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 PC B congener 3,3',4,4'-tetrachlorobiphenyl (CB-77) on fetal thyroxin hom eostasis in the mouse, and to examine a possible underlying mechanism behind the effect. C57BL mice were treated with C-14-labelled or unlab elled CB-77 (1 or 10 mg/kg body wt.) on day 13 of gestation, and contr ol animals were treated with corn oil. The experiment was terminated a t 4 days after exposure. Maternal and fetal plasma and livers, and who le fetuses for homogenate preparation, were collected and analysed for total radioactivity, in vitro binding of I-125-thyroxin to plasma tra nsthyretin (TTR; a thyroxin-transporting protein), and free and total thyroxin (FT4, TT4) levels. Maternal plasma, fetal plasma and homogena tes were also analyzed for presence of CB-77 and metabolites. Results showed a dose-dependent uptake of radioactivity in plasma and liver, f etal plasma C-14-levels being about five-times higher in 10 mg/kg dose d animals as after 1 mg/kg. Fetal plasma levels of total radioactivity were four- to nine-times above maternal levels and corresponded to on ly 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. Polyac rylamide 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 sign ificantly decreased (64 and 55% of control fetuses) after 10 mg/kg tre atment. In conclusion, exposure of pregnant mice to CB-77 results in t he accumulation of the metabolite 4-OH-tCB in fetal mouse plasma. The metabolite binds to TTR and is accompanied by a significant decrease i n fetal plasma T4 levels. A causative correlation between TTR binding and effects on T4 levels is suggested.