Growth failure in second-trimester fetuses with trisomy 21

Growth failure in the Down syndrome is common postnatally, but is thought to be less consistent in fetuses and newborns. We describe the growth of individual organs in 53 second-trimester abortuses with trisomy 21 and compare the organ weights to organ weights from 432 spontaneously aborted, but otherwise normal control specimens. Using multiple regression analysis, we found body weight to be the most significant predictor of all organ weights in normal fetuses; therefore, this variable was used to generate the regression lines to which the organ weights of trisomic specimens were compared. All trisomic fetal organs were found to be small, with an abnormal karyotype being a significant predictor of low organ weight. However, the effect on individual organs was variable, with some organs differing only minimally from the controls. Placental weights were not affected by fetal trisomy. This study demonstrates the presence of well-established, although variably severe, growth retardation in second-trimester fetuses with Down syndrome.     

Standardized residuals as a means for detection of growth alteration in the pathologic human fetus.

This paper introduces and discusses the use of standardized residuals as a technique for comparing the growth of normal and pathologic human fetuses. Anthropometric measures, radiographic measures, and organ weights were regressed on known gestational age of second- and third-trimester fetuses. Standardized residuals were calculated for a group of potentially growth-impaired fetuses. Use of residuals aids in identification of patterns of growth alteration in specific pathologies. Most important, studying the response of developing organ systems to a variety of insults may elucidate mechanisms of growth regulation in the fetus. We emphasize the special quality of the multivariate measures of the core sample of fetuses from the Akron Children's Hospital collection.     

Study of fetal organ growth in Wistar rats from day 17 to 21

A total of 1633 Wistar rat fetuses was used to determine weights of the fetus and several fetal organs on days 17 to 21 of gestation. Heart, lung, liver, kidney, stomach, intestine, brain, femur, thyroid and adrenal weights were recorded. Growth curves of the whole body and organs were calculated. A linear semi-log relationship between organ weight and day of gestation was shown. The doubling weight times were 1.5 days for whole bodies and for organs they ranged between 0.9 (spleen) and 3.4 (adrenals) days. A correlation between the rate of organ growth and the start of the organ function was observed.     

Myogenesis in sheep is altered by maternal feed intake during the peri-conception period

The effect of varying short-term maternal feed intake during the peri-conception period on the development of ovine fetal muscle at mid-gestation was investigated. Superovulated donor Merino ewes (n = 24) were fed a roughage/grain pelleted diet (10.1 MJME/kg dry matter) at either 1.5x maintenance (H; high) or 0.5x maintenance (L; low) from 18 days before until 6 days after ovulation. Embryos were transferred to recipient ewes (n = 60) on day 6. Singleton fetuses were collected on day 75 of gestation and placental weights, fetal body dimensions and fetal organ and muscle weights recorded. The number, type and size of muscle fibres and the dry matter, RNA, DNA and protein content in the semitendinosus muscle were determined. Maternal feed intake did not influence body dimensions, organ development or muscle weights in the fetus. However, L feed intake decreased total muscle fibre number in the fetus by approximately 20% (P = 0.06) compared to H feed intake. This resulted from a reduced secondary to primary fibre ratio (P < 0.05) and indicated that secondary fibre formation occurred at a reduced rate in L fetuses. In addition, protein:DNA ratio tended to be lower in muscles of L fetuses (P < 0.1). It is concluded that restricting feed intake over the peri-conception period reduces or delays myogenesis in fetal sheep. The potential mechanisms by which nutritional availability during this period may influence subsequent myogenic development are discussed.     

Fetal development in the normal thick-tailed bushbaby (Galago crassicaudatus panganiensis)

Fetal development was examined at days 60, 75, 90, 105, 120, or 135 of gestation in 19 thick-tailed bushbaby fetuses (Galago crassicaudatus panganiensis) from 17 normal, timed pregnancies. With the exception of day 135, all fetuses were collected by hysterotomy (gestation = 133 ± 2 days). Various weights and measurements were taken. Although fetal sizes varied widely, crown-rump, crown-heel, upper and lower arm and leg lengths, hand and foot lenghts, and fetal organ weights correlated well with fetal age. Key changes in gross brain morphology and skeletal ossification of cranium, pelvis, tarsals, carpals, and epiphyses were noted. Sternabrae ossification proved highly variable, while ossification in the otic capsule and associated ear structures correlated well with age. These data provide a normal base for studies using fetal developmental parameters whether the purpose is to determine gestational age or to design future studies.     

Ovine fetal development is more sensitive to perturbation by the presence of serum in embryo culture before rather than after compaction

The effects on subsequent fetal development of the presence or absence of serum at different times during IVC of ovine zygotes were studied. Zygotes, recovered from superovulated ewes 36h after intrauterine AI using semen from a single sire, were cultured for 5 days in synthetic oviductal fluid (SOF) media supplemented with either BSA and amino acids (SOF-) or with 10% (v/v) steer serum (SOF+). Serum was present or absent during the first two and last 2 days of IVC giving four treatments (SOF-/SOF-; SOF-/SOF+;SOF+/SOF- and SOF+/SOF+). In total, 224 embryos, including 26 in vivo controls, were transferred singly at day 6 post-AI to synchronous recipients and the products of conception recovered at day 125 of gestation. Presence of serum during IVC had a biphasic effect on embryo development. The inclusion of serum during the first 2 days of IVC retarded early embryo development while the inclusion of serum during the last 2 days of IVC produced more blastocysts by day 6. These effects were independent of each other. The presence of serum during the first 2 days of IVC resulted in increased weights of gravid uterus, placenta, fetus, fetal heart and liver. The incidence of fetuses whose total or organ weights were greater than three standard deviations above the corresponding mean weights of control fetuses was also greater when serum was present during the first 2 days of IVC. However, even when serum was absent throughout IVC there was still an infrequent incidence of fetal weights greater than three standard deviations above the mean for control fetuses. These observations provide evidence that it is the early pre-compaction stages of embryo development that are particularly sensitive to perturbations leading to abnormal fetal development.     

Fetal growth in the baboon during the second half of pregnancy

The normal growth profile of critical fetal organs through the last third of gestation has not been documented in detail in human fetuses or the fetus of any nonhuman primate species. Recent epidemiological studies in human pregnancy suggest that fetal growth plays a major role in the programming of life-long health by modifying cardiovascular, pancreatic, brain, and liver growth. The present study aimed to produce a detailed database of individual organ growth in the fetal baboon in late gestation. Fetal organ weights were obtained from 43 baboon fetuses between 121 and 177 days of gestation. Various organs (brain, heart, kidney, femur, intestines, and spinal cord) showed no sign of slowed growth in late gestation while growth of others (lung, liver, stomach, and bladder) accelerated in late gestation. The fetal adrenal and thymus showed a decrease in growth rate over the final 20 and 10 days of gestation respectively. These observations provide a database that will permit analysis of factors responsible for regulation of normal and altered fetal organ development in this important experimental species.     

Maternal undernutrition from early- to mid-gestation leads to growth retardation,cardiac ventricular hypertrophy,and increased liver weight in the fetal sheep

Early gestation is critical for placentomal growth, differentiation, and vascularization, as well as fetal organogenesis. The fetal origins of adult disease hypothesis proposes that alterations in fetal nutrition and endocrine status result in developmental adaptations that permanently change structure, physiology, and metabolism, thereby predisposing individuals to cardiovascular, metabolic, and endocrine disease in adult life. Multiparous ewes were fed to 50% (nutrient restricted) or 100% (control fed) of total digestible nutrients from Days 28 to 78 of gestation. All ewes were weighed weekly and diets adjusted for individual weight loss or gain. Ewes were killed on Day 78 of gestation and gravid uteri recovered. Fetal body and organ weights were determined, and numbers, morphologies, diameters, and weights of all placentomes were obtained. From Day 28 to Day 78, restricted ewes lost 7.4% of body weight, while control ewes gained 7.5%. Maternal and fetal blood glucose concentrations were reduced in restricted versus control pregnancies. Fetuses were markedly smaller in the restricted group than in the control group. Further, restricted fetuses exhibited greater right- and left-ventricular and liver weights per unit fetal weight than control fetuses. No treatment differences were observed in any gross placentomal measurement. However, caruncular vascularity was enhanced in conceptuses from nutrient-restricted ewes but only in twin pregnancies. While these alterations in fetal/placental development may be beneficial to early fetal survival in the face of a nutrient restriction, their effects later in gestation as well as in postnatal life need further investigation.     

Modulation of the progesterone receptor in the fetal uterus of the progesterone-primed guinea pig in vivo and in organ culture

Guinea pig fetuses were treated with progesterone for 7 days before placing fetal uteri in organ culture to see if progesterone pre-treatment of fetuses in utero would permanently inhibit the spontaneous rise in progesterone receptor which occurs in organ culture. The data show that: the basal level of progesterone receptor in fetal uteri was not affected by the progesterone treatment and progesterone receptor concentrations in vitro were also not inhibited. When guinea pig fetuses were treated sequentially with progesterone and estradiol, estradiol failed to provoke an uterotrophic effect but it retained its ability to stimulate progesterone receptor concentrations.     

Some effects of continuous low-dose congenital exposure to methylmercury on organ growth in the rat fetus

Congenital low-dose exposure of rat fetuses to methylmercury produced smaller offspring without anatomical abnormalities. The present study explored the mechanisms of the smallness of fetuses. The pregnant rats were given methylmercury water (25 ppm) from day 1 of pregnancy continuously until day 20 of gestation. There was a negative correlation of fetal weight and maternal and fetal mercury burden. The whole organ DNA and protein content of the livers and kidneys in the experiments were significantly lower than the control (P less than 0.05) indicating that there were fewer cells per organ in the mercury exposed fetuses. When the data were compared on a per gram of tissue basis, there was no significanct difference, indicating that the number and size of the cells of each were not diminished. The incorporation of 3H-thymidine into fetal tissue DNA was also substantially lower in the experimental group indicating decreased proliferative activity. We conclude from this study that, at least for some major organs, the decreased size in the mercury exposed fetuses is due to fewer cells in the organs due to decreased proliferative activity.     

Trisomy 13 in the fetus

A significant number of fetuses with trisomy 13 are spontaneously or voluntarily lost before birth; however, very few such fetuses have been systemically autopsied. In the present study, ten trisomy 13 fetuses of 130-305 mm in crown-rump length, estimated gestational age from 108 days to 239 days, were examined following either karyotype or ultrasonographic diagnosis and voluntary termination. Mean maternal age was 35.1 years. The spectrum of anatomical features was similar to that observed in neonates or older infants with trisomy 13, namely, holoprosencephaly, cyclopia, microphthalmia, cleft palate and lip, cardiac defect, polydactyly, and cystic kidney. Kidney weights were significantly increased above normal in eight of nine fetuses. Histologically, the cortex of these kidneys showed increased mitotic activity and blastemic appearance, which extended deep into the medullary areas. The weights and histology of other organs were normal except for slight increases in spleen weight.     

封闭群五指山小型猪主要脏器重量与体重的相关性分析

目的测定封闭群五指山小型猪主要脏器重量和脏器系数,对脏器重量与体重的相关性进行分析,并计算出相应的直线回归方程和多元回归方程。方法实验选用6-10月龄普通级封闭群五指山小型猪30头（其中♂16头、♀14头）,分别测定体重和7个主要脏器重量,计算脏器系数,通过SAS软件进行脏器系数的性别间比较和各脏器重与体重间的相关与回归分析。结果性别间比较,小型猪仅有心脏的脏器系数差异有显著性（P〈0.05）。除公猪的胃脏和母猪的肺脏外,所测脏器重量与体重间均有明显的正相关线性关系;多因素分析显示公猪的肝脏和肾脏,母猪的心脏、肝脏和肾脏对各自体重有影响。结论封闭群五指山小型猪主要脏器系数性别间差异较小,其体重与某些脏器重量存在一定的线性关系。     

Amelioration of some metabolic effects produced by hyperthyroidism in late pregnant rats and their fetuses. Effects on lipids and proteins.

We have studied the effect of 40-45 days administration of 1 mg/kg thyroxine on protein and lipid metabolism in liver, heart, lungs, kidneys and adrenal glands of virgin and 21-day pregnant rats and their fetuses and placentae. The chronic administration of thyroid hormone produced significant increases in serum T3 and T4 in both groups as well as in organ weights and protein concentrations in virgin rats, but much smaller modifications in pregnant ones. Hyperthyroidism decreased the weight of fetal livers and increased that of placentae; protein content was increased in all fetal organs. Hyperthyroidism induced increases in phospholipid concentrations in all the organs and in total lipids only in liver and heart of adult rats, which were not counteracted by pregnancy. Pregnant rats had increases in total lipids in liver and kidneys and in adrenal phospholipids. In hyperthyroid fetuses there was an increase in hepatic total lipids and no changes in phospholipids. Hepatic lipogenesis (measured by in vivo incorporation of 3H2O into lipids) was increased by hyperthyroidism in virgin and pregnant rats, but the increase was significantly smaller in the pregnant hyperthyroid rats compared with the virgin ones. Fetal lipogenesis in liver and lung was not changed. In addition, an increase was observed in lipogenic enzyme (fatty acid synthetase and glucose-6-phosphate dehydrogenase) activities in hyperthyroid virgin rats which was prevented by pregnancy. In fetuses only pulmonary glucose-6-phosphate dehydrogenase was increased when expressed in terms of tissue weight. Our results indicate that the metabolic effect of hyperthyroidism is attenuated in pregnant rats and their fetuses, when compared with adult virgin rats, in most of the parameters studied.(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparative study of clonal growth and differentiation of mesenchymal stromal cells from rat fetal liver at different developmental stages

Fetal liver during period of its hematopoietic activity contains mesenchymal stromal cells (MSC) that are known to play a major role in establishing hematopoietic microenvironment. These cells are capable of clonal growing and multilineage differentiation, but only limited data exist about changes in their properties during prenatal development. We compared cloning efficiency of MSC from liver of 14, 16 and 20 day rat fetuses and evaluated their potentials to in vitro osteo- and adipogenesis and in vivo chondrogenesis after whole organ ectopic transplantation. Content of clonogenic MSC in suspension of liver cells was maximal in 16 day fetuses and to a lesser extent in 20 day ones. MSC derived from 16 day fetuses demonstrated maximal potential to estimated lineages. Osteogenic potential of MSC from 14 day fetuses was comparable to whereas their adipogenic and chondrogenic abilities were inferior to that from 16 day fetuses. Cells from 20 day fetuses had only weak adipogenic potency and failed to differentiate into osteogenic of chondrogenic pathways. The results indicate that both number and differentiation potential of MSC in developing rat liver correlate with dynamics of hematopoiesis in this organ. Detected changes may be ascribed to the decline of hematopoiesis in liver and acquisition its definitive functions.     

Low iron diet and parenteral cadmium exposure in pregnant rats: the effects on trace elements and fetal viability

The effects of latent iron deficiency combined with parenteral subchronic or acute cadmium exposure during pregnancy on maternal and fetal tissue distribution of cadmium, iron and zinc, and on fetal viability were evaluated. Timed-pregnant Sprague-Dawley rats were fed on semisynthetic test diets with either high iron (240 mg kg) or low iron (10 mg kg), and concomitantly exposed to 0, 3 or 5 mg cadmium (as anhydrous CdCl₂) per kilogram body weight. Animals were exposed to cadmium from gestation day 1 through 19 by subcutaneously implanted mini pumps (Subchronic exposure) or on gestation day 15 by a single subcutaneous injection (Acute exposure). All rats were killed on gestation day 19. Blood samples, selected organs and fetuses were removed and prepared for element analyses by atomic absorption spectrometry. Low iron diet caused decreases in maternal body weight, maternal and fetal liver weights, placental weights and tissue iron concentrations. By cadmium exposure, both subchronic and acute, tissue cadmium concentrations were increased and the increase was dose-related, maternal liver and kidney zinc concentrations were increased, and fetal zinc concentration was decreased. Cadmium concentration in maternal liver was additionally increased by low iron diet. Acute cadmium exposure caused lower maternal body and organ weights, high fetal mortality, and decreased fetal weights of survivors. In conclusion, parenteral cadmium exposure during pregnancy causes perturbations in essential elements in maternal and fetal compartments. Acute cadmium exposure in the last trimester of gestation poses a risk for fetal viability especially when combined with low iron in maternal diet.     

Teratogenic activity of trichloroacetic acid in the rat

Trichloroacetic acid (TCA) is a by-product of the chlorine disinfection of water containing natural organic material. It is detectable in finished drinking water at levels comparable to the trihalomethanes (30-160 micrograms/L). TCA is also formed in vivo after ingestion of hypochlorite and has been identified as a major metabolite of chlorinated hydrocarbons such as trichloroethylene. The developmental effects of TCA were evaluated in the pregnant Long-Evans rat. Animals were dosed by oral intubation on gestation days 6-15 (plug = 0) with 0, 330, 800, 1,200, or 1,800 mg/kg/day. The vehicle control was distilled water. Maternal observations included clinical signs, weight change, and gross evaluation of organ weights and uterine contents at necropsy (day 20). Live fetuses were examined for external, skeletal, and soft tissue malformation. There were no maternal deaths associated with toxicity prior to sacrifice. Weight gain during treatment was reduced at 800, 1,200, and 1,800 mg/kg. Spleen and kidney weights were increased in a dose-related manner. The mean percent of resorbed implants per litter was 34, 62, and 90 at 800, 1,200, and 1,800 mg/kg, respectively. Live fetuses showed dose-dependent reductions in weight and length. The mean frequency of soft tissue malformations ranged from 9% at the low dose to 97% at the high dose. These were principally in the cardiovascular system (interventricular septal defect, levocardia). Skeletal malformations were found only at 1,200 and 1,800 mg/kg and were mainly in the orbit. Based on these observations TCA was considered to be developmentally toxic in the pregnant rat at doses of 330 mg/kg and above.     

Developmental toxicity evaluation of ELF magnetic fields in Sprague-Dawley rats

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 microT (50, 833, or 5000 mG). Dams received MF or sham exposures for 22 h/day on gestational day 6-20. MF was monitored continuously 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 MF exposed groups and sham control. External, visceral, and skeletal examination of fetuses 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 500 microT during gestation day 6-20 did not produce any biologically significant effect in either dams or fetuses.     

Developmental toxicity of dichloroacetate in the rat.

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

Effect of position in the uterus on the fetal weight of the 21st day of pregnancy in the unilaterally ovariectomized rat

Effects of intrauterine position of the fetuses on the weight of fetal sac, fetus and placenta were investigated on the 21th day of unilaterally (right) ovariectomized pregnant Wistar strain rats. Results were obtained as follows. 1. Litter size was negatively correlated with the mean weights of fetal sac and fetus. 2. The mean weights of male fetal sac and fetus were heavier than those of female ones, while there was no difference in the weight of placenta between male and female. 3. The mean weights of male fetal sac and fetus positioning ovarian end (OV) were lighter than those of ones at the other positions. And the highest frequency of the lightest weight of live fetuses was demonstrated at OV position. 4. The mean weights of male fetal sac and fetus positioning between two males (2M) were heavier than those of ones positioning not next to male (0M). And the mean weight of 2M female fetal sac was heavier than those of 0M one. 5. The mean weights of fetal sac and fetus positioning next to resorbed fetus were heavier than those of ones positioning not next to resorbed fetus.     

Effect of maternal restraint stress on fetal development of ICR mice.

The present study was conducted to elucidate the susceptibility of embryos and fetuses at different gestational stages to the maternal stress in mice. Groups of pregnant ICR mice were subjected to daily 12-h restraint stress, taped in the supine position on a plastic board, on gestational days (GD) 1-4, 5-8, 9-12 and 13-16, respectively. Caesarean sections were performed on gestational day 18, and the fetuses were weighed and examined for morphological defects. During the daily restraint for 4 days, the maternal body weights markedly decreased. Although the body weights recovered gradually after termination of the stress, the recovery was not full until the final stage of pregnancy. Interestingly, restraint stress caused growth retardation of the fetuses, leading to a significant decrease in their body weights, and increased early and late resorptions of embryos and fetuses according to the stress periods. Although the preceding (GD1-4) and concurrent (GD5-8) stresses did not affect embryonic implantation, restraint stress on GD9-12 caused cleft palate. Whereas vertebral abnormalities, mainly bipartite ossification, were observed only in animals stressed on GD5-8, abnormalities of sternebrae, exhibiting asymmetric or bipartite ossification, were enhanced by the stress at all of the gestational stages. On the other hand, the incidence of other malformations including renal malposition and costal abnormalities was not increased by stress at any of the 4 stages. Taken together, the results suggest that intensive restraint stress influences the maternal body weight resulting in growth retardation and increased mortality of embryos and fetuses, in addition to gestational stage-specific ventricular dilatation, cleft palate and sternal abnormalities.