Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin or 2,2 ',4,4 ',5,5 '-hexachlorobiphenyl on vitamin K-dependent blood coagulation in male and female WAG/RIJ-rats

Newborns are susceptible to hemorrhages (hemorrhagic disease of the newborn or HDN) due to vitamin K deficiency. Induction of cytochrome P450 in the f etal liver by maternal anticonvulsant therapy such as phenobarbital or phen ytoin is considered to be a major cause. An observed increase in late hemor rhagic disease (LHD) in breast fed neonates gave rise to the hypothesis tha t 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, 10 0 or 500 mu mol 2,2',4,4',5,5'-hexachlorobiphenyl/kg bw (HxCB) to female an d 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 Leve l (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, refle cting CYP1A1, and total P450 content. HxCB had no effect on female coagulat ion 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 mu mol/kg bw (36 mg/kg ). In general, effects on coagulation factors in male rats exceeded those i n females. In addition, sex-dependent differences of TCDD and HxCB were observed on th e hepatic vitamin K cycle enzyme activities in female and male rats. Vitami n K-dependent (gamma-glutamyl carboxylase activity was mainly induced in fe male rats; 2.3-fold in the highest dose group of TCDD. In male rats only vi tamin 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 b y TCDD or HxCB, thus explaining the observed reduction in factor VII. Final ly, 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. (C) 1998 Elsevier Sci ence Ltd. All rights reserved.