Influence of the Ah locus on the effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin on the hepatic epidermal growth factor receptor.
The present studies examine whether the Ah receptor mediates the effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on the binding capacity of the hepatic epidermal growth factor (EGF) receptor in congenic strains of C57BL/6J mice that differ only at the Ah locus. The Ah locus is believed to encode the Ah receptor, which mediates the induction of cytochrome P4501A1 by TCDD and appears to mediate many of the toxic effects of TCDD. TCDD produced an 80-90% decrease in the maximum binding capacity (both high and low affinity sites) of the hepatic EGF receptor in female Ah-responsive (Ahb/b) and Ah-nonresponsive (Ahd/d) C57BL/6 mice. However, the ED50 for the effects of TCDD on the binding capacity of the EGF receptor was 10-fold higher in the Ah-nonresponsive mice, compared with the Ah-responsive mice (7 versus 0.7 micrograms/kg). TCDD did not affect the hepatic content of two EGF receptor mRNA transcripts (10 and 6 kb), indicating that the effects on the EGF receptor are not pretranslational. Similarly, TCDD did not affect the hepatic content of mRNA for transforming growth factor-alpha, an alternate ligand for the EGF receptor that is synthesized in the liver. In contrast, TCDD markedly increased the hepatic content of the mRNA for cytochrome P4501A1, which is known to be regulated transcriptionally by TCDD. The ED50 for this effect was 10-fold higher in Ah-nonresponsive mice than in Ah-responsive mice (13 versus 1.3 micrograms/kg). This study indicates that the effects of TCDD on EGF receptor ligand binding are mediated by the Ah receptor. However, unlike the effect of TCDD on cytochrome P4501A1, the effects of TCDD on the EGF receptor do not involve changes in the levels of the mRNA for this protein or changes in the mRNA for transforming growth factor-alpha, an alternate ligand for the EGF receptor.
Lin
F H
FH
Laboratory of Biochemical Risk Analysis, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709.
Clark
G
G
Birnbaum
L S
LS
Lucier
G W
GW
Goldstein
J A
JA
D000818:Animals; D015152:Blotting, Northern; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004815:Epidermal Growth Factor / Q000378:metabolism; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D012333:RNA, Messenger / Q000235:genetics; D018336:Receptors, Aryl Hydrocarbon; D011955:Receptors, Drug / Q000502:physiology*; D016211:Transforming Growth Factor alpha / Q000235:genetics
D000072317:Polychlorinated Dibenzodioxins; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D011955:Receptors, Drug; D016211:Transforming Growth Factor alpha; D004815:Epidermal Growth Factor; D003577:Cytochrome P-450 Enzyme System; D066246:ErbB Receptors