K.M. Fase

Relative potencies of polychlorinated dibenzo-p-dioxins (PCDDS), dibenzofurans (PCDFS) and biphenyls (PCBS), for cytochrome P450 1A induction in the mirror carp (Cyprinus carpio)

Abstract Carp received a single i.p. dose of 2,3,7,8-TCDD, 2,3,7,8-TCDF, 1,2,3,7,8-PnCDD, 2,3,4,7,8-PnCDF, 1,2,3,6,7,8,-HxCDD, OCDF, OCDD, 2,3′,4,4′,5-PCB (PCB 118), 3,3′,4,4′,5-PCB (PCB126) or 2,2′,4,4′,5,5′-PCB (PCB 153). Four doses per congener were used increasing by a factor five. Fish were sacrificed after 2 weeks and hepatic cytochrome P450 1A protein content (P450 1A), 7-ethoxyresorufin-O-deethylation (EROD) activity and hepatic concentrations of the inducing compounds were determined. The aim of this study was to determine the relative, P450 1A-inducing potencies (RP) of several PCDDs, PCDFs and PCBs, relative to 2,3,7,8-TCDD. RPs were calculated based on ED50s derived from the administered doses or hepatic concentrations for induction of EROD or P450 1A protein levels. The RPs (molar ED50 TCDD/molar ED50 congener), based on EROD induction and internal concentration, for 2,3,7,8-TCDF, 1,2,3,7,8-PnCDD, 2,3,4,7,8-PnCDF and 1,2,3,6,7,8-HxCDD were 0.03, 0.68, 0.36 and 0.59, respectively. The RPs of PCB 118 and PCB 126 were estimated to be 0.0004 and > 0.005, respectively. No RP could be calculated for OCDD and PCB 153, due to the absence of P450 1A induction by these congeners. PnCDD appeared to be the most potent inducer of hepatic P450 1A. A statistically significant EROD induction was already effected by a concentration of 63.75 pg PnCDD/g liver, which was in the present study the lowest effective concentration of all congeners.

Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin or 2,2′,4,4′,5,5′-hexachloro-biphenyl on vitamin K-dependent blood coagulation in male and female WAG/rij-rats

Abstract Newborns are susceptible to hemorrhages (hemorrhagic disease of the newborn or HDN) due to vitamin K deficiency. Induction of cytochrome P450 in the fetal liver by maternal anticonvulsant therapy such as phenobarbital or phenytoin is considered to be a major cause. An observed increase in late hemorrhagic disease (LHD) in breast fed neonates gave rise to the hypothesis that PCBs and dioxins, P450-inducing contaminants present in human milk, might effect vitamin K-dependent blood coagulation. This hypothesis was studied in rats. Administration of a single oral dose of 0.003, 0.03, 0.3, 3 or 30 nmol 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) per kg bodyweight or 0.75, 4, 20, 100 or 500 μmol 2,2′,4,4′,5,5′-hexachlorobiphenyl/kg bw (HxCB) t0 female and male rats resulted in dose-related reductions of the vitamin K-dependent coagulation factor VII. The highest factor VII reduction in female rats was 44%, observed after TCDD exposure. The Lowest Observed Adverse Effect Level (LOAEL) of TCDD on female factor VII levels was 0.3 nmol/kg bw (96 ng/kg). There was a significant inverse correlation between Factor VII levels and induction of hepatic ethoxyresorufin O-deethylating (EROD) activity, reflecting CYP1A1, and total P450 content. HxCB had no effect on female coagulation factors. In contrast, in male rats only exposure to HxCB, which induces mainly CYP2B1 and 2B2, decreased both coagulation factors dramatically up to 88%. The LOAEL of HxCB on factor VII in male rats was 100 μmol/kg bw (36 mg/kg). In general, effects on coagulation factors in male rats exceeded those in females. In addition, sex-dependent differences of TCDD and HxCB were observed on the hepatic vitamin K cycle enzyme activities in female and male rats. Vitamin K-dependent (γ-glutamyl carboxylase activity was mainly induced in female rats; 2.3-fold in the highest dose group of TCDD. In male rats only vitamin K 2,3-epoxide reductase (KO-reductase) activity was induced 1.7-fold by the highest dose of HxCB. KO-reductase activity in female rats was also increased by TCDD, however, less pronounced than the carboxylase activity. Concluding, the hepatic vitamin K cycle still functions and is not blocked by TCDD or HxCB, thus explaining the observed reduction in factor VII. Finally, the possible role of P450 in vitamin K deficiency is discussed. Based on these results it is suggested to investigate the possible role of PCBs and dioxin-like compounds in LHD in more detail.

Synergistic Effect of 2,2 prime ,4,4 prime ,5,5 prime -Hexachlorobiphenyl and 2,3,7,8-Tetrachlorodibenzo-p-Dioxin on Hepatic Porphyrin Levels in the Rat

Deadline: September 1, 1996 For information please contact: Professor Joan Cranmer, Conference Chair Department of Pediatrics-ACH University of Arkansas for Medical Sciences 4301 W. Markham Street, Slot 512 Little Rock, Arkansas 7205-7 1 99 (501) 320-2986 FAX (501) 320-4978 Environmental Health Perspectives * Volume 104, Number 5, May 1996 557 This content downloaded from 195.34.79.176 on Sat, 21 Jun 2014 11:49:57 AM All use subject to JSTOR Terms and Conditions