Effects of dinocap on otolith development: evaluation of mouse and hamster fetuses at term

The morphology of otoliths in CD-1 mouse and Syrian hamster fetuses exposed to the fungicide dinocap were evaluated at the end of gestation. Pregnant mice were dosed by gavage with 0, 10, 15, 30, or 60 mg/kg/day dinocap in corn oil on days 7-16 of gestation. Pregnant hamsters were dosed by the same route with 0, 50, 100, or 200 mg/kg/day on days 7-14 of gestation. At the end of gestation (day 18 in mice, day 15 in hamsters) dams were killed and all fetuses were removed and fixed overnight in 70% ethanol. Fetal heads were then removed, left in 70% ethanol for at least 3 days, and then dehydrated in a graded ethanol series and cleared with methyl salicylate. Otoliths were examined by darkfield microscopy, and each otolith was scored for morphological completeness on a scale of 0 to 3. Otolith development was complete by day 18 of gestation in control mouse fetuses. Otolith development was complete in many, but not all, of the hamster fetuses by day 15 of gestation. In the mouse, dinocap exposure inhibited fetal otolith formation in a dose-related manner, with a significant effect on total otolith score occurring at 10 mg/kg/day and above. Dinocap affected otolith formation in the hamster only at 100 mg/kg/day (200 mg/kg/day was embryolethal), concomitant with severe maternotoxicity and fetotoxicity.(ABSTRACT TRUNCATED AT 250 WORDS)     

Exposure of the pregnant rat to warfarin and vitamin K1: an animal model of intraventricular hemorrhage in the fetus

Pregnant Sprague-Dawley rats were given daily oral doses of sodium warfarin (100 mg/kg) and concurrent intramuscular injections of vitamin K1 (10 mg/kg). This dosing regimen did not have any apparent deleterious effect on the dams and did not affect the fetuses when administered from day 1 to day 12 of pregnancy. However, similar treatment from day 9 to 20 caused hemorrhage in the fetuses examined on day 21 of gestation. There were no hemorrhages in the control fetuses from dams receiving vitamin K1 only. The lowest effective dose of warfarin, in conjunction with daily doses of vitamin K1, was 3 mg/kg. This dose caused hemorrhage in 28% of fetuses; the incidence of affected fetuses was not further increased by doses of warfarin up to 100 mg/kg. Hemorrhages affected the fetal brain, face, eyes, and ear and occasionally the limbs. Brain hemorrhages were frequently intraventricular and caused various degrees of hydrocephaly. Bony defects were not a feature of prenatal exposure to warfarin. These results show that prenatal exposure of the rat to warfarin and vitamin K duplicates the hemorrhagic abnormalities and pathology associated with prenatal exposure to warfarin in the human. It did not induce bony or facial defects probably because the vitamin K-dependent components of bone development occur postnatally in the rat. This model should allow detailed determination of the role of vitamin K-dependent proteins in development.     

Onset of the constrictive effect of indomethacin on the ductus arteriosus in fetal rats.

The time of onset of the constrictive effect of indomethacin on the ductus arteriosus (DA) in fetal rats was assessed by measurement of the caliber of the DA after maternal treatment with indomethacin on days 19-21 of gestation. The day following overnight mating was regarded as day 0 of gestation. Observation was performed by direct exposure of the DA by hand shaving of intact frozen fetuses. On days 20 and 21, the DA was significantly constricted 3 h after maternal treatment with 1 mg/kg of indomethacin. When the DA was examined at 19 1/2 and 19 2/3 days of gestation (3 h after indomethacin exposure), it was significantly constricted at 19 2/3 days but not at 19 1/2 days. Higher doses of indomethacin (10 and 100 mg/kg) induced a significant constriction of the DA at day 19 1/2, but not at the beginning of the same day (1.00 a.m.). These results suggest that the onset of the susceptibility of the DA to the constrictive effect of indomethacin occurs in the first half of day 19 of gestation.     

Combined embryotoxic action of toluene, a widely used industrial chemical, and acetylsalicylic acid (aspirin)

CFY rats were exposed to inhalation of fresh air at days 10-13 of gestation; at day 12 the dams were given 0, 125, 250, 500, or 1,000 mg/kg acetylsalicylic acid (ASA) by gavage. During the same period of gestation (days 10-13) further groups of rats were exposed to toluene at 1,000, 2,000, and 3,600 mg/m3 atmospheric concentration and were given 250 mg/kg ASA by gavage; two subgroups of animals treated with 250 mg/kg ASA in combination with 3,600 mg/m3 toluene inhalation were given 0, 2.5, or 5 gm/kg glycine 2 hours before the ASA dose. At day 21 the animals were killed and examined for teratogenic effects and histological changes. After 48 hours toluene exposure other groups of rats were treated with ASA or with ASA plus glycine (administered 2 hours earlier) on day 20 of gestation. These animals were killed 2 hours later and the salicylic acid concentration in maternal and embryonic plasma and in amniotic fluid was measured by gas chromatography. With the rising ASA doses both maternal toxicity (increased mortality, decreased food consumption, and weight gain) and embryonic toxicity (postimplantation loss, increased incidence of weight-retarded fetuses, increased minor anomalies and malformations, decreased average weight of fetuses) increased. Toluene was found to potentiate the toxic effect of ASA and to increase both maternal and embryonic toxicity. The type of ASA-induced minor anomalies and malformations was also found to be altered under the effect of toluene pretreatment. By raising the toluene concentration the salicylic acid level in the maternal and embryonic plasma and in the amniotic fluid was increased above the expected concentration. The mechanism of the potentiating interaction should be looked for in the depletion of the glycine pool by toluene (and its metabolites) and in the resultant increase of salicylic acid level. Increasing ASA embryotoxicity caused by toluene can be warded off by glycine administration.     

In utero morphological effects of hydroxyurea on the fetal development in Sprague-Dawley rats

In order to investigate in utero morphological effect of hydroxyurea (HU) in Sprague-Dawley rats, HU was intraperitoneally injected to pregnant Sprague-Dawley rats at a dose of 100 or 200 mg/kg/day during the organogenetic period (days 9-12 of gestation). A dose of 200 mg/kg/day induced growth retardation, high mortality and high incidence of malformations, although a dose of 100 mg/kg/day produced no adverse effects in the next generation. In the HU 200 mg/kg/day group the incidence of malformations in pups at 4 days of age was low as compared with that in fetuses and pups at 21 days of age. Increasing perinatal mortality in fetuses and pups due to severe central nervous system (CNS) malformations and disappearance of some cases of ventricular septal defect after delivery were considered as the possible causes to induce difference in malformation rate in various stage of development. Latent effect on the development of CNS malformations was observed between 4 and 21 days of age. There was no sex difference in teratogenic effect. These findings were compared with those in Wistar rats exposed to HU 200 mg/kg/day. The incidence of perinatal malformations and the stillbirths were significantly higher in the Wistar rats as compared with those in the Sprague-Dawley rats. In addition, such morphological effects of HU as the exencephaly, dilatation of lateral ventricle, anophthalmia, cleft palate and micrognathia are less severe in Sprague-Dawley rat fetuses than in Wistar rat fetuses.     

Developmental toxicity evaluation of Bendectin in CD rats

Bendectin, composed of doxylamine succinate and pyridoxine HCl (1:1), is an antinauseant previously prescribed for nausea and vomiting during pregnancy. The present study examined the maternal and developmental effects of Bendectin (0, 200, 500, or 800 mg/kg/day, po) administered to timed-pregnant CD rats (36-41/group) during organogenesis (gestational days [gd] 6-15). At death (gd 20), all live fetuses were examined for external, visceral, and skeletal abnormalities. At 500 and 800 mg/kg/day, maternal toxicity included reduced food consumption during treatment and for the gestation period, increased water consumption in the posttreatment period, reduced weight gain during treatment, and sedation; water consumption was reduced during treatment and for the gestation period, and maternal mortality (17.1%) was observed only at the high dose. Developmental toxicity included reduced prenatal viability (800 mg/kg/day) and reduced fetal body weight/litter (500 and 800 mg/kg/day). In addition, reduced ossification of metacarpals (800 mg/kg/day), phalanges of the forelimbs (500 and 800 mg/kg/day), and of caudal vertebral centra (all doses) was observed. No increase in percent malformed live fetuses/litter was observed. The proportion of litters with one or more malformed fetuses was higher than vehicle controls only at 800 mg/kg/day, with short 13th rib (to which the test species is predisposed) as the predominant observation. By contrast, a positive control agent (nitrofen, 50 mg/kg/day, po, 14 dams) produced 85% malformed fetuses/litter with the predominant malformation being diaphragmatic hernia. In conclusion, the incidence of litters with one or more malformed fetuses was increased only at a dose of Bendectin which produced maternal mortality (17.1%) and other indices of maternal and developmental toxicity (see Discussion).     

Circadian modification of drug-induced teratogenesis in rat fetuses.

Pregnant Sprague-Dawley rats were injected with hydroxyurea (750 mg/kg) or physiological saline on the 12th day of gestation. Hydroxyurea and saline (control) treated groups were each composed of six subgroups injected at consecutive 4-h intervals (i.e., group 1 at 00(00), group 2 at 04(00),...). All females were injected at the same circadian phase as they were mated. The developmental age of all fetuses was 288 +/- 2 hrs at the time of injection. The fetuses were taken by caesarean section on the 20th or 21st day of gestation. Teratogenesis was greatest when hydroxyurea was administered in the light phase (light-dark 12:12 cycle). Deformity rates correlate with motor activity, mitotic rates and DNA synthesis.     

Role of myometrial constriction in the induction of wavy ribs in rat fetuses

Furosemide, a loop diuretic, was orally administered to pregnant Crj: CD (SD) rats at a dose of 300 mg/kg once on day 16 of gestation. Cartilage bone double staining of day 17 fetuses revealed a delay in ossification. Characteristic rib deformities were not seen until day 18 of gestation. Concomitant with this observation were reductions in the amount of amniotic fluid, compared to controls, on day 18 of gestation and thereafter. When isoxsuprine HCl (2 mg/kg, b.i.d.), a uterine muscle relaxant, was additionally injected ip to pregnant rats on days 17-19 of gestation, the incidence of wavy ribs was significantly (P less than or equal to .05) less than that seen after treatment with furosemide alone. These observations indicate that the myometrial constriction plays a significant role in the induction of furosemide-induced wavy ribs.     

Evaluation of the developmental toxicity of lenalidomide in rabbits

BACKGROUND: Lenalidomide, a thalidomide analog, is indicated for treatment of patients with deletion-5q myelodysplastic syndromes or multiple myeloma. NZW rabbits were used because of sensitivity to thalidomide's teratogenicity. METHODS: Range-finding and pulse-dosing studies preceded a full developmental toxicity study in New Zealand white (NZW) rabbits (25/group) given lenalidomide (0, 3, 10, or 20 mg/kg/day) or thalidomide (180 mg/kg/day) by stomach tube on gestation days (GD) 7-19. Clinical signs, body weights, and feed consumption were recorded daily from GD 7. On GD 29, standard maternal necropsy, uterine content, and fetal evaluations were carried out. RESULTS: In all studies, thalidomide was selectively toxic to development. In the pulse-dosing study, lenalidomide did not affect development at 100 mg/kg/day. Increases in C(max) and AUC(0-24 hr) values for lenalidomide were slightly less than dose-proportional; lenalidomide occurred in the fetuses. At 10 and 20 mg/kg/day, lenalidomide was maternally toxic (reduced body weight gain and feed consumption; at 20 mg/kg/day, weight loss and one abortion). Developmental toxicity at 10 and 20 mg/kg/day included reduced fetal body weights and increased postimplantation losses and fetal variations (morbidity/purple-discolored skin, undeveloped intermediate lung lobe, irregular nasal-frontal suture, and delayed metacarpal ossification). Thalidomide selectively reduced fetal body weight, increased postimplantation loss and caused characteristic limb and other dysmorphology. CONCLUSIONS: The maternal and developmental NOAELs for lenalidomide are 3 mg/kg/day. Unlike thalidomide, lenalidomide affected embryo-fetal development only at maternally toxic dosages, confirming that structure-activity relationships may not predict maternal or developmental effects. No fetal malformations were attributable to lenalidomide.     

Teratogenic effects of a single oral administration of methylmercuric chloride in mice.

The teratogenic effects of methylmercuric chloride (MMC) given orally as a single dose to pregnant ICR mice on day 10 of gestation were examined. The doses tested were 25, 20, 15 and 10 mg/kg. Controls received distilled water orally. Each group consisted of 20 females. Fetuses were taken on day 18 of gestation for teratological study. The number of resorbed or dead embryos was moderately increased in the 25 mg/kg group. Fetuses from dams given 25, 20 and 15 mg/kg MMC weighed significantly less than those in the control group. Many fetuses with malformations were observed in the treated groups; cleft palate occurred in 100, 58.6 and 28.0% of fetuses from dams given 25, 20 and 15 mg/kg MMC, respectively (statistically significant). Hydronephrosis appeared in 23.8 and 18.5% of fetuses from dams given 25 and 20 mg/kg MMC, respectively (statistically significant). Skeletal variations, incomplete ossification of sternebrae, for example, were also observed in the treated groups. These results indicate that MMC is teratogenic so far as cleft palate is concerned and embryotoxic in ICR mice.     

Developmental toxicity of dichloroacetate in the rat.

Dichloroacetic acid (DCA) is a principal by-product of the chlorine disinfection of water containing humic and fulvic acids, and is also a drug of interest in the therapeutic management of metabolic disorders. The developmental effects of DCA were evaluated in the pregnant Long-Evans rat. In two separate studies, animals were dosed by oral intubation on gestation days 6-15 (plug = 0) with 0, 900, 1,400, 1,900 or 2,400 mg/kg/day and 0, 14, 140, or 400 mg/kg/day. The vehicle control was distilled water. Maternal observations included clinical signs, weight change, and gross evaluation of organ weights and uterine contents at necropsy (day 20). Corpora lutea were counted and uteri stained for implantation sites. Live fetuses were examined for external, skeletal, and soft tissue malformations. Seven dams died during treatment (1,400 mg 1/19, 1,900 mg 2/19, 2,400 mg 4/21), and maternal weight gain was reduced at all except the lowest treatment levels. Liver, spleen, and kidney weights increased in a dose-related manner. The mean percentage of resorbed implants per litter was significantly elevated at greater than or equal to 900 mg/kg/day. Live fetuses showed dose-dependent reductions in weight and length at doses above 140 mg/kg. Statistically significant frequencies of soft tissue malformations ranged from 2.6% (140 mg/kg) to 73% (2,400 mg/kg). These were principally in the cardiovascular system and predominantly comprised defects between the ascending aorta and the right ventricle. Skeletal malformations were not observed in significant numbers in any dose group.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effect of prenatal procarbazine treatment on brain development in the rat

Groups of pregnant Sprague-Dawley rats were treated orally with procarbazine, an antineoplastic drug, at dose levels of 0, 1.0, 2.5, 5.0, 7.5, and 10.0 mg/kg/day from days 12 through 15 of gestation. Following normal delivery, offspring were raised until day 21 and sacrificed, and their brains removed and weighed. A dose-dependent micrencephaly, characterized by hypoplasia of the cerebral hemispheres, was seen starting at 2.5 mg/kg/day. In a second study, groups of pregnant female rats were given a single dose of 10 mg/kg procarbazine on gestation day 12, 13, 14, or 15. Micrencephaly occurred in 21-day-old offspring from all groups, with the greatest effect induced on days 13, 14 and 15. Analysis of brain region weights revealed a maximum reduction in neocortex weight in offspring from groups treated on days 13 and 14. The hippocampus, cerebellum, and diencephalon-midbrain were also reduced in size, depending on the day of treatment, while the corpus striatum and pons-medulla were spared. In a final study, embryos from females treated on gestation days 12 through 15 were removed, fixed, and sectioned at 24-hour intervals starting on gestation days 13. Necrosis and cellular degeneration were observed with decreasing severity in the telencephalon, diencephalon, mesencephalon, and medulla. The neocortex of 20-day treated fetuses was characterized by a thickening of the ventricular zone and reduced cellularity of the cortical plate.     

Development in the cynomolgus macaque following administration of ustekinumab,a human anti‐il‐12/23p40 monoclonal antibody,during pregnancy and lactation

BACKGROUND: Ustekinumab is a human monoclonal antibody that binds to the p40 subunit of interleukin (IL) 12 and IL‐23 and inhibits their pharmacological activity. To evaluate potential effects of ustekinumab treatment during pregnancy, developmental studies were conducted in cynomolgus macaques. METHODS: Ustekinumab was tested in two embryo/fetal development (EFD) studies and in a combined EFD/pre and postnatal development (PPND) study. In the EFD studies, pregnant macaques (12/group) were dosed with saline or ustekinumab (9 mg/kg IV, 22.5 mg/kg SC, or 45 mg/kg IV or SC during the period of major organogenesis, gestation day [GD] 20–50). Fetuses were harvested on GD100–102 and examined for any effects on development. In the EFD/PPND study, pregnant macaques were injected with saline or ustekinumab (22.5 or 45 mg/kg SC) from GD20 through lactation day 33. Infants were examined from birth through 6 months of age for morphological and functional development. Potential effects on the immune system were evaluated by immunophenotyping of peripheral blood lymphocytes and immunohistopathology of lymphoid tissues in fetuses and infants and by T‐dependent antibody response (TDAR) to KLH and TTX and by DTH response in infants. Ustekinumab concentrations were measured in serum from dams, fetus, and infants and in breast milk. RESULTS: Ustekinumab treatment produced no maternal toxicity and no toxicity in the fetuses or infants, including no effects on the TDAR or DTH responses. Ustekinumab was present in serum from GD100 fetuses and was present in infant serum through day 120 post‐birth. Low levels of ustekinumab were present in breast milk. CONCLUSIONS: Exposure of macaque fetuses and infants to ustekinumab had no adverse effects on pre‐ and postnatal development. Birth Defects Res (Part B) 89:351–363, 2010. © 2010 Wiley‐Liss, Inc.     

Teratogenic effect of AY 9944 in rats: importance of the day of administration and maternal plasma cholesterol level

An inhibitor of cholesterol synthesis, AY 9944 (trans-1,4-bis(2-chlorobenzylaminomethyl) cyclohexane dihydrochloride) is teratogenic. A single dose of AY 9944 (50 mg/kg or 75 mg/kg) given to Wistar pregnant rats on the second, fourth, sixth, seventh, or eighth day of gestation induced malformations such as holoprosencephaly. They were often limited to isolated pituitary agenesis. The highest percentage of holoprosencephalic fetuses was found when AY 9944 was given on the fourth day of gestation. Whatever the dose and the day of administration, the lower the maternal plasma cholesterol level, the more frequent were holoprosencephalic fetuses. Therefore, it is suggested that the decrease in maternal plasma cholesterol level is at least one of the factors provoking holoprosencephaly.     

Effects of the cytostatic drug cis-platinum on the developing neocortex of the mouse

The effects of the new cytostatic drug cis-diamminedichloroplatinum(II) (cis-platinum) on the developing neocortex of NMRI mouse embryos or fetuses were investigated using light- and electron-microscopic methods. Single doses of 20 mg cis-platinum/kg were applied intraperitoneally on day 10, 11, . . ., or 16 of gestation. After treatment on day 10 or 11-i.e., during the phase of organogenesis-no morphological alterations could be detected in the neuroepithelium. However, after treatment on day 12 or later, the mitotic activity was markedly reduced and a great number of cells had become necrotic within 12-24 h after application of the drug. At the ultrastructural level, the development of necroses began with a condensation of the chromatin, culminating in the formation of large condensation plaques and shrinkage and fragmentation of the cytoplasm. The observed necroses can be classified according to Schweichel and Merker as type I necroses. It is argued that the apparent teratogenic inefficiency of cis-platinum on days 10 and 11 of murine pregnancy is caused by the inability of cis-platinum to pass the placental barrier at this stage of pregnancy.     

Variability in the developmental toxicity of bropirimine with the day of administration

The aim of this study was to determine the mechanism by which bropirimine exerts its developmental toxicity. This drug is an immunomodulator and interferon inducer with antiviral and antitumor activities in experimental models. Timed-pregnant Upj:TUC(SD)spf (Sprague-Dawley) rats were given a single oral (gastric intubation) dose of bropirimine at 200 or 400 mg/kg (doses as high as 100 mg/kg/day have been employed in human cancer trials) on days 5, 6, 7, 8, 9, 10, 11, or 12 of gestation and in a second experiment on day 12, 13, 14, 15, 16, 17, 18, or 19 of gestation. The dams were killed 24 hours after dosing and their uterine contents examined. In a third experiment, bropirimine (400 mg/kg) was administered on day 4 of gestation and the uteri of different groups were examined on day 8, 9, 10, 11, or 12 of gestation. Serum progesterone levels were measured at sacrifice. In the first two experiments a battery of hematologic/clinical chemistry assays also were performed. In all three experiments, bropirimine-related maternal toxicity was observed; such toxicity was characterized by significant decreases in weight gain, relative to the concurrent vehicle controls, as well as significant differences in several blood parameters including platelets, white blood cells, alanine aminotransferase, and aspartate transaminase. In the first experiment, bropirimine treatment on day 11, but not day 12, resulted in significant decreases in the mean number of live embryos per litter. In the second experiment, significant decreases in the number of live fetuses per litter occurred 24 hours after dosing on day 18 (200 and 400 mg/kg groups) or day 19 (400 mg/kg group). Decreases in serum progesterone appeared to correlate well with the embryolethal effects seen after treatment between days 6 and 11 of gestation, but not with the fetal lethality seen when treatment was given on day 17 or 18. The decreases in serum progesterone levels found most likely were the result of a luteolytic effect, although it is unknown if bropirimine has a direct or indirect effect on the corpora lutea. In the third experiment, bropirimine treatment on day 4 of gestation resulted in only slight preimplantational losses, but significant decreases were found in mean number of live embryos per litter after day 9. Uterine decidual necrosis has been observed in the first experiment where bropirimine was given on day 11; however, treatment on day 4 resulted in an apparent decrease in decidual development but not necrosis.     

Effects of eflornithine hydrochloride (DFMO) on fetal development in rats and rabbits

Eflornithine hydrochloride (DFMO) is a highly selective, enzyme-activated, irreversible inhibitor of the enzyme L-ornithine decarboxylase (ODC). Because of its role in the biosynthetic pathway of polyamines, ODC is essential for the growth and development of newly implanted embryonic tissue. In order to assess its effect on embryonic growth and fetal development, at various stages of gestation, DFMO was administered in the drinking water to pregnant rats and rabbits at several concentrations (from 0.03% to 3.0%) and times (from days 7, 10, or 11 through days 18 or 19). Rats were killed on day 21 and rabbits on day 29 of pregnancy (day 1 = day of insemination), and the implantations and fetuses were examined. At a concentration of 1.0% (approximately 1,270 mg/kg/day) in rats and 3.0% (approximately 915 mg/kg/day) in rabbits, maternal food and water consumption and body weight gain were significantly reduced during the treatment period, and all implantations were aborted or resorbed. At lower doses (approximately 200-600 mg/kg/day) fetuses survived to term, though in reduced numbers, and a marked reduction in average fetal weight was seen. At levels of 60 mg/kg/day or lower, there were no deleterious effects to the dams or their offspring. Few malformations were detected at any dose level by gross teratologic examination; nor were any considered to have been drug induced because of their sporadic incidence. The embryotoxicity and severe growth retardation demonstrated by these studies verify that adequate polyamine levels are essential for normal embryonic and fetal development.     

Licorice extract increases cyclophosphamide teratogenicity by upregulating the expression of cytochrome P-450 2B mRNA

BACKGROUND: Since cyclophosphamide is metabolically activated to teratogenic acrolein and cytotoxic phosphoramide mustard by cytochrome P‐450 type 2B (CYP2B), we assessed the effects of licorice, a CYP2B inducer, on the fetal defects induced by cyclophosphamide. METHODS: Pregnant Sprague‐Dawley rats were daily administered with licorice (100 mg/kg) by gavage for 7 days, from the 6th to 12th day of gestation, and intraperitoneally administered with cyclophosphamide (11 mg/kg) 1 hr after the final licorice treatment. On the 20th day of gestation, maternal and fetal abnormalities were determined by Cesarian section. RESULTS: Cyclophosphamide was found to reduce fetal and placental weights without increasing resorption or death. In addition, it induced malformations in live fetuses; 93.8, 41.1, and 100% of the external (skull and limb defects), visceral (cleft palate and ureteric dilatation), and skeletal (acrania, vertebral/costal malformations, and delayed ossification) abnormalities, respectively. When pre‐treated with licorice, cyclophosphamide‐induced body weight loss and abnormalities of fetuses were remarkably aggravated. Moreover, repeated treatment with licorice greatly increased mRNA expression and activity of hepatic CYP2B. CONCLUSIONS: The results indicate that repeated intake of licorice may aggravate cyclophosphamide‐induced body weight loss and malformations of fetuses by upregulating CYP2B. Birth Defects Res (Part B) 92:553–559, 2011. © 2011 Wiley Periodicals, Inc.     

Influence of formaldehyde and Sonacide (potentiated acid glutaraldehyde) on embryo and fetal development in mice

Pregnant outbred albino mice were given formaldehyde or Sonacide (potentiated acid glutaraldehyde) by gavage on days 6--15 of gestation. The mice were killed on day 18, the general health and reproductive status of the dam evaluated, and the fetuses examined and processed in order to characterize external, visceral, and skeletal malformations. Although formaldehyde (stock solution containing 12--15% methanol as a preservative) was lethal to 22 of 34 dams treated with 185 mg/kg/day, and one of 35 dams treated with 148 mg/kg/day, these doses did not produce statistically significant (two-sided p < 0.05 versus controls) teratogenic effects in the fetuses of the surviving dams. Sonacide was also judged not to be teratogenic to the mice employed in this study, in spite of the fact that relatively high doses were employed. The highest doses of Sonacide studied (5.0 ml/kg/day, which is equivalent to 100 mg/kg/day of glutaraldehyde) killed 19 of 35 dams and caused a significant reduction in the mean weight gain of the surviving mothers. In addition, this dose produced a significant increase in the number of stunted fetuses.     

Effects of Combined Dietary Chromium(III) Propionate Complex and Thiamine Supplementation on Insulin Sensitivity, Blood Biochemical Indices, and Mineral Levels in High-Fructose-Fed Rats

Insulin resistance is the first step in glucose intolerance and the development of type 2 diabetes mellitus, thus effective prevention strategies should also include dietary interventions to enhance insulin sensitivity. Nutrients, such as microelement chromium(III) and thiamine, play regulatory roles in carbohydrate metabolism. The objective of this study was to evaluate the insulin-sensitizing potential of the combined supplementary chromium(III) propionate complex (CrProp) and thiamine in insulin resistance animal model (rats fed a high-fructose diet). The experiment was carried out on 40 nine-week-old male Wistar rats divided into five groups (eight animals each). Animals were fed ad libitum: the control diet (AIN-93?M) and high-fructose diets with and without a combination of two levels of CrProp (0.1 and 1?mg Cr/kg body mass/day) and two levels of thiamine (0.5 and 10?mg/kg body mass/day) for 8?weeks. At the end of the experiment rats were sacrificed to collect blood and internal organs for analyses of blood biochemical and hematologic indices as well as tissular microelement levels that were measured using appropriate methods. It was found that both supplementary CrProp and thiamine (given alone) have significant insulin-sensitizing and moderate blood-lipid-lowering properties, while the combined supplementation with these agents does not give synergistic effects in insulin-resistant rats. CrProp given separately increased kidney Cu and Cr levels, while thiamine alone increased hepatic Cu contents and decreased renal Zn and Cu contents.