Alterations in rat brain thyroid hormone status following pre- and postnatal exposure to polychlorinated biphenyls (Aroclor 1254).
The effect of daily oral maternal exposure to 0, 5, or 25 mg/kg body wt of a polychlorinated biphenyl (PCB) mixture (Aroclor 1254) on Days 10 to 16 of gestation on plasma and brain thyroid hormone concentrations and peripheral thyroid hormone concentrations and peripheral thyroid hormone metabolism were examined in fetal and weanling rats. Plasma thyroid hormone levels and hepatic microsomal thyroid hormone glucuronidation were also examined in pregnant rats and the adult offspring. Plasma and brain levels of PCBs and hydroxylated PCB metabolites were analyzed in fetal, weanling, and adult offspring. Maternal exposure to Aroclor 1254 significantly decreased fetal (Gestation Day 20) and neonatal (Postnatal Day 4) plasma total thyroxine (T4) and free T4 levels in a dose-dependent manner. Effects of maternal Aroclor 1254 exposure on plasma total and free T4 concentrations were less pronounced in offspring at 21 days of age and absent 90 days after birth. Plasma concentrations of thyroid-stimulating hormone were unaltered in fetuses, neonates, weanling rats, and adult offspring following maternal treatment with Aroclor 1254. the concentration of T4 was severely depressed in the forebrain and cerebellum of fetal rats on Day 20 of gestation following maternal Aroclor 1254 exposure. Brain triiodothyronine (T3) concentrations in the Aroclor-exposed fetuses were significantly decreased relative to control values only in the low-dose group. On Day 21 postpartum T4 concentrations were significantly decreased in the forebrains of female weanling rats from the 25 mg Aroclor 1254/kg dose group, and no reductions were observed in forebrain T3 concentrations in male or female neonates. The deiodination of T4 to T3 was significantly increased in fetal forebrain homogenates by both PCB treatments. In female weanling brain homogenates the deiodination of T4 to T3 was significantly decreased in the low-dose group and unaltered in the high-dose group. No alterations in brain thyroid hormone metabolism were observed in forebrain homogenates from adult offspring exposed pre- and postnatally to Aroclor 1254. Hepatic microsomal T4 glucuronidation was significantly decreased in fetal microsomes following perinatal PCB exposure and significantly increased in weanling hepatic microsomes in a dose-dependent manner. An accumulation of mainly one PCB metabolite, 2,3,3',4',5-pentachloro-4-biphenylol was observed in fetal plasma and forebrain on Gestation Day 20 and in neonatal and weanling rat plasma on Postnatal Days 4, 21, and 90. The plasma level of 2,3,3',4',5-pentachloro-4-biphenylol was higher than that of the persistent PCB congener 2,2',4,4',5,5'-hexachlorobiphenyl in the control and PCB-exposed offspring up to Postnatal Day 21, and even after 90 days, the 2,3,3',4',5-pentachloro-4-biphenylol was present in amounts approximately equal to those of CB 153. Although PCB levels were relatively high in the weanling rat forebrain, no hydroxylated PCB metabolites were detected. On Day 90 postpartum, plasma levels of PCBs and 2,3,3',4',5-pentachloro-4-biphenylol were still elevated in the offspring of PCB-treated dams relative to controls. These results suggest that the accumulation of hydroxylated PCB metabolites in fetal plasma can reduce fetal plasma T4 levels and accordingly fetal brain T4 levels. However, in late gestational fetuses, the induction of brain type II thyroxine 5'-deiodinase activity compensates for decreases in brain T4 levels, so that brain T3 levels are maintained.
Morse
D C
DC
Department of Toxicology, Agricultural University, Wageningen, The Netherlands.
Wehler
E K
EK
Wesseling
W
W
Koeman
J H
JH
Brouwer
A
A
D000818:Animals; D000831:Animals, Newborn; D013956:Antithyroid Agents / Q000633:toxicity*; D001140:Aroclors / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D001921:Brain / Q000187:drug effects* / Q000196:embryology / Q000378:metabolism; D020111:Chlorodiphenyl (54% Chlorine); D005260:Female; D005333:Fetus / Q000378:metabolism; D005965:Glucuronates / Q000378:metabolism; D007453:Iodide Peroxidase / Q000378:metabolism; D008297:Male; D018811:Maternal Exposure; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D011078:Polychlorinated Biphenyls / Q000097:blood / Q000378:metabolism; D011247:Pregnancy; D051381:Rats; D017208:Rats, Wistar; D013972:Thyrotropin / Q000097:blood; D013974:Thyroxine / Q000097:blood / Q000378:metabolism*; D014284:Triiodothyronine / Q000097:blood / Q000378:metabolism*
D013956:Antithyroid Agents; D001140:Aroclors; D005965:Glucuronates; D014284:Triiodothyronine; D020111:Chlorodiphenyl (54% Chlorine); D013972:Thyrotropin; D011078:Polychlorinated Biphenyls; D007453:Iodide Peroxidase; D013974:Thyroxine