Jönsson J, Rodriguez-Martinez H, Brandt I
Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Swedish University of Agricultural Sciences, Uppsala.
Reprod Toxicol. 1995 May-Jun;9(3):257-64. doi: 10.1016/0890-6238(95)00013-z.
The transplacental transfer, irreversible binding, and ultrastructural lesions in the fetal adrenal cortex were studied following single injections of the persistent DDT-metabolite 3-methylsulphonyl-DDE (MeSO2-DDE) in pregnant C57B1 mice. Tape-section autoradiograms of fetuses on gestation days 12 to 17 revealed a high and tissue-specific accumulation of MeSO2-DDE-14C-derived radioactivity in the fetal adrenal gland. On gestation day 12 the adrenal radioactivity could be extracted with organic solvents, whereas on days 13 to 17 the radioactivity in the adrenal was irreversibly bound and could not be extracted from the tissue. As determined by computer-assisted image analysis of autoradiograms, the uptake of radioactivity in the fetal adrenals increased continuously with gestational age. Electron microscopy revealed mitochondrial degeneration and vacuolation in fetal adrenal cortex cells following injection of MeSO2-DDE (25 mg/kg b.w.) to the pregnant dam. The lesions were clearly visible on days 14 to 15 but most pronounced on days 16 to 17. Administration of the cytochrome P450(11 beta) inhibitor metyrapone to pregnant dams (gestation day 17) reduced the mitochondrial toxicity induced by MeSO2-DDE in the fetal adrenal cortex. In conclusion, the adrenocorticolytic DDT metabolite MeSO2-DDE is transformed to a reactive, cytotoxic metabolite in the fetal adrenal cortex from its earliest stage of development. Hence, the activating cytochrome P450 form, previously proposed to be P450(11 beta), seems to be expressed during gestation days 12 to 13 in the adrenal cortex in the mouse fetus.
在怀孕的C57B1小鼠单次注射持久性滴滴涕代谢物3-甲基磺酰基-DDE（MeSO2-DDE）后，研究了其经胎盘转移、不可逆结合以及对胎儿肾上腺皮质的超微结构损伤。对妊娠第12至17天胎儿的胶带切片放射自显影片显示，胎儿肾上腺中MeSO2-DDE-14C衍生的放射性有高度且组织特异性的积累。在妊娠第12天，肾上腺放射性可用有机溶剂提取，而在第13至17天，肾上腺中的放射性是不可逆结合的，无法从组织中提取。通过对放射自显影片的计算机辅助图像分析确定，胎儿肾上腺中放射性的摄取随胎龄持续增加。电子显微镜显示，给怀孕母鼠注射MeSO2-DDE（25毫克/千克体重）后，胎儿肾上腺皮质细胞出现线粒体变性和空泡化。这些损伤在第14至15天清晰可见，但在第16至17天最为明显。给怀孕母鼠（妊娠第17天）施用细胞色素P450(11β)抑制剂美替拉酮可降低MeSO2-DDE对胎儿肾上腺皮质诱导的线粒体毒性。总之，肾上腺皮质溶解型滴滴涕代谢物MeSO2-DDE在胎儿肾上腺皮质发育的最早阶段就转化为一种具有反应性的细胞毒性代谢物。因此，先前提出的激活细胞色素P450形式似乎是P450(11β)，在小鼠胎儿肾上腺皮质妊娠第12至13天期间表达。
