Dose-response relationships in mice following subchronic exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin: CYP1A1, CYP1A2, estrogen receptor, and protein tyrosine phosphorylation.
The dose-response relationships for different endpoints in different tissues were compared in response to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) treatment. TCDD was administered 5 days a week for 13 weeks at doses ranging from 1.5 to 150 ng/kg/day to female B6C3F1 mice. Ethoxyresorufin-O-deethylase (EROD) activity, a marker for CYP1A1, was increased in liver, lung, and skin at doses as low as 1.5 ng/kg/day. EROD activity did not attain maximal induction. Liver acetanilide-4-hydroxylase activity, a marker for CYP1A2, was significantly induced at 1.5 ng/kg/day and reached maximal induction at 45 ng/kg/day. TCDD treatment significantly increased the amount of phosphorylated forms of three phosphotyrosyl proteins (pp32, pp34, and pp38) in liver S-20 fractions. Changes in these phosphotyrosyl proteins occurred at 1.5 ng/kg/day and reached maximal induction at 4.5 ng/kg/day. No changes in phosphotyrosyl proteins were observed in skin. Hepatic and uterine estrogen receptor levels were not altered at any of the doses tested. These data indicate that induction of CYP1A1, CYP1A2, and the increases in phosphorylated forms of pp32, pp34, and pp38 are sensitive indicators of TCDD exposure. The dose-response curves for increases in CYP1A1, CYP1A2, and phosphorylated pp32, pp34, and pp38 in liver were different from each other. TCDD produces multiple effects with multiple dose-response curves suggesting that there are events in addition to receptor binding that are endpoint specific, leading to different dose-response relationships.
DeVito
M J
MJ
Center for Environmental Medicine and Lung Biology, University of North Carolina, Chapel Hill 27599.
Ma
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Babish
J G
JG
Menache
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Birnbaum
L S
LS
D000818:Animals; D019363:Cytochrome P-450 CYP1A1; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology; D010088:Oxidoreductases / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D000072317:Polychlorinated Dibenzodioxins / Q000008:administration & dosage / Q000633:toxicity*; D011960:Receptors, Estrogen / Q000187:drug effects* / Q000378:metabolism; D012867:Skin / Q000187:drug effects / Q000378:metabolism; D013347:Subcellular Fractions; D014443:Tyrosine / Q000187:drug effects* / Q000378:metabolism; D014599:Uterus / Q000187:drug effects / Q000378:metabolism
D000072317:Polychlorinated Dibenzodioxins; D011960:Receptors, Estrogen; D014443:Tyrosine; D003577:Cytochrome P-450 Enzyme System; D010088:Oxidoreductases; D019363:Cytochrome P-450 CYP1A1