Hydroxylated polychlorinated biphenyls: placental transfer and effects on thyroxine in the foetal mouse.
1. At day 17 of pregnancy, 1 day after maternal intravenous administration (5-50 mumol/kg body wt) of 4-OH-3,5,3',4'-tetrachlorobiphenyl (4-OH-TCB; a CB-77 metabolite), a limited dose-dependent decrease was found both in foetal and maternal total thyroxine (T4) levels (76-81% of control at 50 mumol/kg). Similarly, a 50 mumol/kg dose of a 4-OH-3,5,2',3',4'-pentachlorobiphenyl (4-OH-PeCB1) decreased total T4 levels, whereas 4-OH-2,3,5,3',4'-pentachlorobiphenyl (4-OH-PeCB2) showed no clear effect (both 4-OH-pentaCBs are CB-105 metabolites). Earlier administration (gestation day 10 or 13) of the 4-OH-PCBs had no effect on total T4 at day 17. 2. Placental transfer of 14C-4-OH-TCB to the foetal compartment was dose-related and accumulated mainly in foetal plasma at levels 2-fold those in the maternal plasma at the dose interval 0.5-5.0 mumol/kg body wt, whereas at higher doses (20 and 50 mumol/kg body wt) the foetal and maternal plasma levels were similar. A break-point in the foetal dose/plasma concentration curve at 5.0 mumol/kg indicates saturation of a high-affinity ligand binding above this dose. 3. There was an extensive accumulation of radioactivity in the maternal liver after 14C-4-OH-TCB administration (20-30% of the administered dose). In spite of this the investigated compounds resulted in a small or no effect on EROD/MROD activity in maternal liver and these enzyme activities were not detectable in either exposed or control foetal liver.
Sinjari
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Department of Pharmaceutical Biosciences, Uppsala University, Sweden.
Darnerud
P O
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D000818:Animals; D002250:Carbon Radioisotopes; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D005333:Fetus / Q000187:drug effects* / Q000378:metabolism; D008431:Maternal-Fetal Exchange; D051379:Mice; D008810:Mice, Inbred C57BL; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D010088:Oxidoreductases / Q000378:metabolism; D011078:Polychlorinated Biphenyls / Q000493:pharmacokinetics / Q000633:toxicity*; D011247:Pregnancy; D013974:Thyroxine / Q000037:antagonists & inhibitors* / Q000097:blood; D014018:Tissue Distribution
C111118:2',3,3',4',5-pentachloro-4-hydroxybiphenyl; C111120:2,3,3',4',5-pentachloro-4-hydroxybiphenyl; C111117:3,3',4',5-tetrachloro-4-hydroxybiphenyl; D002250:Carbon Radioisotopes; D003577:Cytochrome P-450 Enzyme System; D011078:Polychlorinated Biphenyls; D010088:Oxidoreductases; C076307:methoxyresorufin-O-demethylase; D019363:Cytochrome P-450 CYP1A1; D013974:Thyroxine