Morse D C, Wehler E K, van de Pas M, de Bie A T, van Bladeren P J, Brouwer A
Department of Toxicology, Agricultural University, Wageningen, The Netherlands.
Chem Biol Interact. 1995 Mar 30;95(1-2):41-56. doi: 10.1016/0009-2797(94)03347-1.
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.
研究了25微摩尔14C标记的3,3',4,4'-四氯联苯（14C-TCB）单次口服剂量在怀孕雌性Wistar大鼠及其胎儿体内的代谢和分布情况。在妊娠第13天给予TCB，并追踪其消除情况7天。对未怀孕的大鼠进行类似处理以作比较。怀孕大鼠粪便中14C-TCB衍生放射性的消除量显著低于未怀孕大鼠。在成年肝脏、血浆、胎盘组织、整个胎儿和胎儿血浆中发现的主要代谢物是3,3',4',5-四氯-4-联苯醇（4-OH-TCB）。在成年动物给药后的7天内，14C-TCB衍生放射性的组织水平（肝脏、腹部脂肪、皮肤、骨骼肌、肾脏和血浆）下降了65%-85%。然而，在同一时期内，14C-TCB衍生放射性在胎儿体内积累了100多倍，气相色谱/质谱分析表明，胎儿体内放射性的积累主要是由于4-OH-TCB，而非母体化合物。在妊娠第20天，胎儿血浆中4-OH-TCB的浓度比母体血浆高14倍。在未怀孕动物给药后长达7天以及怀孕大鼠给药后长达4天，用14C-TCB处理显著降低血浆甲状腺素水平至少28%（怀孕大鼠降低31%）。给药后7天，经TCB处理的怀孕大鼠血浆甲状腺素水平已恢复到对照水平。然而，在给予TCB 7天后，来自经14C-TCB处理的母鼠的胎儿血浆甲状腺素水平显著降低了35%。在给药后第4天和第7天，与对照组相比，经TCB处理的母鼠肝脏微粒体乙氧基异吩恶唑酮-O-脱乙基酶（EROD）活性显著诱导，而在妊娠第20天，对照或经TCB处理的胎鼠肝脏微粒体中未检测到EROD活性。这些数据表明，多氯联苯的羟基化代谢物可能在这些化合物的发育毒性中起作用。
