumor Necrosis Factor-alpha; C037718:trimethyltin hydroxide; D018799:Intercellular Adhesion Molecule-1; D016186:Receptor, Macrophage Colony-Stimulating Factor; D012260:Ribonucleases