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The effects of dietary supplementation with sodium selenite (3.0 or 4.5 ppm Se) for 8 weeks prior to and throughout gestation on sodium salicylate induced embryo- and fetotoxicity (resorptions, fetal deaths, malformations, fetal weight reduction) have been studied in the rat. Salicylate was administered either as daily intragastric bolus doses of 250 mg/kg on gestation days 6-13 (maternal peak and trough salicylate levels of 222-120 micrograms/ml whole-blood) or via constant rate intravenous infusion of 150 mg/kg/day on the same gestation days via implanted osmotic minipumps (stable average maternal blood salicylate level of 120 micrograms/ml = human antirheumatic concentration). Both gavage and infusion of salicylate resulted in an increase of resorptions and fetal deaths as well as a decrease of fetal body weights. Gavage with salicylate also produced about 50% malformed fetuses. Selenite did not protect against the embryotoxic effects of salicylate administered as intragastric bolus doses. However, selenite was found to significantly increase fetal survival rate in the infusion experiment, although it did not counteract the decrease of fetal body weight. In animals fed selenite only, no negative effects on fetal body development were noted. The protective effect of selenite against salicylate induced embryotoxicity is difficult to explain, since very little is known about the mechanisms of salicylate embryotoxicity and the biological effects of selenium. However, an interaction between selenium, via glutathione peroxidase, and salicylate at the level of prostaglandin synthesis could be possible.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a persistent environmental contaminant capable of causing a wide variety of adverse health effects including teratogenesis and altered development. The objective of this study was to compare the developmental toxicity of TCDD in the hamster, rat and guinea pig, which in mature animals exhibit a relatively low, medium and high sensitivity to TCDD, respectively. A single oral dose of TCDD was administered to pregnant rats (0, 1.5, 3.0, 6.0 or 18.0microg/kg) on gestation day 10, pregnant hamsters (0, 1.5, 3.0, 6.0 or 18.0microg/kg) on gestation day 9 and pregnant guinea pigs (0, 0.15 or 1.5microg/kg) on gestation day 14 with fetal analysis on gestation day 20, 15 and 56, respectively. The developmental toxicity of TCDD in the three species included increased fetal mortality, alterations to fetal body weight, body length, organ weight and significant changes to the fetal white blood cell differential counts. Additionally, teratogenic responses were observed in the hamster and rat consisting of cleft palate, kidney congestion, hydronephrosis and intestinal hemorrhaging. Furthermore, the results from this study demonstrate that despite the up to 5000-fold interspecies variability to the acute lethal potency of TCDD observed in mature guinea pigs, rats and hamsters, the developing fetus is uniquely vulnerable to gestational TCDD exposure and displays approximately a 10-fold variability in fetal lethal potency in these species. Together, these results will assist efforts to reduce the uncertainty in the risk assessment for TCDD in sensitive populations, such as the developing embryo and fetus.

2-Bromopropane (2-BP), a halogenated propane analogue, is a substitute for chlorofluorocarbones. The present study was carried out to investigate the potential adverse effects of 2-BP on pregnant dams and embryo-fetal development after maternal exposure on gestational days (GD) 6 through 19 in Sprague-Dawley rats. The test chemical was administered subcutaneously to pregnant rats at dose levels of 0, 250, 500, and 1000 mg/kg per day. All dams were subjected to caesarean section on GD 20 and their fetuses were examined for external, visceral and skeletal abnormalities. In the 1000 mg/kg group, maternal toxicity included an increase in the incidence of abnormal clinical signs, a suppression in the body weight and body weight gain, and a decrease in the food intake. Developmental toxicity included an increase in the fetal deaths, a decrease in the litter size, and a reduction in the fetal body weight. In addition, an increase in the incidence of fetal external, visceral, and skeletal abnormalities was seen. In the 500 mg/kg group, minimal developmental toxicity including decreased fetal body weight and increased fetal ossification delay was observed. There were no adverse effects on either pregnant dams or embryo-fetal development in the 250 mg/kg group. These findings suggest that a 14-day subcutaneous dose of 2-BP is embryotoxic and teratogenic at a maternally toxic dose (i.e., 1000 mg/kg per day) and is minimally embryotoxic at a nonmaternally toxic dose (i.e., 500 mg/kg per day) in Sprague-Dawley rats. In the present experimental conditions, the no-observed-adverse-effect level (NOAEL) of 2-BP is considered to be 500 mg/kg per day for dams and 250 mg/kg per day for embryo-fetal development.

In this study, we examined the relationship between maternal weight gain deficits induced by protein-and-energy restriction (PER) and pregnancy outcome. We also evaluated whether PER would potentiate the developmental toxicity of cyclophosphamide (CP) and hydroxyurea (HU). Two independent experiments--employing two different methods of inducing protein-and-energy malnourishment-were performed. In the first experiment, well-nourished (fed ad libitum, normal diet, 22% of protein, 11.9 kJ/g) and food restricted (fed approximately half of ad libitum food intake, i.e. 12 g/day) rats received CP (0, 5 and 7.5 mg/kg sc) on pregnancy day 11. In the second experiment, well-nourished (normal diet, 24% of protein, 12.4 kJ/g) and malnourished (protein-and-energy deficient diet, 8% of protein, 6.2 kJ/g) rats received HU (0, 300 and 500 mg/kg ip) on pregnancy day 11. PER alone caused pronounced reductions of pregnancy weight gain and low fetal body weight, but induce no embryolethality and, except for a few sternum anomalies, no malformation. PER attenuated embryolethal and teratogenic effects of CP. PER reduced teratogenicity but did not alter effects of HU on embryolethality and fetal body weight. Therefore severe maternal weight gain deficits are not necessarily associated to embryolethality and terata and PER attenuates the teratogenic effects of CP and HU.

The embryotoxic and teratogenic potential of gamma- glycidoxypropyltrimethoxysilane ( GPTS ) was evaluated in rats. Pregnant Sprague-Dawley rats were administered 0, 50, 500, or 1,000 mg/kg/day of GPTS by gavage on days 6 through 15 of gestation. No treatment related signs of toxicity, behavioral alterations or mortalities were observed in any of the pregnant animals. There was no evidence of adverse effects in mean maternal body weight, liver weight or food consumption of the treated females. The number of implantation sites, number of live fetuses per litter, the mean litter size, the sex ratio, the fetal body weight or the crown-rump length were not affected by treatment. The incidence of resorptions among the total fetal population was not altered by the administration of GPTS to pregnant rats, indicating that the test material is not embryolethal in rats at the tested dose levels. Few scattered incidences of fetal alterations in the external, soft tissue or skeletal examinations were seen both among treated and untreated litters, however, no single alteration was observed in treated litters at an incidence which was significantly different from the control. In conclusion GPTS was not embryotoxic or teratogenic in rats at dose levels up to 1000 mg/kg/day.

Flubendazole, the p-fluoroderivative of mebendazole, was suspended in deionized water, and administered by gavage once daily to pregnant rats on days 8 through 15 of pregnancy at 0 (control), 2.5, 10, 40 or 160 mg/kg. Fetuses were removed on day 21 of pregnancy by caesarian section, and examined by routine teratological methods. The highest dose (160 mg/kg) was embryocidal and resulted in a significant increase in the fetal resorption rate. There was a dose-dependent decrease in fetal body weights which was significant at 40 mg/kg or more. The 40 and 160 mg/kg doses induced significant fetal (gross, skeletal and internal) malformations. A variety of gross malformations occurred, i.e. encephalocele, cranial meningocele, omphalocele, ectrodactyly, club foot, defects in tail, anal atresia, shortened backbone and Spina bifida occulta. The skeletal malformations mainly affected the vertebrae and ribs. The most frequently observed internal malformation was hydrocephaly, followed by anophthalmia and/or microphthalmia.

Mycotoxins (frequently referred to as secondary metabolites of toxigenic fungi) are commonly found in foodstuffs and are important because of their association with disease. The mycotoxin diacetoxyscirpenol, or 3-hydroxy-4, 15-diacetoxy-12,13-epoxytrichothec-9-ene (DAS), is produced by numerous species of Fusarium and is reportedly toxic to humans and animals. The teratogenic potential of DAS was determined in time-mated ICR mice. DAS (dissolved in a 1:9 mixture of propylene glycol/saline) was administered intraperitoneally to pregnant mice at levels of 1.0, 1.5, 2.0, 3.0 and 6.0 mg/ kg body weight in a single dose on one of gestation days 7–11 during the period of organogenesis. Term fetuses were examined for anomalies by routine teratologic procedures. Reabsorption frequency was dose-related and occurred as follows: 100% at 6.0 mg/kg on all gestation days tested; 90–99% at 3.0 mg/kg on days 7–9 and 100% on days 10 and 11; 26–51% at 2.0 mg/kg on days 7–9 and 100% on days 10 and 11; 9–77% at 1.5 mg/ kg on days 7–10 and 100% on day 11; 7–34% at 1.0 mg/kg on days 7–11. A significant reduction in mean fetal body weight and a variety of fetal malformations (i.e. external and skeletal) were observed following maternal exposure to DAS. This is the first report to implicate this mycotoxin as a teratogen.

The teratogenic and embryotoxic effects of the antitumor agent titanocene dichloride (TDC) were investigated after application of single doses of TDC (30 or 60 mg/kg) to pregnant mice on days 8, 10, 12, 14 or 16 of gestation. The fetuses were removed on day 18 by caesarian section and examined for external, internal and skeletal malformations as well as for toxic phenomena. The most striking result was the occurrence of cleft palate in numerous fetuses (10% of the fetuses, 30 mg/kg; 40–50%, 60 mg/kg) after TDC application on days 10 and 12. Besides the additional appearance of costal malformations in some fetuses, no other malformations were recognizable. On the other hand, the embryotoxic influence of TDC was significant and caused dimunution of the number of live fetuses per litter, marked and dose-dependent reduction of mean fetal body weight after TDC application on day 8 through day 16 and distinct retardation of skeletal ossification.

Teratogenic effects of secalonic acid D (SAD), a toxic fungal metabolite, produced by P. oxalicum has been studied in rats. Crystalline SAD was injected as a single subcutaneous dose (25 mg/kg) on one of the gestation day 6-10, 12 or 14. Pregnant rats were treated with 15 mg/kg SAD on gestation day 10. Both doses produced teratogenic and fetotoxic effects, although the effects produced with the lower dose were less marked. Treatment on days 9 and 10 resulted in increased fetal resorptions and decreased fetal body weights. The highest number of resorptions, greatest depression of fetal body weights and largest number of malformations occurred when SAD was injected on day 10. Anophthalmia (days 9 and 10), exencephaly (day 9) and defects in limbs, digits and tail (day 10) were the major gross malformations. The main internal soft tissue defects were hydronephrosis (days 9 and 10) and tracheo-esophageal fistula and renal agenesis (day 10). Major skeletal defects involved the vertebrae and ribs. For all of the abnormalities observed, administration of SAD on day 10 of gestation produced the most marked effects in rats.

The embryotoxic and teratogenic effects caused by the inorganic cytostatic drug cis-diamminedichloroplatinum(II) ("cis-platinum") were investigated in mice. Single doses of 2.5, 5, 10 or 20 mg cis-platinum/kg were administered to pregnant mice on day 8, 10, 12, 14 or 16 of pregnancy; on day 18, all fetuses were removed and examined for toxic phenomena and for external, skeletal and internal malformations. A dose-dependent reduction of the number of fetuses per litter, a decrease of fetal body weight, and a marked retardation of skeletal ossification processes reflected the severe embryolethal and embryotoxic influence of cis-platinum; this influence was most pronounced when the drug was applied during organogenesis, i.e. on day 8, 10 or 12 of murine pregnancy. In contrast, the incidence of malformations was surprisingly rare after treatment with cis-platinum: Neither external nor skeletal malformations appeared more frequently than in control populations; most fetal internal organs were without anomalies, however, a portion of 10-20% of the fetuses exhibited slight signs of hydrocephaly after application of cis-platinum on day 12.

The teratogenic effects of a single subcutaneous dose of 1.75 mg/kg ochratoxin A given on day 6 of gestation was compared in weanling rats fed 5% protein diet for 4 weeks followed by normal protein diet (referred to as 5% normal protein diets) for the remainder of the experimental period, rats maintained on 10% protein diet, and rats on a normal protein diet throughout. These different diets are based on total dietary concentration of protein. Of the rats fed 10% protein diet, 22% failed to mate and in 39% failure of fertilization was observed. In rats fed 5% normal protein diets, the fertilization rate was 100%. Ochratoxin A treatment resulted in significant depression of fetal body weight in rats fed 5% normal protein diets and in rats maintained on normal protein diet throughout. Significant numbers of malformations (gross and skeletal) occurred in all the treated groups. Rats on a 5% normal protein diet and rats on the normal diet yielded a significant number of fetuses with internal soft tissue anomalies. The highest incidence of skeletal malformations occurred in ochratoxin A treated rats maintained on 10% protein diet throughout the experiment. Complete rehabilitation took place by replacement of low protein diet with normal protein diet.

The teratogenic potential of Ochratoxin A (OA), was compared in impaired renal function (IRF) and sham-operated (SO) female rats. Surgical removal of approximately 70% of the total renal tissue was accomplished utilizing unilateral ligation/electrocoagulation procedures. Control animals were sham-operated. All animals were allowed a period of 27 days to recover post surgery. IRF rats exhibited normal mating tendencies and the pregnancy rate was 100%. A single, subcutaneous teratogenic dose of OA (1.75 mg/kg) on gestation day 7 resulted in significantly increased fetal resorptions, decreased fetal body weights and increased fetal malformations in both IRF and SO animals, although the incidence of gross malformations was greater in IRF rats. A subthreshold teratogenic dose (i.e. 1 mg/kg) did not produce any significant increase in embryotoxicity or fetal malformations in IRF animals compared to SO rats.