benzofurans and Fetal-Death

Inhibitors of the arachidonic acid cascade were given to pregnant rats during the critical period for morphogenesis of the external genitalia. Groups treated subcutaneously (s.c.) with 0.1 or 0.25 mg/kg/day of triamcinolone acetonide (TA) on gestational days (GD) 14-19 had male fetuses on GD 20 with moderate decreases in absolute anogenital distance (AGD), but gross and histological examinations revealed no alterations to the genital tubercle (i.e., no hypospadias). The s.c. coadministration of arachidonic acid at 100 mg/kg/day had minimal to no effect on AGD in the TA-exposed groups. No effect on AGD was observed in male fetuses from groups administered aspirin orally at 150 mg/kg/day, and only a 6% decrease was observed in the 300-mg/kg/day group. Neither TA nor aspirin adversely affected AGD of female fetuses. In another study, TA was administered on GD 11-19 at dose levels of 0.05 and 0.1 mg/kg/day, and dams were allowed to deliver. High-dose male offspring examined on postcoitum day (PCD) 23, had moderate decreases in AGD. In both studies with TA, there were also significant decreases in offspring weights. The contribution of the decreased weight to the decrease in absolute AGD was examined by a variety of methods (ratio of AGD to cube root of weight or biparietal distance, comparison to weight-matched controls, and covariance analysis). We conclude that TA caused a specific decrease in AGD on GD 20 that was largely reversed by PCD 23. When examined as adults (8 weeks old), the external genitalia of TA-exposed offspring were normal. Thus, the TA-induced decreases in AGD on GD 20 did not predict irreversible malformation. TA also caused other effects, which included a somewhat flattened genital tubercle and apparently thinned and glossy skin between the tubercle and the anus in both sexes on GD 20 and PCD 23, but not as adults. In addition, there were high pup mortality and high incidences of micrognathia and omphalocele (in the 0.25-mg/kg/day group only). Aspirin at 75 or 150 mg/kg/day and a specific lipoxygenase inhibitor (L-656,224) at 1,000 or 2,000 mg/kg/day were also administered from GD 14 to 19, and no offspring effects were observed. Thus, of the three agents that potentially inhibit the arachidonic acid cascade, only triamcinolone produced moderate effects on rat external genitalia that were largely reversible.(ABSTRACT TRUNCATED AT 400 WORDS)

Topics: Abnormalities, Drug-Induced; Animals; Arachidonic Acid; Aspirin; Benzofurans; Female; Fetal Death; Genitalia, Male; Gestational Age; Hypospadias; Male; Pregnancy; Rats; Rats, Inbred Strains; Triamcinolone; Weaning

Polychlorinated dibenzofurans (PCDFs) are highly toxic environmental contaminants which have been involved in several incidents of human poisoning. Two congeners, 2,3,4,7,8-pentachlorodibenzofuran (4-PeCDF) and 1,2,3,4,7,8-hexachlorodibenzofuran (HCDF), have been shown to persist in the tissues of victims of accidental ingestion from Japan and Taiwan. The teratogenicity of these compounds, both alone and in combination, was assessed in C57BL/6N mice. Pregnant mice were treated with 10 ml/kg corn oil containing no PCDFs, 4-PeCDF (0-30 micrograms/kg), HCDF (0-300 micrograms/kg), or a combination of the two on gestation Days 10-13, followed by necropsy on gestation Day 18. Maternal and fetal toxicity were assessed and selected soft tissues were examined for abnormalities. Both chemicals caused hydronephrosis and cleft palate in the absence of any overt toxicity. Hydronephrosis occurred at doses approximately fivefold lower than those causing cleft palate. The combination of 4-PeCDF and HCDF was additive for terata based on responses predicted by probit analysis. In addition, the combination of 2,3,4,5,3',4'-hexachlorobiphenyl (0-60 mg/kg), a structurally related compound also present in PCDF poisoning victims, and 4-PeCDF appears additive. Thus, these chemicals, which cause toxic effects similar to those of 2,3,7,8-tetrachlorodibenzo-p-dioxin, are additive in the induction of fetal anomalies in the mouse.

Topics: Animals; Benzofurans; Body Weight; Cleft Palate; Female; Fetal Death; Fetus; Hydronephrosis; Mice; Mice, Inbred C57BL; Polymers; Pregnancy; Structure-Activity Relationship; Teratogens

Treatment of pregnant C57BL/6N mice with 2,3,7,8-tetrachlorodibenzofuran (TCDF) (0, 250, 500, and 1000 micrograms/kg on gestation day 10 or 0, 10, 30, 50, and 100 micrograms/kg on gestation days 10-13) results in dose-related increases in isolated cleft palates and hydronephrotic kidneys in the offspring. TCDF is teratogenic in 100% of the fetuses at dose levels that are not maternally toxic. The fetal kidney is the most sensitive target organ but the kidney lesions may be reversible.

Topics: Abnormalities, Drug-Induced; Animals; Benzofurans; Cleft Palate; Female; Fetal Death; Gestational Age; Hydronephrosis; Maternal-Fetal Exchange; Mice; Mice, Inbred C57BL; Pregnancy; Teratogens

Topics: Adipose Tissue; Animals; Benzofurans; Birds; Caniformia; Chlorine; Chlorobenzenes; Chromatography, Gas; Dichlorodiphenyl Dichloroethylene; Dioxins; Female; Fetal Death; Liver; Mass Spectrometry; Ovum; Pesticide Residues; Polychlorinated Biphenyls; Pregnancy

Topics: Animals; Benzofurans; Carcinoma 256, Walker; Female; Fetal Death; Hepatectomy; Liver Regeneration; Naphthalenes; Neoplasm Transplantation; Niacinamide; Organ Size; Phenylbutazone; Pregnancy; Pregnancy, Animal; Pyrimidines; Rats; Thalidomide