Toxicological Sciences, Vol 50, 90-97, Copyright © 1999 by Society of Toxicology
DA Delker, BL Yano and BB Gollapudi
The dermal Tg.AC transgenic mouse line is currently being used as a
short-term alternative in vivo model for carcinogenicity screening of drugs
and environmental chemicals. These mice carry multiple copies of an
activated v-Ha-ras oncogene, making them susceptible to promotionally
induced tumorigenesis caused by carcinogen exposure or deep skin wounding.
Transgene expression is associated with tumor development in these animals.
To determine whether tissue injury in organs other than the skin can induce
transgene expression, we characterized the pattern of transgene expression
in naive animals as well as mice treated by oral gavage with cytotoxic
doses of chloroform. Hepatic BrdU labeling was increased 40-fold in females
(240 mg/kg/day) and 20-fold in males (140 mg/kg/day) after 4 days of dosing
with chloroform. An increase in renal BrdU labeling (7-fold) was observed
only in male Tg.AC mice. Although chloroform did not induce v-Ha-ras
expression, in either the liver or the kidney, a constitutive amount of
transgene message was evident in the kidneys of Tg.AC mice. V-Ha-ras
transgene expression also correlated with the expression of GATA-3, a
transcription factor that binds the zeta-globin (zeta-globin) promoter of
the Tg.AC transgene. These studies suggest that chemically induced tissue
injury and regenerative cell proliferation per se are not sufficient for
the induction of transgene expression in the liver and kidney of Tg.AC
mice. Although organs like the kidney may contain the necessary
transcription factors for transgene expression, other factors, yet
unidentified, may impede v-Ha-ras-mediated tumorigenesis in these tissues.
ARTICLES
V-Ha-ras gene expression in liver and kidney of transgenic Tg.AC mice following chemically induced tissue injury
The Dow Chemical Company, Health and Environmental Research Laboratory, Midland, Michigan 48674, USA.
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