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 C-14-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 I-125-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 C-14-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 (similar to 15% of the 4-OH-tCB) and traces (similar to 6%) of two other metabolites, 2-OH-3,3',4,4'-tetrachlorobipheny1 and 5-OH-3,3',4,4'-tetrachlorobiphenyl. Polyacrylamide gel electrophoresis confirmed that the C-14-radioactivity in fetal plasma was bound to TTR, and revealed that in vitro binding of I-125-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.