Teratogenicity of nitrofen (2,4-dichloro-4'-nitrodiphenyl ether) and its effects on thyroid function in the rat.
Nitrofen is a herbicide with potent teratogenic activity in rodent species. Previous studies have indicated that this agent has a stereochemical structure similar to thyroid hormone, and that exposure of adult mice results in depression of thryoxine (T4) levels. The present study was undertaken to determine if teratogenic exposure to nitrofen alters pituitary-thyroid function in nonpregnant, pregnant, and fetal rats, and if these potential alterations could be related to induction of birth defects. In adult thyroparathyroidectomized (TPTX) female rats, nitrofen exposure for 2 weeks resulted in a significant suppression of thyrotropin-stimulating hormone (TSH) levels. When a single dose of nitrofen was administered to euthyroid female rats, a trend toward reduction (p = 0.058) in the release of TSH after a thyrotropin-releasing hormone (TRH) challenge was observed 4 and 5 hr after exposure. Pregnant euthryoid rats given a single dose of nitrofen on Day 11 of gestation had significantly depressed TSH and T4 levels, and fetal T4 levels were markedly depressed at term. Administration of T4 on Day 2 through 22 of pregnancy plus nitrofen on Day 9 through 11 to TPTX dams resulted in a 70% reduction in the frequency of malformed fetuses, especially in regard to the frequency of heart anomalies, compared to nitrofen exposure alone. Competitive displacement studies in radioimmunoassays for T4 and T3 indicated that a nitrofen metabolite (4-hydroxy-2,5-dichloro-4'-aminodiphenyl ether) competed with [125I]T3 for antibody binding, while the parent compound and six isolated metabolites failed to compete with [125I]T4 for antibody binding. These results have been interpreted to indicate that nitrofen teratogenicity is mediated at least in part by alterations in maternal and/or fetal thyroid hormone status, and may be due to a premature and pharmacologic exposure to the embryo to a nitrofen-derived, T3-active metabolite.
D000818:Animals; D001667:Binding, Competitive; D004305:Dose-Response Relationship, Drug; D005260:Female; D008431:Maternal-Fetal Exchange; D010280:Parathyroid Glands / Q000502:physiology; D010647:Phenyl Ethers / Q000633:toxicity*; D011247:Pregnancy; D011485:Protein Binding; D051381:Rats; D013723:Teratogens; D013960:Thyroid Function Tests; D013961:Thyroid Gland / Q000187:drug effects*; D013963:Thyroid Hormones / Q000378:metabolism / Q000502:physiology; D013965:Thyroidectomy
D010647:Phenyl Ethers; D013723:Teratogens; D013963:Thyroid Hormones; C007350:nitrofen