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Fetal circulation is unique and the parameters describing hemodynamic status during development are critical for constructing a fetal physiologically based pharmacokinetic model. To date, a comprehensive review of circulatory changes during fetal development, with a specific focus on developing these models, has not been reported. The objective of this work was to collate, analyze, and mathematically describe physiological information on fetal cardiac output and tissue blood flows during development. A comprehensive literature search was carried out to collate and evaluate the changes to fetal cardiac output and fetal tissue blood flows during growth. The collated data were assessed, integrated, and analyzed to establish continuous mathematical functions describing the average parameter changes and variability during development. Data were available for fetal cardiac output (14 Doppler studies), blood flow through the fetal umbilical vein (15 studies), ductus venosus (6 studies), liver veins (5 studies), brain (4 studies), lungs (5 studies), and kidneys (2 studies). Fetal cardiac output is described as either an age- or weight-dependent function. The latter is preferred as it generates an individualized cardiac output that is correlated to the fetal body weight. Blood flow as a proportion of fetal cardiac output to the liver, placenta, brain, kidneys, and lungs was age varying, whilst for the adipose, bone, heart, muscle, and skin the blood flow proportions were fixed. The pattern of change (with respect to direction and pace) for each of these parameters was different. Despite limitations in the availability of some values, the collected data provide a useful resource for fetal physiologically based pharmacokinetic modeling. Potential applications of these data include predicting xenobiotic exposure and risk assessment in the fetus following the administration of maternally dosed drugs or unintended exposure to environmental toxicants.

Circulatory changes during gestational development of the human fetus have been considered to be similar to those noted in studies of the lamb fetus. Blood flow measurements derived by Doppler ultrasound and magnetic resonance imaging techniques in human fetuses at various stages of gestation have been compared with those in the lamb. Combined ventricular output relative to fetal body weight does not change significantly with growth in the lamb or human. However, the proportion of cardiac output to the brain increases markedly in the human, but only slightly in the lamb fetus in the latter half of gestation. Cardiac output distribution to other organs also changes little in the lamb, but in the human, there is a marked decrease in the proportion distributed to the placenta and an increase in pulmonary flow. The developmental changes in the distribution of combined ventricular output in the human fetus may modify the responses to circulatory disturbances, such as congenital cardiovascular malformations, dependent on gestation.

Limited studies have reported the effect of prenatal alcohol exposure (PAE) on fetal liver development or liver dysfunction. The current review was conducted to systematically review published studies of PAE and liver dysfunction. Pub Med, Embase and Web of Science database were searched using terms of “prenatal alcohol exposure” and “liver” or “fetal alcohol spectrum disease” and “liver”. The pooled effect size of alcohol exposure was assessed by Hedges’s g and 95 % confidence interval (CI) using fixed model or random model depending on the heterogeneity determined by Q test and I 2 statistic. A total of 23 studies were included. The results indicated that gestation alcohol exposure resulted in significant reduction of fetal body weight (Hedges’s g = −6.854 ± 1.149, 95 % CI −9.106 to −4.602, P

Prenatal alcohol exposure is known to cause fetal growth restriction and disturbances in amino acid bioavailability. Alterations in these parameters can persist into adulthood and low birth weight can lead to altered fetal programming. Glutamine has been associated with the synthesis of other amino acids, an increase in protein synthesis and it is used clinically as a nutrient supplement for low birth weight infants. The aim of this study was to explore the effect of repeated maternal alcohol exposure and L-glutamine supplementation on fetal growth and amino acid bioavailability during the third trimester-equivalent period in an ovine model. Pregnant sheep were randomly assigned to four groups, saline control, alcohol (1.75-2.5 g/kg), glutamine (100 mg/kg, three times daily) or alcohol + glutamine. In this study, a weekend binge drinking model was followed where treatment was done 3 days per week in succession from gestational day (GD) 109-132 (normal term ~147). Maternal alcohol exposure significantly reduced fetal body weight, height, length, thoracic girth and brain weight, and resulted in decreased amino acid bioavailability in fetal plasma and placental fluids. Maternal glutamine supplementation successfully mitigated alcohol-induced fetal growth restriction and improved the bioavailability of glutamine and glutamine-related amino acids such as glycine, arginine, and asparagine in the fetal compartment. All together, these findings show that L-glutamine supplementation enhances amino acid availability in the fetus and prevents alcohol-induced fetal growth restriction.

Our preliminary studies demonstrated that Metacavir has potential to become a new anti-HBV agent. The main targets of the toxic effects of Metacavir, in rhesus monkeys, were gastrointestinal tracts, liver, blood, and kidneys, which were not related to mitochondrial effects. In this study, the maternal toxicity, embryo-fetal developmental toxicity and teratogenicity were studied in pregnant Sprague-Dawley rats after intragastric administration of Metacavir (200, 100, 50, 0 mg/kg body weight) during the first 6–15 days of pregnancy. Slower weight gain was observed in 5 out of 21 rats subjected to a 200 mg/kg dose, as well as 2 out of 20 subjected to a 100 mg/kg dose. Compared with the solvent control group, the calibration weight gain in the 200 mg/kg and 100 mg/kg dosage groups respectively, during first 6–20 pregnant days were significantly different (P < 0.01, P < 0.05). Significant dose related adverse effects to other reproductive parameters were not seen in F0 and F1, but the number of stillbirths in high dose group showed notably difference compared with the control group (P < 0.05), while the litter incidence showed no difference. No Metacavir-associated pathological changes were observed. The present research indicated that at a dose of 200 mg/(kg·d) (i.e., 40 times the effective dose in rats), Metacavir shows some maternal toxicity to SD rats. The embryotoxicity in the 200 mg/kg group encompass decreased fetal body weight, and higher fetal mortality rates, compared with the control group. However, the litter incidence showed no statistical difference. All the treated rats displayed normal bone development, no teratogenicity and without adverse effects on fetal development, thus indicating that below a dose of 200 mg/(kg·d) there is no teratogenic side effects.

Cadmium is a heavy metal and widespread environmental toxicant. This study investigated the effects of prenatal Cd exposure on fetal growth and limb development in rats. Pregnant rats were given 0, 4 or 8 mg/kg/day (equivalent to ≈ 0, 30 or 60 ppm) of cadmium as CdSO4 in their drinking water from conception to gestation day 20. Cd significantly (p

The present study’s purpose was to examine the size and location of the thyroid gland using anatomic dissection methods on fetal cadavers. This study was performed on 200 spontaneously aborted human fetuses (100 males and 100 females) aged between 9 and 40 weeks of gestation. Fetuses without any external and internal pathology or anomaly were included in this study. Fetuses were divided into four groups based on gestational ages as follows: first group 9–12 weeks (first trimester), second group 13–25 weeks (second trimester), third group 26–37 weeks (third trimester) and fourth group 38–40 weeks (full term). The fetuses were also grouped into monthly cohorts as follows: 9–12 weeks, 3rd month; 13–16 weeks, 4th month; 17–20 weeks, 5th month; 21–24 weeks, 6th month; 25–28 weeks, 7th month; 29–32 weeks, 8th month; 33–36 weeks, 9th month; and 37–40 weeks, 10th month. The anterior necks of fetuses were dissected and the thyroid glands exposed. Vertebral and laryngeal levels and the dimensions (width, length, thickness and weight) of the fetal thyroid glands were determined by anatomical dissection methods. The dimensions and ratios of the fetal thyroid gland (weight/fetal body weight) were evaluated. The mean values and standard deviations of all parameters by gestational weeks, months, and trimesters were calculated. It was found that all parameters increased with gestational age. No significant differences were observed between genders in all parameters (P > 0.05). There were no significant differences between the right and the left sides for parameters of the thyroid glands. The levels of the superior poles of the thyroid lobes were located at the cervical (C) C1–C3 vertebral bodies. The levels of the inferior poles of the thyroid lobes were located at C4–C5 vertebral bodies. The levels of the superior poles of thyroid lobes were located between the upper ½ and lower ½ of the thyroid cartilage or cricoid cartilage. The levels of the inferior poles of the thyroid lobes were located between the second and sixth tracheal rings. The distance between the superior poles of the thyroid gland and the hyoid bone increased throughout the fetal period. The dimensions of fetal thyroid glands increased with gestational age. The ratio between thyroid gland weights and fetal body weights was unchanged during the fetal period. We believe that the results obtained from this study will be useful in monitoring thyroid glands in the intrauterine period as well as recognizing early diagnosis and treatment of thyroid anomalies. It will also contribute to future studies in obstetrics, perinatology, and fetopathology.

Venlafaxine (VEN), a newer antidepressant of serotonin and noradrenaline reuptake inhibitor (SNRI) class, is commonly used worldwide for clinical management of various forms of depression even during pregnancy. The maternal and fetal safety of this drug has not been established well so far due to lack of metanalysis studies in clinical settings and controlled investigations in rodents as well as availability of contradictory information. Therefore, present study has been planned to investigate the maternal toxicity in relation to food intake and body weight gain; fetal toxicity as fetal weight at GD-19 and neonatal weight at birth; and postnatal development/growth in young-adult rat offspring. In this study selected doses of VEN (25, 40 and 50 mg/kg) were administered to pregnant rats from GD 5–21 through gavage. These doses were equivalent to human therapeutic dose range (75–375 mg/day). Maternal food intake and body weight gain were found substantially reduced due to drug induced hypophagia. The fetal body weight at GD-19 as well as neonatal birth weight of VEN exposed offspring was found significantly deficient which could not reach up to the control level till 8 weeks as compared to control. This study concludes that prenatal exposure of VEN not only induced maternal weight loss and food intake deficit but also induced long-lasting impact on fetal as well as neonatal development and growth in young-adult offspring. Further, cautions are required for weighing the risks and benefits to both fetus and pregnant mothers before recommendation of SNRIs in general and VEN in particular.

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.

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.

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.

A method for forecasting the dates of calving in the saiga population on the basis of average fetal body weight is proposed. The method is based on the relationship between the number of days before calving and the average weight of fetuses, which obviates the necessity of determining fetal age and exact gestation period in this species. The average length of gestation, the dates of the rut in the years studied, and the age of females that have mated immediately upon the onset of the rut and before its cessation have been determined. It is shown that the duration of mass calving depends on the proportion of mature males in the population.

The intestinal damage in gastroschisis (GS) has been attributed to a narrow abdominal wall defect (AWD), among other causes, but this causal effect is difficult to prove in humans. The present experimental study was done to ascertain the damaging effect of clinically extrapolable mild and moderate constriction at the AWD on the intestine of fetuses with GS. AWDs of two different sizes were carried out in the fetal rabbit model: small-ring GS (1.5x bowel diameter, SRG) and large-ring GS (3x bowel diameter, LRG); a group of unoperated littermates served as controls. Fetal body weight, intestinal length and weight, bowel diameter and wall thickness, and histology were checked 7 days later. No statistical difference was found in body weight and bowel diameter among the groups. Intestinal length, weight, and wall thickness were significantly different in the GS groups compared to the controls, but no difference was found between the GS groups. Histology did not show venous stasis, ischemic lesions, or differences in the degree of edema between groups SRG and LRG. Mesothelial hyperplasia was seen in both GS groups. The intestinal changes in length, weight, diameter, wall thickness, and histology in GS should thus not be attributed to the diameter of the AWD.

OBJECTIVE To test the hypothesis that chronic hypoxia upregulates cytochrome c expression in heart, brain, and liver of fetal and maternal rats. METHODS Time-dated pregnant Sprague-Dawley rats were divided into normoxic and hypoxic (48 hours of 10.5% oxygen from days 19 to 21) groups, and were killed on day 21. Tissue levels of cytochrome c in heart, brain, and liver were determined by using monoclonal antiserum for cytochrome c. RESULTS Chronic hypoxia caused a decrease in fetal body weight (5.3 +/- 0.1 to 4.7 +/- 0.1 g) and an increase in heart/body weight ratio (0.0048 +/- 0.0001 to 0.0061 +/- 0.0002). Cytochrome c levels were 4-, 2.6-, and 13-fold higher in heart, liver, and brain, respectively, of the mother than of the fetus. Chronic hypoxia did not change cytochrome c levels in maternal tissues but caused a 70% increase and 54% decrease in cytochrome c levels in the fetal heart and liver, respectively. No difference was observed in the fetal brain. CONCLUSIONS The results suggest that expression of cytochrome c is tissue specific and developmentally regulated. Chronic hypoxia showed differential regulation of cytochrome c levels both developmentally and tissue specifically. The increased sensitivity of cytochrome c in fetal tissue to chronic hypoxia is likely to represent a fetal adaptive mechanism to the stress of chronic hypoxia.

Obstruction of the fetal trachea is a potent stimulus for fetal lung growth and may have therapeutic potential in human fetuses with lung hypoplasia. However, the effects of increased lung expansion on lung development near midgestation, which is the preferred timing for fetal intervention, have not been well studied. Our aim was to determine the effects of increased lung expansion on lung development at 75-90 d of gestation in fetal sheep. In three groups of fetuses (n = 4 for each), the trachea was occluded for either 10 [10-d tracheal occlusion (TO) group] or 15 d (15-d TO group) or left intact (control fetuses). TO for both 10 and 15 d caused fetal hydrops, resulting in significantly increased fetal body weights. Both periods of TO significantly increased total lung DNA contents from 99.8 +/- 10.1 to 246.0 +/- 5.3 and 246.9 +/- 48.7 mg in 10- and 15-d TO fetuses, respectively. TO for 10 and 15 d also increased airspace diameter, although the percentage of lung occupied by airspace was not increased in 10-d TO fetuses due to large increases in interairway distances; this resulted from a large increase in mesenchymal tissue. The interairway distances at 15 d of TO were reduced compared with the 10-d value but were still approximately 30% larger than control values. We conclude that TO at

During human gestation, fetal body size increases considerably and important transformations occur to hemodynamics of the cardiovascular system of the fetus. Vascular compliances and resistances as well as the cardiac function show important changes. In order to investigate these modifications, a mathematical approach based on scaling techniques was developed. Vascular and cardiac parameters of the human fetus were related by allometric equations to the anatomical dimensions of vessels that, in turn, depend on the fetal body weight and the gestational age. A scaling factor (b) was identified for each parameter under study: vascular resistances and flow inertances decrease with gestational age b=--1 for viscous losses and b=--1.33 for convective dissipations, b=--0.33 for flow inertances) whereas vascular compliances remarkably increase (b=1.33). Scaling factors were also adopted for the fetal cardiac parameters, according to experimental data on the development of fetal myocardium. Parameter values calculated for each week of the last trimester of the fetal gestation, were tested using a mathematical lumped parameter model, previously developed for a human fetus near the term of the gestation. The validation of the scaling method adopted for the parameters was performed by comparing the results of the simulations with a group of data obtained by Doppler velocimetry at different stages of fetal normal gestation. The adopted allometric equations were appropriate in describing the development of the human fetal circulatory system. The ductus venosus, the ductus arteriosus, and the foramen ovale, that conclude their function at the birth moment, as well as the lungs and the brain, do not follow the general growth rate and require different scaling factors. © 2000 Biomedical Engineering Society. PAC00: 8719Uv, 8719Hh, 8710+e

The effects of multiple maternal subcutaneous injections of uranyl acetate dihydrate (0.5, 1, and 2 mg/kg/d) from d 6 to d 15 of gestation were evaluated in Swiss mice. External, internal soft-tissue and skeletal examinations of fetuses were performed on gestation d 18. Maternal toxicity occurred in all uranium-treated groups as evidenced primarily by deaths as well as significant decreases in weight gain and in body weight at termination. Although it was not dose-related, embryotoxicity also occurred in all uranium-treated groups (significant increases in the number of nonviable implantations and in the percentage of postimplantation loss). Fetal body weight was significantly decreased at 1 and 2 mg/kg/d, whereas the number of total internal and total skeletal defects showed dose-dependent increases at 0.5, 1, and 2 mg/kg/d. Most morphological defects were developmental variations, whereas malformations were only detected at 1 and 2 mg/kg/d. On the basis of these data, both the maternal no-observable-adverse-effect level (NOAEL) and the NOAEL for embryotoxicity of uranyl acetate dihydrate were below 0.5 mg/kg/d, whereas the NOAEL for teratogenicity was 0.5 mg/kg/d.

Maturation of the glucose reabsorptive process by the fetal kidney was studied in 9 chronic fetal lamb preparations (0.66 to 3.72 kg) and values compared to data obtained from 4 nonpregnant ewes. Blood and urine control values showed a close relationship between fetal glomerular filtration rate (GFR ml/min) and fetal body weight (r=0.78, p

Four types of reproductive toxicity evaluations exist. These significantly differ from all other toxicity studies. Studies are “driven” by the timing or occurrence of mating, pregnancy, abortion, natural delivery, litter size, and viability of offspring. Unique identification of at least two generations and parental historical data are required. Specialized randomization procedures must be used because mating performance determines selection of test animals. Simultaneous recording of multiple data, embryo-fetal-pup units and correlation of these data with parental data must occur. For example, C-sectioning observations must include adult necropsy observations and uterine weights as well as fetal body weights, crown-rump measurements, uterine placement, identification, viability, gender, and gross external anomalies. Correlations must include parental mortality, adverse clinical signs, fertility, body weight changes, food consumption, duration of gestation, duration of delivery, and nursing behavior with e...

Summary: Smoking during pregnancy results in offspring with an average birth weight 200 g less than those of non-smoking mothers. The pathogenesis of this effect is still unknown and there is no general agreement about the causal relationship between maternal smoking and subsequent fetal growth retardation. In the present study, a model of maternal smoking during pregnancy in the rat was established using the P & I Walton Exposure Machine. The study consisted of three groups: control, pair-fed, and smokeexposed. Smoke-exposed animals were exposed continuously to tobacco smoke for cycles of 7 min, 16 times a day from d 5 to d 20 of gestation. On d 21 of gestation, fetuses from all groups were removed by cesarean section, weighed, and dissected. The fetal brain, liver, and lungs as well as the placentas were weighed and analyzed for nucleic acid content. Fetal weight was found to be significantly reduced in both pair-fed and smoke-exposed groups compared with the control group. There was also a significant reduction in fetal body weight of the animals in the smoke-exposed group in comparison to those in the pair-fed group. Exposing the mother to smoke affected neither fetal brain weight nor nucleic acid content whereas fetal liver and lungs showed a significant decrease in both weight and nucleic acid content. These results indicate that the fetal growth retardation associated with maternal exposure to tobacco smoke in the rat corresponds to a disproportionate type. In addition, the present results indicate that the maternal tobacco smoke exposure induced fetal growth retardation without placental growth retardation.

The relationship of body and placental weight with plasma levels of insulin, glucose, glucagon, glucocorticoids and somatomedins in fetal rabbits between 22 days of gestation and term has been investigated. At 22, 24, 26, 28 and 30 days gestation, body and placental weights were strongly correlated and were also significantly correlated with log transformed plasma insulin concentrations in individual fetuses from nulliparous does. At 30 days gestation, mean plasma insulin levels, as well as body and placental weights, were significantly elevated in fetuses from multiparous does (p less than 0.05) and in fetuses whose growth had been increased by surgical reduction in litter size on day 9 of pregnancy (p less than 0.001). Log insulin concentrations in fetuses from multiparous does and in litter-reduced fetuses were also significantly correlated with bodyweight. The correlation coefficient for log insulin and bodyweight in all individual rabbit fetuses at 30 days gestation was 0.69 (p less than 0.001, n = 116). Fetal log plasma glucagon concentrations at 26 and 28 days gestation were negatively correlated with body weight, but were not significantly related at 30 days gestation. Neither glucose nor glucocorticoid concentrations were significantly related to bodyweight in individual fetuses. Plasma somatomedin activity in litter-reduced fetuses at 30 days gestation, was significantly higher (p less than 0.02) than in normal fetuses, but was not significantly correlated with fetal body weight. The observation of strong positive correlation between insulin and bodyweight throughout the last third of gestation reinforces the belief that fetal insulin plays an important role in the regulation of both placental and fetal growth.

The herbicides 2,4-D and 2,4,5-T and many of the esters of these compounds produced cleft palates in CD-1 mice. Silvex and Agent Orange also produced cleft palates. Depending on the dose and means of administration variable responses relating to the production of cleft palates, effect on fetal weight, and effect on fetal mortality were obtained. In order to view these data comprehensively, the Prenatal Development Index was determined. This index was computed from the incidence of malformed fetuses, fetal mortality and fetal body weight. This made it possible to evaluate data from some experiments with feto-toxic doses of compounds in which the high incidence of fetal mortality and consequently low incidence of viable fetuses obscured the response.

Bromofenofos, an organophosphorus anthelmintic, was administered by gavage to rats as a single dose (50 mg/kg) on one of days 6 through 14 of pregnancy. The dams were killed on day 21, and the fetuses were removed, weighed and examined by routine teratological methods. A significant increase in fetal resorptions occurred after administration on days 9 through 13, with a maximum on day 10. Approximately 72% of the implants were resorbed after administration on day 10. Fetal body weights were significantly decreased when dams were treated on day 8 or later. The greatest decrease in fetal body weights was observed on day 10, when the fetuses weighed less than the controls by about 44% on the average. The incidence of fetuses with gross, skeletal and internal malformations was significantly increased on days 8 through 10, on days 8 through 11 and on days 8 and 9, respectively. Although various types of malformations were observed, most of them occurred on day 8, when no significant increase in fetal resorptions did occur. Cleft lip, short tail, brachygnathia, anal atresia, absence of genital tubercle, fused pelvic legs and perineal testicles were seen on day 8 as gross malformations. Skeletal malformations mainly affected the vertebrae and ribs. Major internal malformations on day 8 were hydronephrosis, hydroureter, anophthalmia, cleft palate, agenesis of the bladder and renal agenesis. Anophthalmia and/or microphthalmia were observed on days 8 through 10, with the highest incidence on day 9. To further determine the no-effect levels for embryolethal and teratogenic effects, a single dose of 10, 20, 30 or 40 mg/kg was administered by gavage to rats on days 8 or 10 of pregnancy. The no-effect levels of single oral dose for embryolethal and teratogenic effects were considered to be 40 and 30 mg/kg, respectively.

Pregnant Wistar rats fed control and Zn-deficient diets received daily oral doses of 0, 100, and 300 mg/kg sodium valproate from d 16 to 20 of gestation. Only the highest valproate doses induced a small reduction in fetal body weight in the normally fed group. Zinc deficiency caused a drastic reduction in maternal and only a small reduction in fetal serum Zn concentrations. Valproate treatment had no effect on maternal and fetal serum Zn concentrations.Valproate reduced fetal liver Zn content only in the normally fed group. The reduction of liver Zn content resulted from the reduction of Zn-metallothionein. Valproate did not affect total Zn and Zn-metallothionein in kidneys. Three percent of the Zn-deficient fetuses developed hydronephrosis and hydrops. Valproate treatment drastically enhanced the occurrence of fetal hydronephrosis and hydrops. Valproate induced fetal liver necroses, independent of Zn nutrition.

For largely unknown reasons severe or moderate diabetes of pregnant rats results in pronounced fetal growth retardation. Therefore, some skeletal growth parameters of fetal rats from streptozotocin diabetic mothers were studied in vivo and in vitro. Two days post conception rats were intravenously injected with 65 mg/kg body weight streptozotocin. On day 20 post conception 8 normal and 8 diabetic rat mothers received 5 mu Ci 3-H thymidine intraperitoneally. One day later the experiments were terminated. Fetal body weight and body length were significantly (p less than 0.05-0.001) reduced in the hyperglycaemic rats compared to normal rats, as was the thymidine incorporation into rib cartilage (p less than 0.02). In the cell culture colony formation from isolated chondrocytes of normal and hyperglycaemic fetuses was determined. Proinsulin, insulin (62.5-250 ng/ml), insulin-like growth factor I and II (6.25-25 ng/ml) significantly (p less than 0.05-0.001) augmented colony formation in a dose-dependent manner, with the somatomedins being 8 times more effective than proinsulin or insulin. Isolated chondrocytes from hyperglycaemic compared to normal fetuses formed significantly (p less than 0.05-0.001) fewer colonies in the basal state and in response to all 4 hormones. The results confirm the growth retardation of fetuses from diabetic rat mothers. A reduced responsiveness of chondrocytes from hyperglycaemic fetuses to various growth factors could be demonstrated as compared to cells from normal fetuses.

Mild hyperglycaemia was induced in unrestrained pregnant rats from day 20.5 to day 23.5 of pregnancy, using a continuous glucose infusion. Control rats were infused with distilled water. In post-mature fetuses from glucose-infused rats, raised plasma glucose and insulin concentrations were related to increased body weight (6.03 +/- 0.07 g) and total carcass fat (2.02 +/- 0.04% of fresh weight) compared with control fetuses of the same age (5.35 +/- 0.07 and 1.5 +/- 0.04 g, respectively). Concurrently, the rate of lipogenesis in the carcass, estimated from the incorporation of tritium from tritiated water into fatty acids, was significantly increased in fetuses from glucose infused rats compared with control rats (6.00 +/- 0.34 versus 2.62 +/- 0.27 and 3H2O X h-1 X g tissue-1, respectively.

The hormonal and metabolic factors which contribute to fetal growth are poorly understood. In the present experiments pregnant rats were continously infused from day 18 to 20 post conception with saline (S) or amino acids (AA: 2.5g/kg/day). After an overnight fast of 14 hours fetal body weight, fetal serum somatomedin (SM, porcine cartilage bioassay) and the "endogenous" fetal cartilage bioactivity were determined (=incorporation of 35SO4 into the fetal costal cartilage in response to 0, 5 or 10 per cent normal rat serum). Results: AA-compared to S-infusions increased fetal body weight (S:4.0±0.5*g, n=9; AA: 4.9±0.3*g, n=6; p

It is unknown why fetal rats of diabetic mothers are smaller than normal. Therefore, pregnant rats were infused i.v. from day 19 to 21 with saline (S) or 40% Glucose (G). Fetal body weight and the thymidine incorporation into fetal a) rib cartilage in vivo and b) isolated chondrocytes in response to normal fetal or maternal rat serum were determined. Bodyweights were lower in G: 4.17 ± 0.17 g, n=18 than in S: 4.32 ± 0.14g, n=24, < 0.05. In S thymidine incorporation in vivo was higher in small compared to big fetuses: r= -0.531, n=55, < 0.001. Opposite results were obtained in group G: r= +0.542, n=54, < 0.001. The results of the thymidine incorporation into isolated chondrocytes are shown in the table (cpm/105 cells). (M ± SEM; n=12, a< 0.05; b < 0.001 versus 0% serum) Chondrocytes of hyperglycemic fetuses did not respond to maternal serum, which suggests that both adult and fetal growth factors are needed for appropriate fetal growth.