Biophotonic imaging in HO-1.luc transgenic mice: real-time demonstration of gender-specific chloroform induced renal toxicity.
The metabolism of luciferin in mice transgenic for luciferase (luc) produces light that may be detected trans vivo by an intensified CCD camera (biophotonics). Thus, the generation of transgenic promoter-luciferase animals for genes regulated by specific toxic processes, coupled with real-time evaluation of site-specific gene expression may provide novel, non-invasive biomarkers which are predictive of developing toxicity in vivo. As part of a programme to evaluate the potential of biophotonics for predictive toxicology we have conducted a series of studies in HO-1.luc transgenic mice. Male and female animals were treated with chloroform (200 mg/kg, p.o., daily for 5 days) and imaged 2 and 6 h after dosing. During a 2-day washout period, female animals were treated daily with testosterone prior to repeat administration of chloroform for a further 5 days. Comparison of the in vivo response of the luciferase reporter with markers of toxicity measured ex vivo (differential gene expression of adaptive antioxidant response genes, clinical chemistry and microscopic examination) confirms the gender-specific difference in chloroform renal toxicity in HO-1.luc transgenic mice and its reversal following androgenisation of females and correlates with the expression of the endogenous haem oxygenase-1 (HO-1) gene. These studies demonstrate the capacity of biophotonics for real-time site-specific gene expression, which may be predictive of developing toxicity.
Weir
Lucinda R
LR
Safety Assessment, GlaxoSmithKline R&D, Ware, Hertfordshire SG12 0DP, UK.
Schenck
Emanuel
E
Meakin
Jackie
J
McClure
Fiona
F
Driver
Roy
R
Walker
Sarah
S
Lynch
Anthony M
AM
D000818:Animals; D001835:Body Weight; D002725:Chloroform / Q000633:toxicity*; D003199:Computer Systems; D003952:Diagnostic Imaging; D004326:Drinking; D004435:Eating; D005260:Female; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics*; D051547:Heme Oxygenase-1; D007668:Kidney / Q000187:drug effects*; D008099:Liver / Q000187:drug effects; D008156:Luciferases / Q000235:genetics*; D008163:Luminescent Measurements; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D008822:Mice, Transgenic; D012727:Sex Characteristics; D018675:Toxicity Tests / Q000379:methods*
D008565:Membrane Proteins; D002725:Chloroform; D008156:Luciferases; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse