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Objective: The objective of this study was to explore factors influencing the accuracy of transvaginal digital examination for determining fetal head position during the first stage of labor. Materials and Methods: Fetal head position was assessed in 87 women in the first stage of labor at term with normal singleton cephalic presentation. Transvaginal digital examinations were performed by attending midwives and were followed immediately by transabdominal ultrasound assessments performed by a single sonographer. Accuracy was defined as agreement of the results of each examination. Multivariate logistic regression analysis was performed to determine the independent factors influencing accuracy. Results: In only 40.3% of patients (n = 35) were transvaginal digital examinations consistent with ultrasound assessments. Multivariate logistic regression analysis showed that the accuracy of digital examinations was significantly associated with cervical dilatation more than 7 cm (odds ratio, 3.01; 95% confidence interval [CI], 1.03-9.4), birth weight less than 2,500 g (odds ratio, 8.68; 95% CI, 1.08-86.28), and the anterior occiput position group (odds ratio, 4.73; 95% CI, 1.76-13.49). Conclusions: The present study demonstrates that transvaginal digital examination is less accurate than ultrasonography for determining fetal head position during the first stage of labor. The results suggest that ultrasound assessments should be routinely performed in patients with a cervical dilatation less than 7 cm, an estimated fetal body weight more than 2,500 g, the occiput posterior position, or the occiput transverse position.

OBJECTIVE: To evaluate morphological alterations in rat fetuses treated with fluoxetine and imipramine during the "critical" period of gestation. METHOD: Fifteen female rats were separated into three groups (n = 5) and treated with 10 mg/kg/day of test substances on the ninth, tenth and eleventh day of pregnancy: G1, fluoxetine; G2, imipramine hydrochloride; G3 (control), saline. On day 21, cesarean sections were performed to release the fetuses, whose bodies were weighed and macroscopically analyzed. The placenta was also weighed. The fetuses were then fixed and their encephala removed and weighed. Sections of the frontal lobe were taken for histological neuron counting. RESULTS: G1 and G2 showed the highest fetal body weight. Placental weight showed statistical differences (p < 0.01): G1 weighed more than G2 and G3. Otherwise, G2 exhibited the highest encephalon weight, statistically differing from G3 (control) and fluoxetine-treated G1 (p < 0.01). However, G1 did not statistically (p > 0.01) differ from the control group. G3 showed the highest number of neurons per area when compared to G1 and G2 (p < 0.01). CONCLUSION: The use of antidepressants in rats caused an increase in fetal weight and a decrease in the number of fetal frontal lobe neurons, thus suggesting that the use of antidepressants by pregnant women can induce depression in fetuses due to alterations in their neural development. OBJETIVO: Avaliar as possíveis alterações ocorridas em nível macroscópico e microscópico de fetos de ratas submetidas ao tratamento com fluoxetina e imipramina durante o período "crítico" da gestação. MÉTODO: Quinze ratas, posteriormente ao acasalamento, foram divididas em três grupos experimentais (n = 5): G1, tratadas com 10mg/kg/dia de fluoxetina; G2, tratadas com 10mg/kg/dia de cloridrato de imipramina, e G3 (controle), tratadas com 10mg/kg/dia de solução fisiológica a 0,9%, no 9º, 10º e 11º dias de prenhez das ratas. Posteriormente à cesária, no 21º dia de prenhez, analisou-se macroscopicamente o peso fetal e placentário. Os fetos foram fixados e houve a remoção do encéfalo para pesagem e preparação das lâminas do tecido neuronal para contagem de neurônios do lobo frontal. RESULTADOS: O G1 e G2 apresentaram maior peso fetal. O G1 apresentou maior peso placentário, diferindo do G2 e G3 (p < 0,01). De forma diferente, o G2 possuiu maior peso encefálico, diferindo do G3 e G1 (p < 0,01). G1 não diferiu estatisticamente do grupo controle (p > 0,01). O G3 exibiu maior número de neurônios, por área, do lobo frontal em relação a G1 e G2 (p < 0,01). CONCLUSÃO: A adoção dos antidepressivos causou, nos fetos, aumento de peso e redução da contagem de neurônios do lobo frontal, sugerindo que a indicação de antidepressivos às gestantes pode induzir a depressão nos fetos por alterações em seu neurodesenvolvimento.

Sodium warfarin was administered daily to Sprague-Dawley rats from gestational day 8 to day 22 to examine the effects of this compound on the developing fetal skeleton and on the vitamin K-dependent bone and cartilage proteins. At a dose of 175 micrograms/kg of sodium warfarin there was a 43% mortality rate among the dams. Maternal prothrombin times and serum osteocalcin levels were slightly elevated but not significantly. In the surviving litters, fetal bone osteocalcin and gamma-carboxyglutamic acid were significantly reduced (50 and 57%, respectively, on gestational day 22) when compared to age- and/or weight-matched control pups. The high correlation of osteocalcin content in long bone (R = 0.64) and calvariae (R = 0.77) to fetal body weight observed in control fetuses was not seen in the warfarin-exposed pups. Examination of alizarin-stained warfarin-exposed fetal skeletons for ossification centers showed no difference from controls. However, analysis of the tibial growth showed several changes compared to control that included (1) widened hypertrophic zones, (2) increased calcification of the hypertrophic zones, and (3) disorganization of the hypertrophic cells. These results suggest that the growth plate abnormalities seen with prenatal warfarin exposure relate to the inhibition of the vitamin K-dependent proteins of the skeletal system.

Smoking during pregnancy has been shown to result in an increased risk of low birth weight. However, the mechanisms underlying this association are poorly understood. The insulin-like growth factor (IGF) system plays a critical role in the regulation of feto-placental growth and development, and abnormal processing of proIGF-II may alter its biological function. Our goal was to investigate the effects of exposure to nicotine on maternal, fetal, and neonatal IGF-II processing. Nulliparous female Wistar rats were randomly assigned to receive saline (vehicle) or nicotine bitartrate (1 mg x kg(-1) x d(- 1)). After mating, dams were euthanized at embryonic days 15, 18, and 21, and fetal body weight was recorded. Serum (fetal and maternal) was collected for determination of the IGF-II profile by Western blot analysis. Nicotine exposure prevented the decrease in maternal IGF-II processing seen in controls with advancing gestation. However, there was no influence of nicotine on fetal levels of IGF-II. Postnatally (postnatal day [PND] 21), pups exposed to nicotine in utero had decreased levels of big IGF-II. Our results show, for the first time, that nicotine exposure prevents the decrease of IGF-II processing in the maternal compartment. This may represent a compensatory mechanism allowing the mother to counteract the negative influence of nicotine on fetal growth and development. Our postnatal findings of suppressed IGF-II may help explain some of the long-term health complications seen in individuals exposed to smoking in utero.

The present investigation was performed to examine the effect of artemether on rat pregnancy and embryonic/fetal development during different phases of pregnancy. Artemether was administered orally to Wistar rats at doses 3.5 and 7 mg/kg during blastogenesis, organogenesis and fetal period. When administered during blastogenesis, the preimplantation loss, number of implantations, resorptions, living fetuses, external and skeletal examination did not differ from those of control, however the higher dose induced reduction in fetal body weight and caused pre-term delivery in 3 of 10 pregnant rats. During organogenesis complete fetal resorption was observed in all dams treated with the higher dose, while in the lower dose 32% of implants were resorbed and live fetuses showed decreased fetal weight with low incidence of skeletal retardation. Artemether did not adversely affect prenatal development in rats treated during the fetal period although the higher dose level induced reduction in fetal body weight. In conclusion, no evidence of maternal toxicity, artemether was embryolethal at 3.5 and 7 mg/kg when dosed during organogenesis, the surviving fetuses showed fetal growth retardation without incidence of malformations, treatment during blastogenesis and fetal period had no lethal or teratogenic effect although the mean fetal body weight was significantly lower than control.

Methyl iodide (MeI), an intermediate used in the manufacture of some insecticides and pharmaceuticals, is under review for U.S. registration as a non-ozone-depleting alternative to methyl bromide in the pre-plant soil fumigation market. Guideline (OPPTS 870.3700) developmental toxicity studies in New Zealand White (NZW) rabbits showed dose-dependent increases in the litter proportions of late fetal deaths and postimplantation loss and/or decreased fetal body weight following inhalation exposure of pregnant rabbits to MeI during gestation days (GD) 6-28. A subsequent phased-exposure study was performed to pinpoint the critical window of gestational exposure that produced the rabbit fetotoxicity. Artificially inseminated NZW female rabbits were exposed to 20 ppm MeI vapors by whole-body inhalation (6 h/day) throughout major organogenesis and fetal development (GD 6-28), during early gestation (GD 6-14) or mid-gestation (GD 15-22) only, or during 2-day intervals late in gestation (GD 23-24, 25-26, or 27-28). No maternal or developmental toxicity was elicited from maternal exposure during GD 6-14, 15-22, or 27-28. However, MeI-related fetotoxicity, including increased litter proportions of late fetal deaths with or without corresponding decreases in fetal body weight, were observed for females exposed during GD 6-28 (p < .01), 23-24 and 25-26. Although the increase in late-stage fetal death for each of the 2-day exposures on GD 23-24 and GD 25-26 was not statistically significant, as noted for the combined total of fetal deaths during the GD 6-28 exposure, it can be deduced that the gestational window of GD 23-26 was the most susceptible window of exposure for eliciting developmental toxicity in rabbits exposed to MeI vapors.

We previously reported that the administration of dibutyltin dichloride (DBTCl) by nasogastric intubation during the entire period of organogenesis, days 20-50 of pregnancy, was embryolethal, but not teratogenic, in cynomolgus monkeys. The present study was conducted to further evaluate the developmental toxicity of DBTCl given to pregnant monkeys on 3 consecutive days during organogenesis. Cynomolgus monkeys were given DBTCl at 7.5 mg/kg body weight/day by nasogastric intubation on days 19-21, 21-23, 24-26, 26-28, 29-31, 31-33, or 34-36 of pregnancy, and the pregnancy outcome was determined on day 100 of pregnancy. Embryonic/fetal loss was observed in 1 female given DBTCl on days 19-21, 2 females given DBTCl on days 24-26, and 1 female given DBTCl on days 34-36. There were no effects of DBTCl on developmental parameters in surviving fetuses, including fetal body weight, crown-rump length, tail length, or placental weight. No external, internal, or skeletal malformations were detected in fetuses in any group. DBTCl did not affect the incidence of fetuses with skeletal variation or skeletal ossification of fetuses. These data confirm our previous findings that DBTCl was embryolethal, but not teratogenic, in cynomolgus monkeys.

The objective of this study was to evaluate the developmental toxic potential of diallyl phthalate (DAP) in rats. Pregnant Sprague-Dawley rats were given DAP at doses of 0 (olive oil), 100, 150, 200, and 250 mg/kg/day, by gavage (5 ml/kg), on Gestational Days (GD) 6 through 20. Gross examination at necropsy revealed liver lesions in dams given 150 mg/kg/day or higher doses. In addition, maternal weight gain and food consumption were significantly reduced at 200 and 250 mg/kg/day. There was no significant increase in the incidence of resorptions, or malformations, at any dose. Fetal body weight was significantly reduced at 200 and 250 mg/kg/day. There was a significant increase in the incidence of fetuses with skeletal variations at 250 mg/kg/day. Retarded ossification of certain bones (i.e. forelimb and hindlimb phalanges, metatarsals, and caudal vertebrae) was also observed. There was no sign of developmental toxicity at 100 and 150 mg/kg/day. Thus, DAP caused fetal toxicity at doses which also produced maternal effects, but no embryolethality or teratogenicity.

This study evaluates the protective effects of Korean garlic juice against the toxicity of methyl mercuric chloride (MMC) in relation to fetal ossification in pregnant Fischer 344 rats. This study has as its basis, both theory and data that neutral amino acids in garlic juice have protective effects against mercury poisoning. Pregnant rats were dosed in various combination with 20 mg MMC/kg body wt. and 0.5 or 1.0 garlic juice/kg body wt. on the 7th day of gestation. Fetuses were extracted from the dams on 20th day of gestation, and the fetal bones were stained and measured. The results obtained are as follows: 1. Fetal body weights, body lengths, and head length were significantly decreased by as much as 23.5%, 21.3%, 15.5% respectively in 20 mg/wt kg methyl mercuric chloride groups (p and of controls. 3. The ossified pectoral girdles were significantly decreased by as much as 66.6% in clavicle, and in other areas in the 20 mg/wt kg methyl mercuric chloride groups (p and of the controls. 4. The ossified pelvic girdles were significantly decreased by as much as 57.1% and 56.1% in two ischium, in metacarpals in the 20 mg/wt kg methyl mercuric chloride groups (p and of the controls. 5. The ossified terenebrae were unchanged or significantly decreased; 0.0% in 5th, 54.1% in 1st, 83.9% in 2nd, 75.0% in 3rd, 72.7% in 4th, 79.8% in 6th of 20 mg/wt kg methyl mercuric chloride groups (p and of the controls. 6. The ossified ribs were significantly decreased by as much as in 20 mg/wt kg methyl mercuric chloride groups (p and of the controls. In conclusion, Korean garlic juice significantly protected against the toxicity of MMC in relation to the fetal ossification in pregnant rats.

Pregnant Targhee ewe lambs (n = 32; BW = 45.6 +/- 2.2 kg) were allotted randomly to 1 of 4 treatments in a completely randomized design to examine the effects of level and source of dietary Se on maternal and fetal visceral organ mass, cellularity estimates, and maternal jejunal crypt cell proliferation and vascularity. Diets contained (DM basis) either no added Se (control) or supranutritional Se from high-Se wheat at 3.0 ppm Se (SW) or from sodium selenate at 3 (S3) or 15 (S15) ppm Se. Diets were similar in CP (15.5%) and ME (2.68 Mcal/kg of DM) and were fed to meet or exceed requirements. Treatments were initiated at 50 +/- 5 d of gestation. The control, SW, S3, and S15 treatment diets provided 2.5, 75, 75, and 375 microg of Se/kg of BW, respectively. On d 134 +/- 10 of gestation, ewes were necropsied, and tissues were harvested. Contrasts, including control vs. Se treatments (SW, S3, and S15), SW vs. S3, and S3 vs. S15, were used to evaluate differences among Se levels and sources. There were no differences in ewe initial and final BW. Full viscera and liver mass (g/kg of empty BW and g/kg of maternal BW) and maternal liver protein concentration (mg/g) and content (g) were greater (P < 0.04) in Se-treated compared with control ewes. Maternal liver protein concentration was greater (P = 0.01) in SW vs. S3 ewes, and content was greater (P = 0.01) in S15 compared with S3 ewes. Maternal jejunal mucosal DNA concentration (mg/g) was greater (P = 0.08) in SW compared with S3 ewes. Total number of proliferating cells in maternal jejunal mucosa was greater (P = 0.02) in Se-fed compared with control ewes. Capillary number density within maternal jejunal tissue was greater (P = 0.08) in S3 compared with SW ewes. Selenium treatment resulted in reduced fetal heart girth (P = 0.08). Fetal kidney RNA (P = 0.04) and protein concentrations (mg/g; P = 0.03) were greater in Se-treated compared with control ewes. These results indicate that supranutritional dietary Se increases cell numbers in maternal jejunal mucosa through increased crypt cell proliferation. No indications of toxicity were observed in any of the Se treatments.

The developmental toxicity of pepsin inhibitor isolated from Ascaris suum , a gastrointestinal nematode parasite, was evaluated. An embryo–fetal development study was conducted in BALB/c mice. Groups of 21 mated females were treated by intraperitoneal injection (0.3 ml/30 g body weight) with 0.9% NaCl solution vehicle or isolated Ascaris pepsin inhibitor (API) at dose levels of 50, 100, 150 or 200 mg/kg body weight/day on gestation days (GD) 6–15. Maternal food consumption, body weight, and clinical signs were monitored throughout gestation. Cesarean sections were performed on GD 18 and gravid uterine weight, implantation sites, early and late resorptions, live and dead fetuses were collected. Live fetuses were weighed and examined for external, visceral and skeletal variations and malformations. Maternal body weight gain, gravid uterine weight, food consumption were significantly decreased after injection of higher doses of API (100–200 mg/kg/day). All doses of API exhibited an embryotoxic effect (high rate of intrauterine resorption). The percentage of postimplantation loss in the groups with administered API was higher (over 4–11 times) than that in control group. Fetotoxicity was observed in all treatment groups in a dose-related manner and it was evidenced by increased dead fetuses, decreased fetal weight, increased visceral variations and reduced skeletal ossification. Fetal hydronephrosis and internal hydrocephalus were noted at 150, and 200 mg/kg/day. In summary, the maternal toxicity no-observed-adverse-effect level (NOAEL) was 50 mg/kg/day and the low-observed-adverse-effect level (LOAEL) was 100 mg/kg/day under the conditions of this study. However, the developmental toxicity LOAEL was 50 mg/kg/day based on decreased fetal body weight and prenatal mortality.

Triphenyltin-hydroxide (TPTH) is used as agricultural fungicide in Brazil and elsewhere. This study was undertaken to evaluate the developmental toxicity of TPTH in mice. Swiss Webster mice were treated by gavage with TPTH (0, 3.75, 7.5, 15 and 30 mg/kg bw/day) on gestation days (GD) 6-17. Caesarean sections were performed on GD 18, and implantations, resorptions and live and dead fetuses were counted. Half of each litter was fixed and examined for visceral anomalies while the remaining fetuses were cleared and stained with Alizarin Red S for skeleton evaluation. A reduced pregnancy weight gain (after subtraction of uterine weights), smaller thymus, spleen and liver, and deaths indicated that dosesor = 7.5mg/kg body wt/day were toxic to mothers. At the two highest doses, TPTH enhanced embryolethality and reduced fetal body weight. The incidence of cleft palate (not seen in controls) was augmented (36.8%) at the highest dose of TPTH, while palatine bone defects were increased at the lowest dose (3.75 mg/kg bw/day). Soft-tissue anomalies, such as misshapened thymus, and malpositioned testes and uteri, were more frequent at doses of TPTHor = 7.5 mg/kg bw/day. TPTH also caused a dose-related increase of fetal skeleton variations (e.g. poorly ossified skull bones) and malformations (misshapened Axis and skull bones). In conclusion, TPTH was toxic to the embryos (NOAEL3.75 mg/kg bw/day) at doses that were not overtly toxic to their mothers.

Aims To investigate the effects of intra-amniotic vascular endothelial growth factor (VEGF) treatment on surfactant pool sizes and surfactant protein (SP) gene expressions in fetal rat lung. Method On the 18th day of gestation, an abdominal midline incision was performed on timed pregnant Sprague–Dawley rats and the two uterine horns were exposed. VEGF (2.5 μg or 5.0 μg) and saline were injected into the amniotic cavity of the left and right uterine horns, respectively. On the 19th day of gestation, fetuses were delivered by caesarean section. Results We analyzed the data between the fetuses within the same dam in each group. Mean fetal body weight and lung tissue saturated phosphatidylcholine and total phospholipids were comparable between control and VEGF-treated rats at each VEGF dosage. Lung SP mRNA expressions were comparable between control and VEGF 2.5 μg-treated rats. VEGF 5.0 μg treatment increased lung SP mRNA expressions and the values were statistically significant for SP-B and SP-D mRNAs when compared with the control rats. Conclusions These results suggest that VEGF might have potential therapeutic implications in enhancing fetal lung maturation.

Limiting maternal nutrient intake during ovine adolescent pregnancy progressively depleted maternal body reserves, impaired fetal nutrient supply, and slowed fetal soft tissue growth. The present study examined placental growth, angiogenic gene expression, and vascular development in this undernourished adolescent model at Days 90 and 130 of gestation. Singleton pregnancies were established, and ewes were offered an optimal control (C; n = 14) or low (L [0.7 3 C]; n = 21) dietary intake. Seven ewes receiving L intakes were switched to C intakes on Day 90 of gestation (L-C). Fetal body weight (P < 0.01) and glucose concentrations (P < 0.03) were reduced in L versus C pregnancies by Day 130, whereas L-C group values were intermediate. Placental cellular proliferation, gross morphology, and mass were independent of maternal nutrition at both Day 90 and 130. In contrast, capillary area density in the maternal caruncular portion of the placentome was reduced by 20% (P < 0.001) at both stages of gestation in L compared with C groups. Caruncular capillary area density was equivalent in the L and L-C groups at Day 130. Placental mRNA expression of five key angiogenic ligands or receptors increased (P < 0.001) between Days 90 and 130 of gestation. VEGFA mRNA expression was higher (P < 0.04) in L compared with C and L-C pregnancies at Day 130, but otherwise gene expression of the remaining angiogenic factors and receptors analyzed was unaffected by maternal intake. Undernourishing the pregnant adolescent dam restricts fetal growth independently of changes in placental mass. Alterations in maternal placental vascular development may, however, play a role in mediating the previously reported reduction in maternal and hence fetal nutrient supply. adolescent pregnancy, angiogenesis, female reproductive tract, fetus, placenta, placental vascular development, pregnancy, progesterone, undernutrition

The developmental toxicity of toluene was evaluated via whole body inhalation exposure, in pregnant Sprague Dawley rats exposed to toluene (99.9% pure) from gestation day (GD) 6-15 inclusive, 6h/day, at concentrations of 0, 250, 750, 1500 and 3000ppm (0, 938, 2812, 5625 and 11250mg/m(3)). Doses were selected from a preliminary study performed over a range of concentrations from 0 to 5000ppm, in which maternal and fetal toxicity were observed at 2000ppm and above. This study has been cited in various regulatory documents and is presented here to allow greater accessibility to results and conclusions. Toluene induced clinical signs in pregnant dams (ataxia, hyper-responsivity, increased water intake, decreased food consumption) at 3000ppm, ataxia and hyper-responsivity at 1500ppm, and reduced maternal body weight gain at 1500 during the exposure period only and at 3000ppm from initiation of exposure to GD20. At Caesarean section on GD20, no adverse effects on implantation, number and viability of fetuses, or fetal sex distribution were observed. Litter weight and mean fetal weight was reduced at 3000ppm and mean fetal weight was reduced at 1500ppm. Instances of reduced or unossified skeletal elements occurred at the same dose levels. Mean fetal weight was also reduced at 250ppm but not at 750ppm. Extensive statistical analysis of fetal body weight data support the conclusion that there is no toxicologically significant dose-related effect on fetal body weight at or below 750ppm. Low incidences (

The present study was undertaken to evaluate the toxicity of diphenyl ditelluride [(PhTe)(2)] exposure on the progeny of Wistar male rats. Male rats were exposed to (PhTe)(2) subcutaneously for 4 weeks (wk) at the dose of 0.006 mg/kg and 8-wk at the dose of 0.003 mg/kg, prior to mating with unexposed females. The body and sex organ weights of male rats were not affected in both 4- and 8-wk (PhTe)(2)-exposed groups. The gravid uterus weight and the body weight gain (overall or corrected) during the pregnancy were not statistically different to those obtained from females mated with control males. The number of implantation sites, resorptions and live and dead fetuses were not affected by male exposure to (PhTe)(2). Fetal body weight and crown-rump length were not affected, as well. Examination of the fetuses from both exposed groups for external and skeletal changes did not reveal any male-mediated effect of (PhTe)(2). The current study indicated that (PhTe)(2) given sub-chronically (4- or 8-wk) to male rats had no adverse effects on their progeny.

The purpose of this study was to determine whether letrozole, a potent aromatase inhibitor, could prolong gestation and/or delay parturition in rats. Seventy-five rats were divided into five groups of 15 rats each. Group I and group II rats were administered letrozole orally at doses of 0.002 and 0.02 mg/kg/day from days 15 through 21 of pregnancy, respectively. Rats in group IA were administered a concomitant estradiol cyclopentylpropionate (ECP) injection on day 15 and 0.002 mg/kg letrozole in that same manner as for group I. Rats in group IIA were administered concomitant ECP on day 15 and 0.02 mg/kg letrozole in the same manner as for group II. The control group received sterile saline only. Study and control groups were compared with respect to gestational length, parturition time, fetal mortality rate, stillbirth rate, and fetal body weight. Oral administration of letrozole both at daily doses of 0.002 mg/kg/day (group I) and 0.02 mg/kg/day (group II) consistently prolonged gestation and parturition time. The values of stillbirth rate, fetal mortality rate, and fetal body weight of group I were similar to those in the control group; conversely, fetal mortality rate and stillbirth rate of group II were higher than those values in the control group, and fetal body weight of group II was lower than in the control group. It was observed that concomitant injection of ECP effectively reversed the deleterious effects of letrozole on gestational length, parturition time, fetal mortality rate, stillbirth rate, and fetal body weight. The results of this study indicate that the aromatase inhibitor letrozole can prolong gestation and delays parturition in rats. Its deleterious effects on parturition can be reversed by ECP injection.

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 Cmax and AUC0–24 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. Birth Defects Res (Part B), 2007. © 2007 Wiley-Liss, Inc.

In view of the increased use of anilofos for crop protection and ever increasing arsenic levels in drinking water in many countries, the coexistence of arsenic and anilofos in the environment is a reality and simultaneous exposure of humans and animals to these contaminants could be potentially hazardous. The aim of the present study was to examine whether coexposure to arsenic at the groundwater contamination level could alter the embryofetal toxicity of anilofos in rat model. Anilofos (100 mg kg(-1) day(-1)) and sodium arsenite (1 mg arsenic kg(-1) day(-1)) were administered by gavage either individually or in combination to the pregnant rats from day 6 to day 15 of gestation. Arsenic did not produce any significant effects either on maternal or fetal parameters at the given dose. Anilofos alone significantly decreased maternal weight gain, feed and water intakes, gravid uterine weights, number of live fetuses and fetal body weights and increased resorptions. There were increased incidences of gross, skeletal and visceral anomalies in the fetuses of anilofos-treated group. The main skeletal abnormality was increased intercostal space, while the visceral anomaly was an interventricular septal defect. Treatment with the combination of arsenic and anilofos significantly enhanced the fetal changes with much greater magnitude compared with the effects produced by anilofos alone. Anomalies such as midfacial cleft, exencephaly and anophthalmia were seen only in the fetuses of the combination group. The results show that anilofos interferes with embryofetal development and coexposure with arsenic at environmentally realistic concentrations produces additive or synergistic effects on the developmental toxicity of anilofos in rats.

Dibutyltin dichloride (DBTCl) has been shown to be teratogenic in rats. The present study was conducted to determine the teratogenic potential of DBTCl given to pregnant monkeys during the entire period of organogenesis. Cynomolgus monkeys were dosed once daily by nasogastric intubation with DBTCl at 0, 2.5 or 3.8 mg/kg on days 20–50 of pregnancy, the whole period of organogenesis. The pregnancy outcome was determined on day 100 of pregnancy. In both DBTCl-treated groups, a significant increase in the incidence of pregnant females with soft stool and/or diarrhea, and with yellowish stool was observed. Maternal body weight gain at 3.8 mg/kg and food consumption at 2.5 and 3.8 mg/kg were decreased during the administration period. The survival rate of fetuses at terminal cesarean sectioning was decreased in the DBTCl-treated groups and significantly decreased at 2.5 mg/kg. There were no changes in the developmental parameters of surviving fetuses, including fetal body weight, crown-rump length, tail length, sex ratio, anogenital distance and placental weight, in the DBTCl-treated groups. No external, internal or skeletal malformations were found in the fetuses in any group. Although internal and skeletal variations were found, no difference in the incidence of fetal variation was noted between the control and DBTCl-treated groups. No effect on skeletal ossification was observed in fetuses in the DBTCl-treated groups. The data demonstrate that DBTCl is embryolethal but not teratogenic in cynomolgus monkeys.

The present study was conducted to evaluate the toxicity of diphenyl diselenide [(PhSe)2] exposure on the progeny of Wistar male rats. Male rats were exposed to (PhSe)2 subcutaneously for 4 weeks at the dose of 5.0 mg/kg and 8 weeks at the dose of 2.5 mg/kg, prior to mating with unexposed females. No lethality was noted in any group. At term of exposure period, 4-week exposed male rats presented significant decrease in the body weight. Sex organ weights were similar in (PhSe)2-exposed and control male groups. The number of implantation sites in females mated with males exposed to (PhSe)2 for 8 weeks was significantly higher than those of the respective control group. Male exposure to (PhSe)2, administered for 4 and 8 weeks, did not change fetal body weight. Gross examination of fetuses from 4- to 8-week exposed groups did not reveal the appearance of external anomalies. Examination of live fetuses for ossification centers did not show significantly difference between groups. No increase in the incidence of skeletal anomalies was observed in fetuses obtained from females impregnated with (PhSe)2-exposed males. The current study indicated that (PhSe)2 given sub-chronically (4 or 8 weeks) to male rats had no adverse effects on their progeny.

RESUMOO objetivo deste trabalho foi avaliar possíveis efeitos do extrato das vargens de bordão-de-velho (Samanea tubulosa benth) sobre a reprodução em ratas Wistar. O extrato foi preparado a partir da secagem e trituração das vagens, seguida por maceração com etanol e, posteriormente, concentrado em rotavapor. Ratas Wistar gestantes foram tratadas com 75 mg.100 g-1 de peso corporal de extrato de S. tubulosa e o grupo controle recebeu 1ml/100 g-1 de peso corporal de solução salina por gavagem durante 19 dias. Após eutanásia no 20º dia, as seguintes variáveis foram analisadas: peso corporal fetal, peso dos fetos e placentas, número de corpos lúteos e de reabsorções, implantação, fetos vivos e mortos. O extrato de vagens de S. tubulosa apresenta toxicidade para o feto causando malformações, reabsorções fetais e diminuição pronunciada do peso ao nascer. Contudo, o extrato de vagens de S. tubulosanão influencia no número de corpos lúteos e número de implantações. ABSTRACTThe aim of this study was to evaluate possible effects of pods from bordão-de-velho (Samanea tubulosa benth) extract on the reproduction of female rats.The extract was prepared by maceration wtith ethanol of dried and crushed pods, then it was concentrated in rotary evaporator. The pregnant Wistar rats were treated with a dose of 75 mg.100 g-1of body weight of Samanea tubulosa extract, by gavage , whereas the control group received 1ml.100g-1of saline by the same route for 19 days. After the euthanasia of the animals at day 20th,the following variables were analyzed: fetal body weight, weight of fetuses and placentas, number of corpora lutea, resorption points, live and dead fetuses and number of embryonic implantations. The extract from S. tubulosa pods, at the dose studied, showed toxicity causing fetal abnormalities, fetal resorption and pronounced decrease in the weight of offspring at birth. On the other hand, , the treatment with extract of S.tubulosa pods had no influence over corpora lutea and implantation numbers.

Objective To evaluate the effects of Ramadan fasting on fetal development and outcomes of pregnancy. Methods We performed this study in Antakya State Hospital of Obstetrics and Child Care, between 28 June 2014 and 27 July 2014 (during the month of Ramadan). A total of two hundred forty healthy pregnant women who were fasting during Ramadan, were included in the groups. The three groups were divided according to the trimesters. The each group was consisted of 40 healthy pregnant women with fasting and 40 healthy pregnant women without fasting. For evaluating the effects of Ramadan on fetus, ultrasonography was performed on all pregnant women in the beginning and the end of Ramadan. We used the essential parameters for the following measurements: increase of fetal biparietal diameter (BPD), increase of fetal femur length (FL), increase of estimated fetal body weight (EFBW), fetal biophysical profile (BPP), amniotic fluid index (AFI), and umbilical artery systole/diastole (S/D) ratio. Results No significant difference was found between the two groups for the fetal age, maternal weight gain (kilogram), estimated fetal weight gain (EFWG), fetal BPP, AFI, and umbilical artery S/D ratio. On the other hand, a statistically significant increase was observed in maternal weight in the second and third trimesters and a significant increase was observed in the amniotic fluid index in second trimester. Conclusion In Ramadan there was no bad fetal outcome between pregnant women with fasting and pregnant women without fasting. Pregnant women who want to be with fast, should be examined by doctors, adequately get breakfast before starting to fast and after the fasting take essential calori and hydration. More comprehensive randomized studies are needed to explain the effects of fasting on the pregnancy and fetal outcomes.

Objectives The objective of the present study is to investigate the mechanism of perfluorooctane sulfonate-induced low body weight of fetus by analysis of glucocorticoid metabolizing enzyme 11β-hydroxysteroid dehydrogenase 2 and gene expression profiling of the placenta after in utero PFOS exposure. Study design Pregnant Sprague–Dawley dams were gavaged with 0, 5, and 20 mg/kg body weight PFOS daily from gestational day 12–18. On gestational day 18, pregnant dams were euthanized, placentas, and fetuses were collected. Main outcome measures Body weights of fetuses and placentas were measured, the corticosterone levels in fetal serum, and 11β-hydroxysteroid dehydrogenase 2 as well as the placental gene profiling were analyzed. Results 20 mg/kg PFOS significantly reduced fetal body weight and placental weight. Both 5 and 20 mg/kg PFOS increased fetal serum corticosterone levels. PFOS potently inhibited placental 11β-hydroxysteroid dehydrogenase 2 activity. Of 21,910 genes, 45 genes were significantly downregulated ≥2 fold by 20 mg/kg PFOS, including extracellular matrix ( Slpi and Pi16 ), growth factors and hormones ( Trh and Pdf ), ion transporters ( Aqp1 , S100a4 , and Abp1 ), signal transducers ( Kap and Ampd3 ), and structural constituents ( A2m and Des ). Conclusions PFOS exposure may alter placental development and function, causing intrauterine growth restriction via inhibiting placental 11β-hydroxysteroid dehydrogenase 2.

Unlike other visceral organs, myocardial weight is maintained in relation to fetal body weight in intrauterine growth restriction (IUGR) fetal sheep despite hypoinsulinemia and global nutrient restriction. We designed experiments in fetal sheep with placental insufficiency and restricted growth to determine basal and insulin-stimulated myocardial glucose and oxygen metabolism and test the hypothesis that myocardial insulin sensitivity would be increased in the IUGR heart. IUGR was induced by maternal hyperthermia during gestation. Control (C) and IUGR fetal myocardial metabolism were measured at baseline and under acute hyperinsulinemic/euglycemic clamp conditions at 128–132 days gestation using fluorescent microspheres to determine myocardial blood flow. Fetal body and heart weights were reduced by 33% ( P = 0.008) and 30% ( P = 0.027), respectively. Heart weight to body weight ratios were not different. Basal left ventricular (LV) myocardial blood flow per gram of LV tissue was maintained in IUGR fetuses compared to controls. Insulin increased LV myocardial blood flow by ∼38% ( P 2 = 0.71) in both control and IUGR animals. Basal LV myocardial glucose delivery and uptake rates were not different between IUGR and control fetuses. Insulin increased LV myocardial glucose delivery (by 40%) and uptake (by 78%) ( P

This chapter presents the wildlife toxicity assessment for nitroguanidine (NQ), a stable explosive compound used as a propellant in cartridges. This wildlife toxicity assessment addresses only toxicity to mammals, as data for amphibians, reptiles, and birds were lacking. Acute, chronic, and reproductive studies represented three mammalian species (rats, mice, and rabbits) in two orders, and showed limited toxicity of NQ to mammals. Water consumption was the most consistent effect. At high doses (1,000 mg/kg/day) other affects included death, reduced body weight gain, and reduced food consumption, which were attributed to decreased palatability and interference with digestion at 1,000 mg/kg/day. In developmental/reproduction studies, reduced fetal body weight and increased incidence of minor developmental alterations were noted. Thus, in mammals, the no and low observed adverse effect levels (NOAEL and LOAEL) for NQ were estimated to be 316 mg/kg/day and 1,000 mg/kg/day, respectively.

Thiodiglycol (TDG) is used commercially as a solvent in antifreeze solutions, dyestuffs for printing, and as part of the process by which polyvinyl chloride is manufactured. It is also either a starting material or a precursor in the production of the chemical warfare agent sulfur mustard. TDG toxicity data for birds, amphibians, and reptiles were lacking. For mammals, acute, subacute, and subchronic studies were available representing two species in two orders. Adverse effects of TDG include reduced body weight, as well as increased kidney weight, increased urine output, and decreased urine pH, which may indicate functional deficits in the kidney. Reproductive and developmental effects were observed in one species representing one order and include decreased maternal and fetal body weight and decreased maternal food consumption. No and low observed adverse effect levels (NOAEL and LOAEL) of TDG for mammals of 129 mg/kg/day and 387 mg/kg/day respectively, were developed. The sole inhalation study suggests exposures of 5.4 mg/L TDG or less are not likely toxic. Dermal studies gave sufficient data for TRV development resulting in a NOAEL of 118 mg/kg and a LOAEL of 1,180 mg/kg.

Phenol is a petroleum-derived chemical used to produce compounds like phenolic resin polymer for military composite armor manufacture. Studies were available representing four mammalian species in two orders. Phenol displays generalized and nonspecific target organ toxicity. Two species (one order) had confirmed reproductive/developmental effects that ranged from reduced maternal and fetal body weight to reduced fetal survival. No and low observed adverse effect levels (NOAEL and LOAEL) of phenol in mammals of 12 and 36 mg/kg/day, respectively, were developed. One inhalation and two dermal studies were available, but were insufficient for Toxicity Reference Value (TRV) development. In amphibians (eight species, two orders), observed effects included growth retardation, edema, and intestinal and ocular malformations. No and low observed adverse effect concentrations (NOAEC and LOAEC) of 0.001 and 0.005 mg/L, respectively, were developed. Phenol toxicity data to develop TRVs for birds and reptiles were lacking.

This study investigated the potential adverse effects of amitraz on the initiation and maintenance of pregnancy in Sprague-Dawley rats as well as its effects on embryo-fetal development after maternal exposure during the entire pregnancy period. Amitraz was administered to pregnant rats by gavage from days 1 to 19 of gestation at dose levels of 0, 3, 10, and 30 mg/kg/day. All dams underwent a caesarean section on day 20 of gestation and their fetuses were examined for any external, visceral, and skeletal abnormalities. At 30 mg/kg, maternal toxicity manifested as an increase in the incidence of abnormal clinical signs and a lower body weight gain and food intake. Developmental toxicity included an increase in the fetal death rate, a decrease in the litter size, and a reduction in the fetal body weight. In addition, there was an increase in the incidence of fetal external, visceral, and skeletal abnormalities. At 10 mg/kg, maternal toxicity observed included a decrease in the body weight gain and a decrease in food intake. In addition, minimal developmental toxicity, including a decrease in the fetal body weight, an increase in the visceral and skeletal aberrations, and a delay in fetal ossification. There were no signs of either maternal toxicity or developmental toxicity at 3 mg/kg. These results show that amitraz administered during the entire pregnancy period in rats is embryotoxic and teratogenic at the maternally toxic dose (i.e., 30 mg/kg/day) and is minimally embryotoxic at a minimally maternally toxic dose (i.e., 10 mg/kg/day). Under these experimental conditions, the no-observed-adverse-effect level of amitraz for both dams and embryo-fetal development is estimated to be 3 mg/kg/day.

Deoxynivalenol (DON, vomitoxin), is one of the most common contaminants of cereal grains world-wide. The effects of DON on fetal development were assessed in Charles River Sprague–Dawley rats. Pregnant female rats were gavaged once daily with DON at doses of 0, 0.5, 1, 2.5, or 5 mg/kg body weight on gestation days (GD) 6–19. At cesarean section on GD 20, reproductive and developmental parameters were measured. All females survived to cesarean section. DON caused a dose-related increase in excessive salivation by the pregnant females, a reaction probably linked to the lack of emetic reflex in rats. At 5 mg/kg, feed consumption and mean body weight gain were significantly decreased throughout gestation, mean weight gain (carcass weight), and gravid uterine weight were significantly reduced, 52% of litters (12/23) were totally resorbed, the average number of early and late deaths per litter was significantly increased, average fetal body weight and crown-rump length were significantly decreased, the incidence of runts was significantly increased, and the ossification of fetal sternebrae, centra, dorsal arches, vertebrae, metatarsals, and metacarpals was significantly decreased. At 2.5 mg/kg, DON significantly decreased average fetal body weight, crown-rump length, and vertebral ossification. These effects may be secondary to maternal toxicity and the reduced size of the fetuses. The incidence of misaligned and fused sternebrae was significantly increased at 5.0 mg/kg. No adverse developmental effects were observed at 0.5 and 1.0 mg/kg. Dose-related increases in maternal liver weight-to-body weight ratios were observed in all treated groups (significant at 1, 2.5, and 5 mg/kg). The weight changes were correlated with dose-related cytoplasmic alterations of hepatocytes. The NOEL for maternal toxicity for this study is 0.5 mg/kg based on the dose-related increase in liver-body weight ratio at 1 mg/kg. The NOEL for fetal toxicity is 1 mg/kg based on the general reduction in fetal development at 2.5 and 5 mg/kg. DON is considered a teratogen at 5 mg/kg day in Sprague–Dawley rats based on the anomalous development of the sternebrae.

In humans, the occurrence of prenatal exposure to ethanol is difficult to validate objectively. Increased concentration of fatty acid ethyl esters (FAEE) in the meconium of the newborn may be a biomarker of prenatal ethanol exposure. The validity of this proposed biomarker was tested in pregnant guinea pigs that received chronic oral administration of 4 g ethanol/kg maternal body weight/day (n=8), isocaloric-sucrose/pair-feeding (n=8) or water (n=2) throughout gestation. At gestational day 65 (term, gestational day 66 to 69), each dam and her offspring were euthanized, and meconium was collected from the term fetal large intestine. Eight individual FAEE (lauric, myristic, palmitic, palmitoleic, stearic, oleic, linolenic and arachidonic AEE) were measured by gas chromatography--flame ionization detection and confirmed by gas chromatography--mass spectrometry. The chronic maternal ethanol regimen decreased fetal body weight and brain weight. There was virtually no measurable FAEE in the meconium for the water group (n=3 fetuses). For meconium of the ethanol offspring (n=25 fetuses) compared with the sucrose offspring (n=23 fetuses), the total FAEE concentration was 8-fold higher; and lauric, palmitic, stearic and oleic AEE concentrations were at least 5-fold higher for the ethanol group. The data indicate that fetal meconium FAEE constitute a biomarker of prenatal ethanol exposure for a maternal ethanol regimen that restricts fetal development, with an inverse relationship between meconium total FAEE concentration and both body weight and brain weight.

Previous studies in rodents and sheep show that maternal nutrient restriction during pregnancy alters fetal renal development. To date, no studies using fetal baboon RNA with human Affymetrix gene chips have been published. In the present study we have (1) evaluated the specificity of the Affymetrix human gene array ‘Laboratory on a Chip’ system for use with fetal baboon mRNA and (2) investigated the effects of moderate maternal global nutrient restriction (NR; 70% of ad libitum animals) from early (30 days gestation (dG)) to mid-gestation (90 dG; term = 184 dG) on the fetal baboon kidney. Morphometric and blood measurements were made on 12 non-pregnant baboons before they were bred. All baboons were fed ad libitum until 30 days pregnant, at which time six control baboons continued to feed ad libitum (control – C) while six received 70% of the C diet on a weight adjusted basis. Fetal kidneys were collected following caesarean section at 90 dG, with samples flash frozen and fixed for histological assessment. Fetal hip circumference was decreased in the NR group (68 ± 2 versus 75 ± 2 mm), while fetal body weight and all other measurements of fetal size were not different between C and NR at 90 dG. Maternal body weight was decreased in the NR group (12.16 ± 0.34 versus 13.73 ± 0.55 kg). Having established the specificity of the Affymetrix system for fetal baboon mRNA, gene expression profiling of fetal kidneys in the context of our maternal nutrient restriction protocol shows that NR resulted in a down-regulation of genes in pathways related to RNA, DNA and protein biosynthesis, metabolism and catabolism. In contrast, genes in cell signal transduction, communication and transport pathways were up-regulated in the NR group. These changes indicate that even a moderate level of maternal global NR impacts fetal renal gene pathways. Our histological assessment of renal structure indicates decreased tubule density within the cortex of NR kidneys compared with controls. The number of glomerular cross-sections per unit area were unaffected by NR, suggesting that tubule tortuosity and/or tubule length was decreased in the NR kidney. Taken together the changes indicate that NR results in accelerated fetal renal differentiation. The negative impact of poor maternal nutrition on the fetal kidney may therefore be in part due to shortening of critical phases of renal growth resulting in decreased functional capacity in later life. These findings may have important implications for postnatal renal function, thereby contributing to the observed increased predisposition to hypertension and renal disease in the offspring of nutrient restricted mothers.

Background/Purpose The goal in the treatment of gastroschisis is to prevent intestinal injury. Corticosteroids are known by their effects at the inflammatory response and by the improvement on the intestinal maturity. The authors evaluated the effects of maternal corticosteroid administration on the intestines of rats that underwent fetal gastroschisis. Methods A Correia-Pinto–modified gastroschisis rat model was used. Two groups were assessed: the control group (group 1) and the dexamethasone group (group 2). Each group was composed of control and sham fetuses, and fetuses with gastroschisis. Fetal body weight, intestinal weight, intestinal length, and protein were assessed. Histologic analysis involved measures of intestinal loop diameter, total intestinal wall, mucosa and submucosa, both circular and longitudinal muscle layers, and serosal thicknesses. Differences between groups and subgroups were tested by the analysis of variance method with a significant P value less than .05. Results Dexamethasone decreased in all the morphometric data except in the intestinal length. Dexamethasone increased the intestinal protein content in fetuses with gastroschisis, and control and sham fetuses. In both groups, all histologic parameters were increased in fetuses with gastroschisis ( P Conclusions Dexamethasone caused a substantial decrease in intestinal weight in GFs, increased the intestinal protein content, and it may be useful in decreasing the intestinal damage of gastroschisis.

BACKGROUND: In pregnant women, antiretroviral drugs improve maternal health and reduce vertical transmission of human immunodeficiency virus to the infant. However, few nonclinical studies have examined the potential for adverse drug interactions. METHODS: On gestational days (GD) 6–16, mice were dosed with vehicle, ddI (360, 1440, or 2880 mg/kg/day, p.o.), d4T (60, 240, or 480), or ddI/d4T combinations (360/60, 1440/240, or 2880/480). Daily doses were divided into two equal parts that were administered ≥6-hr apart. Body weight, clinical signs, and feed consumption were monitored. Pregnancies (22–24/group) were confirmed at necropsy. Maternal liver and gravid uterine weights (GUW), uterine implants (resorption, live or dead fetus), fetal body weight, gender, and morphologic anomalies (external, visceral, skeletal) were recorded. RESULTS: Maternal body weight, clinical signs, and GUW were unaffected. Maternal weight change corrected for GUW was greater than controls at 60 and 480 d4T. Relative feed consumption during treatment was increased relative to controls at 1440 and 2880 ddI and 2880/480 ddI/d4T. Relative maternal liver weight was elevated above controls at 240 and 480 d4T and 2880/480 ddI/d4T, and above the constituent dose of ddI at 1440/240 and 2880/480 ddI/d4T. Liver weight was not affected by ddI and there was no significant drug interaction. Prenatal mortality and morphologic anomalies were not increased. Fetal body weight showed only a decreasing trend for ddI/d4T, no effect for ddI or d4T, and no statistically significant drug interaction. CONCLUSIONS: In pregnant mice, ddI/d4T combinations were not associated with well-defined developmental toxicity or adverse drug interactions. Birth Defects Research (Part B) 77:207–215, 2006. © 2006 Wiley-Liss, Inc.

The aim was to determine experimentally the factors that increase the risk of venous occlusion by applying a standardised tightening force to isolated perfused umbilical cords tied in a true knot in vitro. Umbilical cords were collected from patients undergoing Caesarean section. Cords were clamped, isolated and studied within 15 min. The umbilical vein was cannulated, the cord tied in a true knot and traction was applied using standard weights. The umbilical vein was perfused with modified Krebs solution at a constant pressure of 40 mmHg and the attached weight increased until perfusion ceased. The cord mass index (weight/length), hydration index/100[(dry weight/wet weight)!100], and coiling index (coils/length) were determined. Cord morphometric analysis was performed on 193 cords. Intra uterine growth restriction was associated with decreased cord mass index (p Z 0.002) and increased coiling index (p Z 0.002). Venous perfusion experiments were performed on 75 cords. Using multivariate regression analysis, cord morphometric factors that increased the risk of cord occlusion were decreased cord mass index (p Z 0.008), decreased cord hydration index (p Z 0.004), and low venous flow capacity (p Z 0.001). During experimental cord knotting with applied traction, the susceptibility to venous occlusion was increased with low cord mass index, low cord hydration index and low venous flow capacity. These cord characteristics were associated with low fetal body weight and intrauterine growth restriction. An increased susceptibility to cord occlusion may contribute to the higher perinatal morbidity and mortality in growth restricted pregnancies. Placenta (2005), 26, 753e757

Prenatal exposure to 100 mg/kg atrazine (ATR) delays mammary gland (MG) development in resulting female offspring of Long-Evans rats. To determine if the fetal MG was sensitive to ATR effects during specific periods of development, timed-pregnant dams (n = 8/group/block) were dosed for 3- or 7-gestation day (GD) intervals (GD 13-15, 15-17, 17-19, or 13-19) with 100 mg ATR/kg/day or vehicle (C), and their offspring were evaluated for changes. Mammary glands taken from pups prenatally exposed to ATR displayed significant delays in epithelial development as early as postnatal day (PND) 4 compared to C, with continued developmental delays at later time points that varied by time of exposure. However, the most persistent and severe delays were seen in the GD 17-19 and GD 13-19 ATR exposure groups, demonstrating statistically similar growth retardation. Because MG developmental deficits persisted into adulthood, we hypothesized that ATR-exposed animals may have had difficulties nursing their young. Females exposed prenatally to either ATR (as defined) or C (n = 4 litters/group) were bred, and the resulting F 2 offspring from GD 17-19 and GD 13-19 exposure groups were significantly smaller in body weight (BW) than C. In a separate study, it was determined that ATR (25-100 mg/kg), delivered from GD 15-19, did not decrease fetal body weights on GD 20, even though the higher doses significantly decreased weight gain of the dosed dams. These data suggest that the consequences of brief ATR exposure during a critical period of fetal MG development (GD 17-19), are both delayed MG development of the offspring and inadequate nutritional support of F 2 offspring, resulting in adverse effects on pup weight gain.

We investigated the relationship between fetal body weight at term (pregnancy day 21) and the extent of ossification of sternum, metacarpus, metatarsus, phalanges (proximal, medial and distal) of fore- and hindlimbs and cervical and coccygeal vertebrae in Wistar rats. The relationships between fetal body weight and sex, intrauterine position, uterine horn, horn size, and litter size were determined using historical control data (7594 fetuses; 769 litters) of untreated rats. Relationships between body weight and degree of ossification were examined in a subset of 1484 historical control fetuses (154 litters) which were subsequently cleared and stained with alizarin red S. Fetal weight was independent of horn size, uterine horn side (left or right) or intrauterine position. Males were heavier than females and fetal weight decreased with increasing litter size. Evaluation of the skeleton showed that ossification of sternum, metacarpus and metatarsus was extensively complete and independent of fetal weight on pregnancy day 21. In contrast, the extent of ossification of fore- and hindlimb phalanges and of cervical and sacrococcygeal vertebrae was dependent on fetal body weight. The strongest correlation between body weight and degree of ossification was found for hindlimb, medial and proximal phalanges. Our data therefore suggest that, in full-term rat fetuses (day 21), reduced ossification of sternum, metacarpus and metatarsus results from a localized impairment of bone calcification (i.e., a malformation or variation) rather than from general growth retardation and that ossification of hindlimb (medial and proximal) phalanges is a good indicator of treatment-induced fetal growth retardation.

To clarify the characteristics of the radioadaptive response in mice, we compared the incidence of radiation-induced malformations in ICR mice. Pregnant ICR mice were exposed to a priming dose of 2 cGy (667 muGy/min) on day 9.5 of gestation and to a challenging dose of 2 Gy (1.04 Gy/min) 4 h later and were killed on day 18.5 of gestation. The incidence of malformations and prenatal death and fetal body weights were studied. The incidence of external malformations was significantly lower (by approximately 10%) in the primed (2 cGy + 2 Gy) mice compared to the unprimed (2 Gy alone) mice. However, there were no differences in the incidence of prenatal death or the skeletal malformations or the body weights between primed and unprimed mice. These results suggest that primary conditioning with low doses of radiation suppresses radiation-induced teratogenesis.

Dimethylcyclosiloxanes (DMCS) are components of silicone gel containing implants and are known inducers of human drug metabolizing enzymes. The effects of the major DMCS, octamethyltetracyclosiloxane (D4) on cytochrome P450 (CYP) induction were examined in young adult, mature, and pregnant female Sprague-Dawley rats. Also, the ability of D4 administered to pregnant dams to affect CYP expression in fetal liver was examined. Female young, mature, and pregnant Sprague-Dawley rats were administered 0, 5, 20, and 100 mg/kg D4 daily by gavage for 8 days. Liver microsomal CYP (CYP2B, CYP3A, CYP1A) concentrations were evaluated by Western blots using specific antisera, and CYP activities were assayed using CYP selective assays. D4 treatment resulted in a significant induction of CYP2B and CYP3A isoforms. CYP induction was dose and age dependent. A comparison of the inducibility of CYP3A protein by D4 in rats from different age groups showed that the degree of increase was the highest in the pregnant rats at doses of 20 mg/kg D4 or higher. The mature rats had a lesser degree of responsiveness than did the young rats at the dose of 100 mg/ kg D4. Significant increases in CYP2B immunoreactive protein concentrations were observed in young and mature rats given D4 at doses >5 mg/kg and in pregnant rats at doses >20 mg/kg. Maximal CYP2B induction detected with blotting was more than 90-fold in mature rats; however, no significant changes were detected in CYP1A expression. There was a 20% increase of liver to body weight ratio in the mature rats treated with 100 mg/kg D4. D4 has different inductive properties in female rats of different ages and reproductive status. Also, D4 administered to the pregnant dam is capable of inducing CYP expression in fetal liver as well as decreasing fetal body weight. © 2005 Wiley Periodicals, Inc. J Biochem Mol Toxicol 19:129–138, 2005; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jbt.20059

BACKGROUND: Appropriate maternal nutrition and body weight gain during pregnancy is well established as a major factor in healthy prenatal development in humans. Given the role of nutrition and body weight gain in normal development, pharmaceuticals intended to reduce appetite and promote weight loss will generate developmental toxicity data that may be challenging to interpret. To aid with this, the effects of feed restriction, and subsequent reduction in maternal body weight gain, on embryo-fetal development was investigated in the rabbit. METHODS: Groups of 15 pregnant New Zealand White rabbits were offered 150 (control), 110, 75, 55, 35, and 15 g feed/day from gestation day (GD) 7–19. Cesarean sections were carried out on GD 29 and fetuses were examined for external, visceral, and skeletal development. RESULTS: Maternal body weights at the end of the feed restriction period (GD 20) were 0.97, 0.98, 0.93, 0.94, and 0.86 × control for the 110, 75, 55, 35, and 15 g feed/day groups, respectively. Only at 15 g feed/day was there a net maternal body weight loss (the GD 20 body weight was 0.93 × the GD 6 body weight) at the end of the feed restriction period. Six does aborted in the 15 g feed/day group; there were no other abortions associated with feed restriction. Fetal body weight was significantly reduced at 75, 55, 35, and 15 g feed/day (0.95, 0.90, 0.86, and 0.84 × control, respectively). There were no external or visceral malformations or variations, and no skeletal malformations associated with feed restriction. The incidence of fetuses with sternebrae 5 or 6 unossified was increased at feed levels ≤75 g/day. At a feed level of 35 g/day there was an increase in unossified metatarsals and metacarpals, and an increase in the number of fetuses with a reduced number of caudal vertebrae ossified. Although these findings were not increased at a feed level of 15 g/day, the lack of dose response was likely due to increased abortion and subsequent decrease in fetuses available for evaluation at 15 g feed/day. CONCLUSION: These data demonstrate that feed restriction to feed levels that produce substantial reductions in maternal body weight gain can result in developmental toxicity expressed by abortion, reduced fetal weight, and alterations in ossification. Abortion only occurred when feed was restricted to an amount that produced maternal body weight loss (15 g feed/day) whereas reduced fetal weight and increased incidence of fetuses with unossified sternebrae, metatarsals, metacarpals, or caudal vertebrae were noted at feed levels of ≤75 g/day. There were no fetal malformations associated with feed restriction. Birth Defects Res B 74:424–430, 2005. © 2005 Wiley-Liss, Inc.

Moxifloxacin (Avelox®) is a fluoroquinolone antibiotic with a broad spectrum of activity and bactericidal action. Moxifloxacin has in vitro activity against a wide range of Gram- positive and Gram-negative organisms. The safe use of moxifloxacin in human pregnancy has not been established. In order to evaluate the genotoxic and embryo toxic effects of (Avelox)® during pregnancy, Avelox was administrated orally to female mice with doses (8.7, 17 and 26 mg/kg/day) from 1 to 17 days of pregnancy. Caesarean sections were completed on gestation day 18 and complete fetal examinations and cytogenetic analysis were conducted. Decreases in the fetal body weights and increases in the external visceral and skeletal anomalies were found in all doses of (8.7, 17 and 26 mg) Avelox compared to the controls. Cytogenetic analysis in mothers and embryos revealed that all the tests doses produced chromosomal aberrations and micronuclei (MN) formations in a dose dependent manner compared to the controls. These results indicate that Avelox has a maternal and embryotoxic effects on the female mice and their embryos when administered with a recommended and above the recommended dose during pregnancy.

To determine the ratio of fetal lung volume (FLV) to fetal body weight (FBW) by using ultrasonography (US) and magnetic resonance (MR) imaging and to evaluate the usefulness of this ratio in predicting pulmonary hypoplasia (PH) in fetuses at high risk.MR imaging lung volumetry and US biometry were performed in 90 fetuses at 25-39 weeks gestation. In the control group of 73 fetuses, normal lung development was confirmed at neonatal follow-up and the normative ratio of MR imaging-measured FLV to US-estimated FBW (FLV/FBW) was determined. The high-risk group included 17 fetuses at risk for PH. The FLV/FBW was compared between the control and high-risk groups and with US parameters for predicting the development of PH in the high-risk group. Measurements 2 or more standard deviations below the mean control group measurement were considered abnormal. Comparisons of the FLV/FBW between groups were made by using the Student t test. The association between development of PH and measurement of each parameter was analyzed by using the Fisher exact probability test.In the control group, the FLV/FBW decreased with gestational age during the third trimester and had a normal distribution (mean ratio, 0.028 mL/g; range, 0.015-0.444 mL/g). The mean FLV/FBW for the nine fetuses with PH (0.012 mL/g +/- 0.008) was significantly lower (P.001) than that for the control group (0.028 mL/g +/- 0.007). Fetuses with abnormal FLV/FBW values were at significantly greater risk (P.05) for PH development. Abnormal FLV/FBW values had higher diagnostic accuracy than abnormal US parameters. Sensitivity of the FLV/FBW was 89% (eight of nine fetuses); specificity, 88% (seven of eight fetuses); positive predictive value, 89% (eight of nine fetuses); negative predictive value, 88% (seven of eight fetuses); and accuracy, 88% (15 of 17 fetuses).The FLV/FBW reflects the adequacy of intrauterine lung growth and can help predict PH.

The chronic inhibition of nitric oxide (NO) synthesis with Nomega-nitro-L-arginine methyl ester (L-NAME) induces a preeclampsia-like syndrome including hypertension and intrauterine growth retardation (IUGR) in pregnant rats. We tested the traditional herbal medicine Toki-shakuyaku-san (TS) for beneficial effects in this model. L-NAME was infused subcutaneously into pregnant rats from day 14 of gestation. TS (1 g/kg, 2 g/kg) was administered by gavage from day 14 to 20. Systolic blood pressure was measured on day 19. On day 20, rats were sacrificed and serum NO levels, placental weight, fetal body weight, fetal cerebrum weight and the thickness of the cerebral cortex were analyzed. TS (1 g/kg, 2 g/kg) inhibited L-NAME-induced hypertension. The decrease in fetal body weight, cerebrum weight and thickness of the cerebral cortex was abrogated by TS (2 g/kg). The effect of TS on blood pressure was found only in the rats that were both pregnant and infused with L-NAME. L-arginine, at the amount equivalent to that contained in TS, showed no effect. Further, the change in serum NO levels induced by TS was only marginal. TS thus improved the hypertension and IUGR in preeclampsia rats induced by L-NAME in a NO-independent manner. These data suggested that TS may be beneficial for the treatment and prevention of preeclampsia.

The potential for reproductive toxicity of an antisense oligonucleotide designed to inhibit ICAM-1 was evaluated as part of the safety assessment for this compound. Since antisense compounds are often specific to the species in which they are intended to work, both the human and murine active ICAM-1 inhibitors were tested (ISIS 2302 and ISIS 3082, respectively). Male and female mice were treated prior to cohabitation, through cohabitation, gestation, delivery, and weaning. Mice were treated with 0, 3, 6, and 12 mg/kg ISIS 2302 or ISIS 3082 by daily i.v. injection. Reproductive indices evaluated included estrus cycling, sperm count and motility, fertility, litter parameters, fetal development, delivery, fetal body weight, lactation, and weaning. Behavioral assessment and reproductive capacity of the F1 generation mice was assessed on selected animals. Concentrations of oligonucleotide in selected maternal target organs, placenta, fetal tissues, and expressed milk were also measured. There were no changes in reproductive performance, litter parameters, fetal development, or postnatal development in mice treated with either ISIS 2302 or ISIS 3082. Maternal liver and kidney contained dose-dependent concentrations of oligonucleotide, but there was relatively little or no oligonucleotide measured in placenta, fetal tissues, or expressed milk. Neither the human nor murine-specific antisense inhibitor of ICAM-1 produced any reproductive toxicity in mice, and exposure of fetus or pups was negligible. Birth Defects Res B 71:359–367, 2004. © 2004 Wiley-Liss, Inc.

We evaluated a 9-amino-acid peptide, SALLRSIPA (SAL), an agonist of activity-dependent neurotrophic factor (ADNF), for its protective properties against fetal alcohol-related brain growth retardation, using an established liquid diet model of alcohol-related neurodevelopmental disorder (ARND) in C57BL/6 mice. Alcohol exposure during neurulation reduced body weight, head size, and specifically brain weight and volume. Major gross brain deficits include underdevelopment of brain areas, cortical thinning, ventricle enlargement, and restricted midline neural tissue growth leading to openings at the roof/floor plate. SALLRSIPA (SAL) treatment increased fetal body weight and restored brain weight, brain volume, and regional brain size. Furthermore, SAL restored cortical thickness, reduced the size and frequency of neural tube openings, and attenuated ventricular enlargement. The ability of SAL to antagonize alcohol-retarded brain growth and development of forebrain and midline neural tube at midgestation suggests its potential use as an antagonist against fetal alcohol- rendered microencephaly early in development.

We have investigated the effects of a 5 day infusion of cortisol into fetal sheep, in which the hypothalamus and pituitary were surgically disconnected (HPD), on fetal pituitary-adrenal function. Fetal HPD and vascular catheterization were carried out at between 104 and 124 days gestation. Cortisol was administered (3.5 mg 24 h-1) for 120 h between 134 and 140 days (HPD + F group; n = 5) and saline was administered during the same gestational age range to HPD (HPD group; n = 12) and intact fetal sheep (Intact group; n = 6). Cortisol infusion into the HPD fetal sheep did not suppress the mRNA levels for Proopiomelanocortin (POMC) in the fetal anterior pituitary at 139/140 days gestation (POMC mRNA: 18S rRNA: Intact 0.40 +/- 0.05; HPD 0.56 +/- 0.07; HPD + F 0.49 +/- 0.07). Similarly, there was no significant effect of either HPD or cortisol infusion on the plasma concentrations of immunoreactive (ir) ACTH or ACTH(1-39). The adrenal: fetal body weight ratio was significantly higher, however, in the HPD + F (88.4 +/- 8.7 mg kg-1) and Intact groups (84.1 +/- 5.6 mg kg-1) when compared with the HPD fetal sheep (63.7 +/- 5.4 mg kg-1). The ratio of total IGF-II mRNA: 18S rRNA was similar in the adrenals of the Intact (0.48 +/- 0.09), HPD (0.78 +/- 0.09) and HPD + F (0.71 +/- 0.11) groups. The ratios of CYPIIA1, 3 beta-HSD and CYP21A1 mRNA: 18S rRNA were significantly lower in adrenals from the HPD group when compared to those in the Intact group and were not restored to normal by cortisol infusion. We have therefore demonstrated that cortisol does not act directly at the fetal pituitary to suppress POMC synthesis or ACTH secretion in late gestation. Cortisol does, however, stimulate fetal adrenal growth after HPD in the absence of any effects on adrenal IGF-II or steroidogenic enzyme mRNA levels. The data provide evidence that an intact hypothalamic-pituitary axis and cortisol each play an important role in the stimulation of adrenal growth and steroidogenesis which occurs during the last 10-15 days of gestation in the sheep.

The zidovudine derivative, 5-bromo-6-methoxy-5,6-dihydro-3-azidothymidine-5'-( p-bromophenyl) methoxy alaninyl phosphate (WHI-07), is a dual-function spermicidal and anti-HIV agent with contraceptive and microbicidal activity. In previous subchronic and reproductive toxicity studies and a two-year carcinogenicity study, daily intravaginal application of 0.5 to 2.0% WHI-07 via a gel-microemulsion, was shown to cause no local, systemic and reproductive toxicity or increased carcinogenicity in mice. To evaluate the developmental toxicity potential of WHI-07 in a nonrodent model, subgroups of 20 superovulated NZW rabbits were artificially inseminated and exposed intravaginally to a gel-microemulsion containing 0, 0.5, 1.0, or 2.0% WHI-07 during major organogenesis [gestation days 6—18]. The dose of WHI-07 was equivalent to 1 .4 × 106 to 5 .7 × 106 times its anti-HIV IC50 and 1400 to 5700 times its spermicidal EC50. Throughout the duration of the experiment (GD 0-29), clinical observations, food consumption, and body weights were recorded. Reproductive and fetal parameters were evaluated following uterotomies on GD 29. Measurements included numbers of corpora lutea, pregnancy, number and distribution of implantations, resorptions, live and dead fetuses, fetal weight, sex ratio, and gross external and skeletal malformations and variations. Maternal food consumption and body weight gain were unaffected by WHI-07 treatment. Hematologic and clinical chemistry determinations on GD 19 and 29 revealed no treatment-related maternal effects. Prior studies of repeated intravaginal administration of WHI-07 gel-microemulsion revealed lack of local toxicity to rabbit vaginal mucosa. In the current study, no drug-related gross lesions were apparent at necropsy. Reproductive indices, ie, pregnancy rate, gravid uterine weights, litter size, number of corpora lutea, implantation sites, pre- and postimplantation losses, viable fetuses, resorptions, fetal body weights, and fetal sex ratio, were not affected by intravaginal exposure to WHI-07. External, and skeletal examinations of fetuses for malformations and variations did not reveal any evidence of teratogenicity in any WHI-07-treated groups. Intravaginal administration of WHI-07 at concentrations as high as 2% did not produce teratogenicity or other developmental toxicity in rabbit conceptus. These findings indicated that WHI-07 shows unique clinical potential to become the active ingredient of a new female-controlled topical microbicidal vaginal contraceptive for women who are at high risk of acquiring HIV/AIDS.

The aim of this study was to evaluate the potential mutagenic effects of ginseng (herbal medicine) on maternally treated postimplanted mouse foetuses. A total of 60 adult albino female mice were used and divided into 6 groups (10 females each). The first group (I) served as a control group and received oral doses of the vehicle (0.5 ml disteled water ) for 60 days before pregnancy to 13th day of pregnancy. The rest 5 groups received orally 4mg/kg.bw of ginseng for 7, 14, 30, 45 and 60 days before day 0 of gestation and extended to 13th day of pregnancy. Then 6 females of each group were sacrificed, feotuses sample from each female were taken and subjected to cytogenetic analysis. The rest females of each group (4 females) were continuously treated and sacrificed at day 17 of getation, foetuses were examined morphologically and for different features such as implanation sites, living feotuses, resorbed foetuses and foetus body weight. Chromosome analysis of the present study (Table 1) revealed that there were numerical aberrations (peridiploidy). There was a difference only between group II and III in respect to hypodiploid (2n-), meanwhile, hyperdiploid (2n+) were more frequent in group IV and VI than that in control group (group I). For the total numerical aberrations, there were significant differences between groups II, VI compared to the control group. All groups had little frequencies of structural aberrations especially for chromatid gaps, breaks and fragments. There were a significant differences between group IV and VI compared with the control group for the deletions. Chromosome breaks were more frequent in the groups III and IV compared to the control group, whereas groups V, VI had more frequencies of centromeric attenuations than the control group. There were no differences between control group and the rest of all groups investigated for implantation sites, living foetuses and resorbed foetuses (Table 2), whereas for gross malformation, 5.41 % of group VI where abnormal and the rest of all groups had no malformations. For the mean fetal body weight, there was a significant difference among the control group (I) and the groups number II, III and VI. We conclude that treatment with ginseng as a herbal medicine may cause fetal chromosomal aberrations as well as gross malformation especially when taken for a long time and extended during pregnancy. So, we recommend that the use of ginseng during first trimester of pregnancy should be with caution.

To identify possible effects of horizontally polarized magnetic field (MF) exposure on maintenance of pregnancy and embryo-fetal development, an MF exposure system was designed and constructed and 96 time-mated female Sprague‐Dawley (SD) rats (24/group) received continuous exposure to 60 Hz MF at field strengths of 0 (sham control) and 5, 83.3, or 500 mT (50, 833, or 5000 mG). Dams receivedMForshamexposuresfor22h/dayongestationalday6‐20.MFwasmonitoredcontinuously throughout the study. There were no evidences of maternal toxicity or developmental toxicity in any MF exposed groups. Mean maternal body weight, organ weights, and hematological and serum biochemical parameters in groups exposed to MF did not differ from those in sham control. No exposure related differences in fetal deaths, fetal body weight, and placental weight were observed between MFexposedgroups and shamcontrol. External, visceral, and skeletal examination offetuses demonstrated no significant differences in the incidence of fetal malformations between MF exposed and sham control groups. In conclusion, exposure of pregnant rats to 60 Hz at MF strengths up to 500mTduringgestationday 6‐20didnotproduceanybiologicallysignificanteffect ineitherdamsor fetuses. Bioelectromagnetics 24:231‐240, 2003. � 2003 Wiley-Liss, Inc.