Metabolism and biochemical effects of 3,3',4,4'-tetrachlorobiphenyl in pregnant and fetal rats.
The metabolism and distribution of a single oral dose of 25 mumol 14C-labelled 3,3',4,4'-tetrachlorobiphenyl (14C-TCB) were investigated in pregnant female Wistar rats and their fetuses. TCB was administered on day 13 of gestation and the elimination was followed for 7 days. Non-pregnant rats were treated similarly for comparison. Fecal elimination of 14C-TCB derived radioactivity was significantly lower in pregnant rats than in non-pregnant rats. The major metabolite found in adult liver and plasma, placental tissue, whole fetuses and fetal plasma was 3,3',4',5-tetrachloro-4-biphenylol (4-OH-TCB). Tissue levels (liver, abdominal fat, skin, skeletal muscle, kidney and plasma) of 14C-TCB-derived radioactivity declined by 65-85% over a 7-day period following administration in the adult animals. However, 14C-TCB-derived radioactivity accumulated more than 100-fold in the fetuses over the same time period, and GC/MS analysis revealed that the fetal accumulation in radioactivity was due primarily to 4-OH-TCB, and not the parent compound. On day 20 of gestation, concentrations of 4-OH-TCB were 14 times greater in fetal plasma than maternal plasma. Treatment with 14C-TCB significantly reduced plasma thyroxine levels by at least 28% up to 7 days after administration in non-pregnant animals and up to 4 days after administration in pregnant rats (31% decrease). By 7 days after administration plasma thyroxine levels had returned to control levels in the TCB-treated pregnant rats. However, fetal plasma thyroxine levels were significantly decreased by 35% in fetuses from 14C-TCB-treated dams 7 days after TCB administration. Hepatic microsomal ethoxyresorufin-O-deethylase (EROD) activity was significantly induced in TCB-treated dams relative to controls at 4 and 7 days after administration, while no EROD activity was detected in hepatic microsomes from control or TCB treated fetal rats at day 20 of gestation. These data suggest that hydroxylated metabolites of polychlorinated biphenyls may play a role in the development toxicity of these compounds.
Morse
D C
DC
Department of Toxicology, Agricultural University, Wageningen, The Netherlands.
Wehler
E K
EK
van de Pas
M
M
de Bie
A T
AT
van Bladeren
P J
PJ
Brouwer
A
A
D000818:Animals; D002250:Carbon Radioisotopes; D019363:Cytochrome P-450 CYP1A1; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects / Q000378:metabolism; D005243:Feces / Q000737:chemistry; D005260:Female; D005333:Fetus / Q000187:drug effects* / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000196:embryology / Q000378:metabolism; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D010088:Oxidoreductases / Q000187:drug effects / Q000378:metabolism; D011078:Polychlorinated Biphenyls / Q000097:blood / Q000378:metabolism* / Q000494:pharmacology*; D011247:Pregnancy; D011270:Pregnancy, Animal / Q000097:blood / Q000187:drug effects* / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D013963:Thyroid Hormones / Q000097:blood; D014018:Tissue Distribution
D002250:Carbon Radioisotopes; D013963:Thyroid Hormones; D003577:Cytochrome P-450 Enzyme System; D011078:Polychlorinated Biphenyls; D010088:Oxidoreductases; D019363:Cytochrome P-450 CYP1A1; C028451:3,4,3',4'-tetrachlorobiphenyl