Transplacental toxicity of 3-methylsulphonyl-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 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.
Jönsson
J
J
Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Swedish University of Agricultural Sciences, Uppsala.
Rodriguez-Martinez
H
H
Brandt
I
I
D000302:Adrenal Cortex / Q000187:drug effects* / Q000196:embryology / Q000648:ultrastructure; D000818:Animals; D001345:Autoradiography; D003633:Dichlorodiphenyl Dichloroethylene / Q000031:analogs & derivatives* / Q000378:metabolism / Q000633:toxicity; D004359:Drug Therapy, Combination; D005314:Embryonic and Fetal Development / Q000187:drug effects*; D004785:Environmental Pollutants / Q000633:toxicity*; D005260:Female; D008431:Maternal-Fetal Exchange / Q000187:drug effects*; D008797:Metyrapone / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000648:ultrastructure; D011247:Pregnancy
D004785:Environmental Pollutants; D003633:Dichlorodiphenyl Dichloroethylene; C055238:1-chloro-4-(2,2-dichloro-1-(4-chlorophenyl)ethenyl)-3-(methylsulfonyl)benzene; D008797:Metyrapone