Acute cadmium exposure induces stress-related gene expression in wild-type and metallothionein-I/II-null mice.
This study examined the effect of acute cadmium on stress-related gene expression and free radical production in wild-type and metallothionein-I/II-null (MT-null) mice. Atlas Toxicology arrays showed that acute cadmium (40 micromol/kg as CdCl(2), ip for 3 h) markedly increased the expression of genes encoding heat-shock proteins, heme oxygenase-1, and genes in response to DNA damage/repair. The expression of genes encoding cytochrome P450 enzymes, UDP-glucuronosyltransferases, Mn-superoxide dismutase, and catalase was suppressed by cadmium. MT-null mice were more sensitive than wild-type mice to cadmium-induced, stress-related gene expression, in accord with greater activation of transcription factor AP-1 and phosphorylated JNK and ERK. To evaluate free radical production, mice were simultaneously given the spin trap agent, N-tert-butyl-alpha-phenylnitrone (PBN, 250 mg in DMSO/kg, ip) with cadmium, and livers were removed 30 min later for PBN-trapped radical extraction with chloroform:methanol (2:1), and detected with electron spin resonance (ESR). Cadmium treatment caused detectable ESR signals for PBN adducts as well as lipid peroxidation in the liver similarly in both wild-type and MT-null mice. Thus, the mechanism of acute cadmium toxicity involves multiple facets including oxidative damage and aberrant gene expression, and absence of MT exacerbates Cd-induced aberrant gene expression.
Liu
Jie
J
Laboratory of Comparative Carcinogenesis, Mail Drop F0-09, NCI at NIEHS, Research Triangle Park, NC 27709, USA. Liu6@niehs.nih.gov
Kadiiska
Maria B
MB
Corton
J Christopher
JC
Qu
Wei
W
Waalkes
Michael P
MP
Mason
Ronald P
RP
Liu
Yaping
Y
Klaassen
Curtis D
CD
D000818:Animals; D030801:Animals, Genetically Modified; D002104:Cadmium / Q000633:toxicity*; D005609:Free Radicals / Q000032:analysis / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects* / Q000235:genetics; D018882:Heat Stress Disorders / Q000235:genetics / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008668:Metallothionein / Q000172:deficiency* / Q000235:genetics; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D018384:Oxidative Stress / Q000235:genetics* / Q000502:physiology; D018808:Transcription Factor AP-1 / Q000378:metabolism
D005609:Free Radicals; D018808:Transcription Factor AP-1; D002104:Cadmium; D008668:Metallothionein; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases