Effects of neonatal diethylstilbestrol exposure on c-fos and c-jun protooncogene expression in the mouse uterus.
Quantitative and cell-type-specific expression of c-fos and c-jun genes after 17beta-estradiol (E2) stimulation, was investigated in the uteri of neonatally diethylstilbestrol (DES)-exposed and ovariectomized adult mice (neoDES-mice), employing Northern blot analysis, immunohistochemistry and in situ hybridization. The c-fos mRNA level before E2 injection (at baseline) was about 2.2-fold higher in neoDES-mice than in vehicle-treated control mice. In controls, E2 treatment transiently increased c-fos mRNA levels, showing a peak value (15.8-fold relative to the baseline) after 2 hours. In neoDES-mice, c-fos mRNA level reached a peak showing a 2.1-fold increase compared with its baseline value 1 hour after E2 injection. Immunohistochemistry and in situ hybridization revealed that c-fos protein (Fos) and mRNA are induced in the epithelium and vascular endothelium in both groups. Most uterine epithelia of neoDES-mice revealed low sensitivity to the c-fos expression after E2 administration compared with those of vehicle-treated controls, whereas few epithelia showed high c-fos mRNA expression even at baseline. The c-jun mRNA concentration in the neoDES-mice uteri at baseline was 70% of that in vehicle-treated controls. At 1 hour after E2 injection, c-jun mRNA levels increased 1.8-fold in controls and 1.3-fold in the neoDES-mice relative to each baseline value. There were no significant differences in the distribution pattern of c-jun protein (Jun) and mRNA in the uteri of either groups; E2 stimulated c-jun mRNA expression in the stromal and myometrial cells but suppressed it in the epithelial cells, whereas intensity of c-jun immunostaining increased in the three cell types. The permanent changes in the expression of estrogen-regulated protooncogenes, c-fos and c-jun genes, by neonatal DES exposure may be responsible for the wide range of abnormalities in the genital tract of mature animals.
Yamashita
S
S
Keio Junior College of Nursing, Keio University, School of Medicine, Tokyo, Japan. shuji@mc.med.keio.ac.jp
Takayanagi
A
A
Shimizu
N
N
D000818:Animals; D000831:Animals, Newborn / Q000378:metabolism*; D015152:Blotting, Northern; D002273:Carcinogens / Q000633:toxicity*; D004054:Diethylstilbestrol / Q000633:toxicity*; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects*; D016762:Genes, fos / Q000187:drug effects*; D016758:Genes, jun / Q000187:drug effects*; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D051379:Mice; D012313:RNA / Q000096:biosynthesis / Q000302:isolation & purification; D011960:Receptors, Estrogen / Q000096:biosynthesis; D014599:Uterus / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure
D002273:Carcinogens; D011960:Receptors, Estrogen; D012313:RNA; D004054:Diethylstilbestrol