In vivo bioluminescent monitoring of chemical toxicity using heme oxygenase-luciferase transgenic mice.
Transgenic mice expressing the luciferase (luc) gene under the control of the heme oxygenase-1 promoter (Ho1) were used to measure the induction of heme oxygenase in response to known toxicants. Transgenic Ho1-luc expression was visualized in vivo using a low-light imaging system (IVIS). Ho1-luc activation was compared to Ho1-luc expression, HO1 protein levels, standard markers of toxicity, and histology. Male and female Ho1-luc transgenic mice were exposed to acute doses of cadmium chloride (CdCl2, 3.7 mg/kg), doxorubicin (15 mg/kg), and thioacetamide (300 mg/kg). These agents induced the expression of Ho1-luc in the liver and other tissues to varying degrees. The greatest increase in Ho1-luc activity was observed in the liver in response to CdCl2; intermediate responses were observed for doxorubicin and thioacetamide. Induction of the Ho1-luc transgene by these agents was similar to endogenous protein levels of heme oxygenase as assessed by Western blotting, and generally correlated with plasma levels of circulating enzymes reflecting hepatic or general tissue damage. Histopathology confirmed the toxic effects of CdCl2 on liver and kidney; doxorubicin on kidney, liver, and intestine; and thioacetamide on the liver. Tissue damage was much more pronounced than the luciferase expression following thioacetamide treatment when compared with tissue damage and bioluminescence of the other toxicants. Nevertheless, the induction of Ho1-luc expression following exposure to these agents suggests that the Ho1-luc transgenic mouse may prove useful as a model for in vivo screening of compounds that induce luciferase expression as a marker of toxicity.
Malstrom
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Xenogen Corporation, Alameda, CA 94501, USA. Scott.Malstrom@xenogen.com
Jekic-McMullen
D
D
Sambucetti
L
L
Ang
A
A
Reeves
R
R
Purchio
A F
AF
Contag
P R
PR
West
D B
DB
D000410:Alanine Transaminase / Q000378:metabolism; D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D000900:Anti-Bacterial Agents / Q000633:toxicity; D001219:Aspartate Aminotransferases / Q000378:metabolism; D015153:Blotting, Western; D019256:Cadmium Chloride / Q000633:toxicity; D003402:Creatine Kinase / Q000378:metabolism; D004317:Doxorubicin / Q000633:toxicity; D005260:Female; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics*; D007668:Kidney / Q000201:enzymology; D008099:Liver / Q000201:enzymology; D008156:Luciferases / Q000235:genetics*; D008163:Luminescent Measurements; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D013853:Thioacetamide / Q000633:toxicity; D018675:Toxicity Tests / Q000379:methods*
D000900:Anti-Bacterial Agents; D013853:Thioacetamide; D004317:Doxorubicin; D008156:Luciferases; D006419:Heme Oxygenase (Decyclizing); D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D003402:Creatine Kinase; D000469:Alkaline Phosphatase; D019256:Cadmium Chloride