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 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 micromol 2,2',4,4',5,5'-hexachlorobiphenyl/kg bw (HxCB) to 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 micromol/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 (gamma-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.
Bouwman
C A
CA
Research Institute of Toxicology, University of Utrecht, The Netherlands. ca.bouwman@gr.nl
Van Dam
E
E
Fase
K M
KM
Koppe
J G
JG
Seinen
W
W
Thijssen
H H
HH
Vermeer
C
C
Van den Berg
M
M
D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects*; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D019362:Cytochrome P-450 CYP2B1 / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005167:Factor VII / Q000378:metabolism; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D006128:Growth / Q000187:drug effects; D006490:Hemostatics / Q000097:blood / Q000494:pharmacology*; D007770:L-Lactate Dehydrogenase / Q000097:blood; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D011078:Polychlorinated Biphenyls / Q000494:pharmacology*; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D012727:Sex Characteristics; D014812:Vitamin K / Q000097:blood / Q000494:pharmacology*
D006490:Hemostatics; D000072317:Polychlorinated Dibenzodioxins; D014812:Vitamin K; D005167:Factor VII; D003577:Cytochrome P-450 Enzyme System; D011078:Polychlorinated Biphenyls; D007770:L-Lactate Dehydrogenase; D019363:Cytochrome P-450 CYP1A1; D019362:Cytochrome P-450 CYP2B1; D016660:NAD(P)H Dehydrogenase (Quinone); C014024:2,4,5,2',4',5'-hexachlorobiphenyl