TRANSPLACENTAL TOXICITY OF 3-METHYLSULFONYL-DDE IN THE DEVELOPING ADRENAL-CORTEX IN MICE

The transplacental transfer, irreversible binding, and ultrastructural lesions in the fetal adrenal cortex were studied following single inj ections of the persistent DDT-metabolite 3-methylsulphonyl-DDE (MeSO(2 )-DDE) in pregnant C57B1 mice, Tape-section autoradiograms of fetuses on gestation days 12 to 17 revealed a high and tissue-specific accumul ation of MeSO(2)-DDE-C-14-derived radioactivity in the fetal adrenal g land. 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 autoradi ograms, the uptake of radioactivity in the fetal adrenals increased co ntinuously with gestational age. Electron microscopy revealed mitochon drial degeneration and vacuolation in fetal adrenal cortex cells follo wing injection of MeSO(2)-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) inhibito r metyrapone to pregnant dams (gestation day 17) reduced the mitochond rial toxicity induced by MeSO(2)-DDE in the fetal adrenal cortex. In c onclusion, the adrenocorticolytic DDT metabolite MeSO;?-DDE is transfo rmed to a reactive, cytotoxic metabolite in the fetal adrenal cortex f rom its earliest stage of development. Hence, the activating cytochrom e P450 form, previously proposed to be P450(11 beta), seems to be expr essed during gestation days 12 to 13 in the adrenal cortex in the mous e fetus.