Binding of a 3,3', 4,4'-tetrachlorobiphenyl (CB-77) metabolite to fetal transthyretin and effects on fetal thyroid hormone levels in mice.
The present study was conducted in order to study the effect of the PCB congener 3,3', 4,4'-tetrachlorobiphenyl (CB-77) on fetal thyroxin homeostasis in the mouse, and to examine a possible underlying mechanism behind the effect. C57BL mice were treated with 14C-labelled or unlabelled CB-77 (1 or 10 mg/kg body wt.) on day 13 of gestation, and control animals were treated with corn oil. The experiment was terminated at 4 days after exposure. Maternal and fetal plasma and livers, and whole fetuses for homogenate preparation, were collected and analysed for total radioactivity, in vitro binding of 125I-thyroxin to plasma transthyretin (TTR; a thyroxin-transporting protein), and free and total thyroxin (FT4, TT4) levels. Maternal plasma, fetal plasma and homogenates were also analyzed for presence of CB-77 and metabolites. Results showed a dose-dependent uptake of radioactivity in plasma and liver, fetal plasma 14C-levels being about five-times higher in 10 mg/kg dosed animals as after 1 mg/kg. Fetal; plasma levels of total radioactivity were four- to nine-times above maternal levels and corresponded to only one compound, the metabolite 4-OH-3,3', 4',5-tetrachlorobiphenyl (4-OH-tCB). 4-OH-tCB was the major metabolite also in whole fetuses, with only small amounts of the parent compound (approximately 15% of the 4-OH-tCB) and traces (approximately 6%) of two other metabolites, 2-OH-3,3, 4,4'-tetrachlorobiphenyl and 5-OH-3,3', 4,4'-tetrachlorobiphenyl. Polyacrylamide gel electrophoresis confirmed that the 14C-radioactivity in fetal plasma was bound to TTR, and revealed that in vitro binding of 125I-T4 to fetal TTR was reduced to 50% of control values in treated animals (10 mg/kg body wt.). Fetal plasma FT4 and TT4 levels were significantly decreased (64 and 55% of control fetuses) after 10 mg/kg treatment. In conclusion, exposure of pregnant mice to CB-77 results in the accumulation of the metabolite 4-OH-tCB in fetal mouse plasma. The metabolite binds to TTR and is accompanied by a significant decrease in fetal plasma T4 levels. A causative correlation between TTR binding and effects on T4 levels is suggested.
Darnerud
P O
PO
Toxicology Division, National Food Administration, Uppsala, Sweden.
Morse
D
D
Klasson-Wehler
E
E
Brouwer
A
A
D000818:Animals; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D005312:Fetal Blood / Q000378:metabolism; D005333:Fetus / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D011078:Polychlorinated Biphenyls / Q000097:blood / Q000378:metabolism* / Q000633:toxicity*; D011228:Prealbumin / Q000378:metabolism*; D011247:Pregnancy; D013974:Thyroxine / Q000097:blood / Q000378:metabolism*; D014018:Tissue Distribution
D011228:Prealbumin; D011078:Polychlorinated Biphenyls; D013974:Thyroxine; C028451:3,4,3',4'-tetrachlorobiphenyl