Polychlorinated aromatic hydrocarbon lethality, mixed-function oxidase induction, and uroporphyrinogen decarboxylase inhibition in the chick embryo: dissociation of dose-response relationships.
Effects on survival of chick embryos and on the activity of hepatic enzymes involved in heme biosynthesis and hemoprotein function were compared as a function of dose of 3,4,3',4'-tetrachlorobiphenyl (TCB), 3,4,5,3',4',5'-hexachlorobiphenyl (HCB), 2,3,6,2',3',6'-HCB, and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) at 24 hr and at 9 days after polyhalogenated aromatic hydrocarbon (PAH) administration. 2,3,6,2',3',6'-HCB did not alter enzyme activities or survival. The other PAH increased delta-aminolevulinic acid synthetase up to 10- to 20-fold after 24 hr or 9 days of exposure. Hepatic porphyrins and uroporphyrinogen decarboxylase (Uro-D) activity were unaffected except by 3,4,3',4'-TCB which after 9 days of exposure increased porphyrins slightly (less than 2-fold) at 500 and 1000 nmol/egg and decreased Uro-D by 20% at 1000 nmol/egg. 3,4,3',4'-TCB, 3,4,5,3',4',5'-HCB, and TCDD preferentially induced cytochrome P-448-mediated mixed-function oxidases. The degree of induction was the same or greater after 9 days of exposure than after 24 hr. The three PAH increased aminopyrine demethylase and 7-ethoxycoumarin deethylase up to 2-fold and aryl hydrocarbon hydroxylase (AHH) 10- to 12-fold. 7-Ethoxyresorufin deethylase (7-ER) was increased 45-fold by 3,4,3',4'-TCB, 28-fold by 3,4,5,3',4',5'-HCB, and 55-fold by TCDD. The three PAH decreased survival after 9 days but not after 24 hr. Decreases in survival were accompanied by decreased thymus weights and increased incidences of pericardial and subcutaneous edema in surviving embryos. 3,4,3',4'-TCB caused dose-related decreases in survival at 100 to 1000 nmol/egg. 3,4,5,3',4',5'-HCB decreased survival at 500 and 1000 nmol/egg and TCDD at 6 nmol/egg. The effects on survival were greatest for 3,4,3',4',-TCB and least for TCDD, notwithstanding that all three PAH induced AHH to the same degree and that TCDD caused the greatest induction of 7-ER. The results demonstrate that the dose-response relationships for hepatic induction and lethality are dissociated and that the maximal induction levels are not correlated with the incidence of lethality. The findings indicate that the induction per se does not lead directly to toxicity and that other factors must intervene. The results further show that PAH lethality occurs independently of effects on hepatic Uro-D.
D000624:5-Aminolevulinate Synthetase / Q000096:biosynthesis; D000818:Animals; D002642:Chick Embryo; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis; D004147:Dioxins / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000187:drug effects; D006418:Heme / Q000096:biosynthesis; D007928:Lethal Dose 50; D008099:Liver / Q000187:drug effects / Q000196:embryology / Q000201:enzymology*; D006899:Mixed Function Oxygenases / Q000096:biosynthesis; D011078:Polychlorinated Biphenyls / Q000633:toxicity*; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*
D004147:Dioxins; D000072317:Polychlorinated Dibenzodioxins; D006418:Heme; D003577:Cytochrome P-450 Enzyme System; D011078:Polychlorinated Biphenyls; D006899:Mixed Function Oxygenases; D000624:5-Aminolevulinate Synthetase; C027309:3,4,5,3',4',5'-hexachlorobiphenyl; C028451:3,4,3',4'-tetrachlorobiphenyl