Decreased ligand binding to the hepatic glucocorticoid and epidermal growth factor receptors after 2,3,4,7,8-pentachlorodibenzofuran and 1,2,3,4,7,8-hexachlorodibenzofuran treatment of pregnant mice.
2,3,4,7,8-Pentachlorodibenzofuran (PeCDF) and 1,2,3,4,7,8-hexachlorodibenzofuran (HCDF) are environmental contaminants which mimic many of the toxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Like TCDD, these polychlorinated dibenzofurans (PCDFs) induce hepatic benzo[a]pyrene hydroxylase activity (BPH) and possess high affinity for the Ah receptor. Another similarity of these PCDFs to TCDD is their ability to induce teratogenic effects such as cleft palate and hydronephrosis in mice. Recent studies have shown that TCDD modifies the equilibrium binding kinetics of the rat liver cytosolic glucocorticoid receptor (GRc) and the hepatic plasma membrane epidermal growth factor (EGF) receptor. To gain a better understanding of the action of halogenated hydrocarbons on these cytosolic and membrane-bound receptor systems during pregnancy, we investigated the biochemical effects of PeCDF and HCDF on the binding kinetics of maternal mouse liver GRc and EGF receptors and the induction of BPH activities. Pregnant C57BL/6N mice were treated once daily on gestation Days 10 through 13 with PeCDF (0-30 micrograms/kg) or HCDF (0-300 micrograms/kg). Hepatic [3H]dexamethasone and [125I]EGF equilibrium binding studies indicated that all doses of PeCDF tested (10, 20, and 30 micrograms/kg) significantly reduced the GRc and EGF receptor maximum binding capacities but did not affect the binding affinities of these receptors when compared to corn oil-treated control pregnant mice. Similar effects were observed for doses of HCDF greater than or equal to 100 micrograms/kg. These data suggest that the dibenzofuran-mediated decreases in GRc and EGF receptor binding capacities are similar to those caused by TCDD. Although the mechanism of action is not yet clear, our results indicate that halogenated aromatic compounds in addition to TCDD have profound effects on both steroid and growth factor receptor systems.
Ryan
R P
RP
Laboratory of Biochemical Risk Analysis, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709.
Sunahara
G I
GI
Lucier
G W
GW
Birnbaum
L S
LS
Nelson
K G
KG
D000818:Animals; D001572:Benzofurans / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D066246:ErbB Receptors / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D008099:Liver / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity; D011247:Pregnancy; D011965:Receptors, Glucocorticoid / Q000187:drug effects* / Q000378:metabolism
D001572:Benzofurans; D000072317:Polychlorinated Dibenzodioxins; D011965:Receptors, Glucocorticoid; C051412:1,2,3,4,7,8-hexachlorodibenzofuran; D066246:ErbB Receptors; C038890:2,3,4,7,8-pentachlorodibenzofuran