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U J Eriksson

Publications and source records attributed to U J Eriksson.

At least 19 recordsLinked to original sources
PubMed2006

Suramin-restricted blood volume in the placenta of normal and diabetic rats is normalized by vitamin E treatment.

Previously maternal and fetal alterations resembling human pre-eclampsia were induced in pregnant rats by injections of the angiogenesis inhibitor Suramin. These alterations were aggravated by maternal diabetes and partly rectified by vitamin E supplementation. In the present study we evaluated the morphology of placentae and kidneys in this model. Non-diabetic and streptozotocin-induced diabetic pregnant rats of two rat strains (U and H) were treated with Suramin or saline, and given standard or vitamin E-enriched food. On gestational day 20 one placenta and the left kidney of the mother were collected for morphological and stereological analysis. In the placental trophospongium Suramin treatment caused cysts, which were further enhanced by maternal diabetes. Vitamin E treatment had no effect on the vacuolization. In the placental labyrinth of the non-diabetic rats Suramin treatment restricted maternal placental blood volume and increased the interface between maternal and fetal circulation. These changes were reversed by vitamin E treatment. Diabetes increased slightly the interface between the circulations in both rat strains. Suramin treatment decreased the interface, and vitamin E further decreased the interface in the diabetic U rats, whereas neither treatment affected the maternal-fetal interface in the diabetic H rats. The kidneys of Suramin-treated and diabetic rats were heavier compared to controls. Suramin treatment and maternal diabetes damaged renal glomeruli to a similar extent. Vitamin E treatment diminished the Suramin- and diabetes-induced glomerular damage in U rats, but not in H rats. The average cell count per glomerulus was decreased by Suramin in the U rats. Vitamin E treatment did not affect cell number per glomerulus in any group. We conclude that Suramin-injected pregnant rats constitute a valid animal model for placental dysfunction and pre-eclampsia, also from the histological perspective. The present work supports the notion that one important effect of untreated maternal diabetes may be impaired placentation, leading to oxidative stress, morphological damage, and compromised placental function.

Animals↗
PubMed2005

Experimental intrauterine growth retardation in the rat causes a reduction of pancreatic B-cell mass, which persists into adulthood.

BACKGROUND AND OBJECTIVES: The aim of this study was to investigate the possibility that intrauterine growth retardation (IUGR) causes alterations of glucose tolerance, insulin secretory response to glucose, and pancreatic B-cell growth, and if such changes may persist into adulthood. METHODS: Pregnant rats were operated on day 16 of pregnancy ad modum Wigglesworth to induce IUGR. Operated rats gave birth to viable offspring but litter size was reduced. The mothers nursed their pups, which were subsequently weaned and reared to an age of 3 months in apparent good health. RESULTS: At 1 day of age, IUGR pups were 10% lighter than control newborns whose mothers had been subjected to a sham operation. Pancreatic B-cell mass and insulin content were reduced by 35-40% in newborn IUGR offspring. Postnatal growth did not differ between IUGR and control animals of either sex and the difference in body weight at birth was not apparent from 1 week of age and onwards. Tests performed at 3 months of age could not demonstrate differences in glucose tolerance between IUGR and control animals. In females, but not in males, the peak insulin secretory response to glucose was lower in IUGR animals compared to controls. In the 3-month-old rats, B-cell mass was reduced by 40% in male and by 45% in female IUGR rats compared to controls, a reduction corresponding to a similar decrease in pancreatic insulin content (male reduction 48%, female reduction 45%). CONCLUSIONS: In the rat, IUGR causes a diminution of pancreatic B-cell mass which persists into adulthood. Normal glucose tolerance could be maintained but it is conceivable that increasing demands on insulin secretion may not be met by the reduced B-cell mass and that impaired glucose tolerance and even diabetes would hence develop.

Animals↗
PubMed2005

Placental dysfunction in Suramin-treated rats--a new model for pre-eclampsia.

Impaired placentation and oxidative stress are proposed to play major roles in the pathogenesis of placental dysfunction and pre-eclampsia. This study was carried out to evaluate if inhibited angiogenesis by Suramin injections in early pregnancy may cause a condition resembling pre-eclampsia in rats. Rats of two different Sprague-Dawley strains, U and H, were given intraperitoneal injections of Suramin or saline in early pregnancy. The outcome of pregnancy was evaluated on gestational day 20. Suramin injections caused increased blood pressure and decreased renal blood flow in the U rats. In both rat strains Suramin decreased the placental blood flow and caused fetal growth retardation. In both strains the placental concentration of the isoprostane 8-epi-PGF2alpha was increased, indicating oxidative stress. The serum concentration of Endothelin-1 was increased in the U rats. The U strain had a lower basal placental blood flow, and the effects of Suramin were more pronounced in this strain. We conclude, that Suramin injections to pregnant rats cause a state of placental insufficiency, which partly resembles human pre-eclampsia. The induction of this condition is at least partly mediated by oxidative stress, and is subject to varied genetic susceptibility.

Angiogenesis Inhibitors↗
PubMed2003

Maternal diabetes in the rat impairs the formation of neural-crest derived cranial nerve ganglia in the offspring.

AIMS/HYPOTHESIS: Maternal diabetes mellitus increases the risk for fetal malformations. Several of these malformations are found in organs and tissues derived from the neural crest. Previous studies have shown changes in fetal organs of neural crest origin in experimental diabetes and changes in migration of neural crest cells exposed to high glucose in vitro. METHODS: We used whole-mount neurofilament staining of embryos from normal and diabetic mothers to investigate the development of cranial nerve ganglia. Neural tube explants were cultured in 10 and 40 mmol/l glucose and cell death and caspase activity was measured with flow cytometry. RESULTS: The development of cranial ganglia V, VII, VIII, IX and X was impaired in day 10-11 embryos of diabetic rats. There was also a higher rate of cell death of neural crest derived cells cultured in 40 mmol/l glucose for 20 h (35% compared to 12% in 10 mmol/l). However, exposure of cells to 40 mmol/l glucose in culture did not increase the activation of the cell death effector proteins-caspases-measured as cellular binding of the activated caspase marker VAD-FMK. This suggests that the cell death is not caused by caspase-dependent apoptosis or that the caspases are activated at an earlier stage. CONCLUSION/INTERPRETATION: The development of neural crest-derived structures is disturbed already at the organogenic period in embryos of diabetic rats and this deteriorated development could be due to high-glucose induced increase in cell death of neural crest derived cells.

Animals↗
PubMed2001

Induction of embryonic dysmorphogenesis by high glucose concentration, disturbed inositol metabolism, and inhibited protein kinase C activity.

BACKGROUND: Exposure to a diabetic environment causes excess reactive oxygen species (ROS), decreased prostaglandin E(2) (PGE(2)) concentration, and increased embryonic maldevelopment. The aim of the present work was to study whether embryonic dysmorphogenesis is also dependent on alterations of inositol and associated intracellular metabolites. METHODS: Day 9 rat embryos were cultured for 24 or 48 hr and evaluated for gene expression. Day 10 and day 11 embryos from normal and diabetic rats were also examined. RT-PCR was used to study embryonic gene expression of protein kinase C (PKC) and cytosolic phospholipase A(2) (cPLA(2)). RESULTS: Embryos exposed to 30 mmol/L glucose (30G), 500 or 750 micromol/L of scyllo-inositol (500SI or 750SI) had higher malformation score than control embryos cultured in 10 mmol/L glucose (10G). Adding 1.6 mmol/L inositol to the 30G or 750SI culture medium partly corrected these embryos, and completely normalized 500SI embryonic development. Adding 0.5 mmol/L N-acetylcysteine (NAC) or 280 nmol/L PGE(2) protected, and failed to protect, the SI-exposed embryos, respectively. 10G embryos exposed to the PKC inhibitor GF-109203X displayed dose-dependent dysmorphogenesis. Addition of 1.6 mmol/L inositol or 0.5 mmol/L NAC to the PKC-inhibitor-exposed 10G embryos largely normalized the outcome, whereas PGE(2) again failed to protect embryonic development. 30G culture tended to decrease the expression of cPLA(2) after 24 hr in vitro. We also found decreased mRNA levels of cPLA(2) in offspring of diabetic rats on gestational day 10 and of PKC on day 11, as compared with normal offspring. CONCLUSIONS: High glucose concentration causes dysmorphogenesis in embryos by an interaction of oxidative stress and inositol depletion.

Abnormalities, Drug-Induced↗
PubMed2001

Increased rate of lipid peroxidation and protein carbonylation in experimental diabetic pregnancy.

AIMS/HYPOTHESIS: Maternal Type I (insulin-dependent) diabetes mellitus is associated with an increased risk for fetal malformations and spontaneous abortions. Although the pathogenic mechanism is not fully understood, reactive oxygen species have been shown to contribute to the pathogenesis in experimental studies. By measuring 8-iso-PGF2alpha and protein carbonyls, radical oxygen damage to lipids and proteins can be estimated. The aim of this study was to investigate the status of lipid peroxidation and protein carbonylation in mothers and fetuses in experimental diabetic pregnancy. METHODS: Non-pregnant and pregnant rats with and without streptozotocin-induced diabetes were studied after 4 weeks of diabetes or at gestational day 19, respectively. Gross morphology of the offspring was studied and 24 h urine, plasma, amniotic fluid, maternal and fetal livers were collected. Concentrations of 8-iso-PGF2alpha, 15-keto-DH-PGF2alpha and other oxidative stress variables were measured. RESULTS: Malformation and resorption rates were increased in diabetic litters, whereas fetal weights were decreased in the control rats. There were no statistically significant differences in maternal plasma concentrations of 8-iso-PGF2alpha, but plasma protein carbonyl content was increased in the diabetic groups. Pregnancy increased 24 h urinary excretion of 8-iso-PGF2alpha in diabetic rats but not in the control rats. There was no difference in the amniotic fluid concentration of 8-iso-PGF2alpha between the normal and the diabetic group. However, in the diabetic group there was a correlation between the uterine horn concentration of 8-iso-PGF2alpha and the percentage of resorptions. CONCLUSIONS/INTERPRETATION: In diabetic pregnancy, both diabetes and pregnancy are promoting oxygen radical damage. Fetal oxidative stress markers do not clearly reflect fetal morphology.

Amniotic Fluid↗
PubMed2001

Combined treatment with vitamin E and vitamin C decreases oxidative stress and improves fetal outcome in experimental diabetic pregnancy.

The aim was to investigate whether dietary supplementation of a combination of the two antioxidants, vitamin E and vitamin C, would protect the fetus in diabetic rat pregnancy at a lower dose than previously used. Normal and streptozotocin-induced diabetic rats were mated and given standard food or food supplemented with either 0.5% vitamin E + 1% vitamin C or 2% vitamin E + 4% vitamin C. At gestational d 20, gross morphology and weights of fetuses were evaluated. Vitamins E and C and thiobarbituric acid reactive substances were measured in maternal and fetal compartments. In addition, protein carbonylation was estimated in fetal liver. Maternal diabetes increased the rate of malformation and resorption in the offspring. High-dose antioxidant supplementation decreased fetal dysmorphogenesis to near normal levels. The low-dose group showed malformations and resorptions at an intermediate rate between the untreated and the high-dose groups. Thiobarbituric acid reactive substances were increased in fetal livers of diabetic rats and reduced to normal levels already by low-dose antioxidative treatment. Protein carbonylation rate was also increased in fetal liver of diabetic rats; it was normalized by high-dose treatment but only partially reduced by low-dose antioxidants. We conclude that combined antioxidative treatment with vitamins E and C decreases fetal malformation rate and diminishes oxygen radical-related tissue damage. However, no synergistic effect between the two antioxidants was noted, a result that may influence future attempts to design antiteratogenic treatments in diabetic pregnancy. Oxidatively modified proteins may be teratogenically important mediators in diabetic embryopathy.

Animals↗
PubMed2000

Malformations in offspring of diabetic rats: morphometric analysis of neural crest-derived organs and effects of maternal vitamin E treatment.

BACKGROUND: We have previously reported on a malformation-prone Sprague-Dawley rat substrain (U), which presents a high frequency of micrognathia in the offspring of diabetic mothers. This malformation is related to impaired development of the cranial neural crest cells (NCC); the defect may be prevented by antioxidative treatment of the mother. METHODS: We have therefore investigated whether fetuses of diabetic rats display other malformations associated with altered cranial NCC development and whether maternal vitamin E supplementation may affect such malformations. RESULTS: Fetuses of diabetic rats showed low-set external ears, severely malformed Meckel's cartilage, small thyroid and thymus, and absence of parathyroid glands. Cardiac anomalies were frequently observed, including rightward displacement of the aorta, double outlet right ventricle (DORV), persistent truncus arteriosus (PTA) combined with ventricular septal defects due to a malaligned outlet septum. The malformations in the outflow tract included abnormalities of the great arteries; right-sided aortic arch/descending aorta, and double aortic arches. These defects tended to occur together within individual fetuses. Maternal dietary treatment with 2% vitamin E markedly reduced the severity of the malformations. CONCLUSIONS: The phenotypic appearance of these defects is strikingly similar to the DiGeorge anomaly in humans, which has been found in children of diabetic mothers together with an overrepresentation of PTA and DORV. The malformations associated with defective NCC development in the offspring of diabetic U rats show several morphological similarities to those in humans; hence the teratogenic mechanisms may be similar and accessible for study.

Animals↗
PubMed2000

Purification, characterization, and biological compartmentalization of rat fetal antigen 1.

This study has established the rat as an animal model for the analysis of the biological role of fetal antigen 1 (FA1), a protein previously described in humans and mice. FA1 was purified from rat amniotic fluid by immunospecific affinity chromatography. Immunochemical identity between mouse and rat FA1 was established by crossed tandem immunoelectrophoresis. Molecular size was analyzed by mass spectrometry (33 kDa). The amino acid composition was determined, and the amino acid sequence was analyzed. The overall amino acid composition and sequence of the 28 first N-terminal amino acids were identical to the corresponding parts of rat preadipocyte factor 1 and rat adrenal zona glomerulosa protein. Extensive sequence similarity was found between rat and mouse FA1 (86%) and between rat and human FA1 (82%). The concentration of FA1 in fetal serum, maternal serum, urine, and amniotic fluid in rats was determined using an ELISA. The highest concentrations were found in fetal serum and amniotic fluid around Day 18 of pregnancy. This is the first report on the physicochemical characteristics and compartmentalization of rat FA1.

Amino Acid Sequence↗
PubMed2000

Pathogenesis of diabetes-induced congenital malformations.

The increased rate of fetal malformation in diabetic pregnancy represents both a clinical problem and a research challenge. In recent years, experimental and clinical studies have given insight into the teratological mechanisms and generated suggestions for improved future treatment regimens. The teratological role of disturbances in the metabolism of inositol, prostaglandins, and reactive oxygen species has been particularly highlighted, and the beneficial effect of dietary addition of inositol, arachidonic acid and antioxidants has been elucidated in experimental work. Changes in gene expression and induction of apoptosis in embryos exposed to a diabetic environment have been investigated and assigned roles in the teratogenic processes. The diabetic environment appears to simultaneously induce alterations in several interrelated teratological pathways. The complex pathogenesis of diabetic embryopathy has started to unravel, and future research efforts will utilize both clinical intervention studies and experimental work that aim to characterize the human applicability and the cell biological components of the discovered teratological mechanisms.

Animals↗
PubMed2000

Increased mRNA levels of Mn-SOD and catalase in embryos of diabetic rats from a malformation-resistant strain.

Previous studies have suggested that reactive oxygen species (ROS) are mediators in the teratogenic process of diabetic pregnancy. In an animal model for diabetic pregnancy, offspring of the H rat strain show minor dysmorphogenesis when the mother is diabetic, whereas the offspring of diabetic rats of a sister strain, U, display major morphologic malformations. Earlier studies have shown that embryonic catalase activity is higher in the H than in the U strain, and maternal diabetes increases this difference in activity. The aim of this study was to characterize the influence of genetic predisposition on diabetic embryopathy by comparing the mRNA levels of ROS-metabolizing enzymes in the two strains. We determined the mRNA levels of catalase, glutathione peroxidase, gamma-glutamylcystein-synthetase, glutathione reductase, and superoxide dismutase (CuZn-SOD and Mn-SOD) in day 11 embryos of normal and diabetic H and U rats using semiquantitative reverse transcription-polymerase chain reaction. The mRNA levels of catalase and Mn-SOD were increased in H embryos as a response to maternal diabetes, and no differences were found for the other genes. Sequence analysis of the catalase promoter indicated that the difference in mRNA levels may result from different regulation of transcription. Sequence analysis of the catalase cDNA revealed no differences between the two strains in the translated region, suggesting that the previously observed difference in the electrophoretic mobility in zymograms is due to posttranslational modifications. An impaired expression of scavenging enzymes in response to ROS excess can thus be an integral part of a genetic predisposition to embryonic dysmorphogenesis.

Animals↗
PubMed1999

Hyperglycemia-induced embryonic dysmorphogenesis correlates with genomic DNA mutation frequency in vitro and in vivo.

Congenital malformations affecting multiple organ systems are at least three times more common in infants of mothers with IDDM than in infants born to nondiabetic mothers. Numerous studies have confirmed the teratogenic effect of hyperglycemia on the developing embryo, although no direct mechanism has been determined. In this study, we aimed to correlate the frequency of lacI mutations with degree of hyperglycemic exposure and severity of malformations in mouse embryos from in vitro cultures. Day 8 transgenic mouse embryos cultured in 30 or 50 mmol/l glucose for 48 h exhibited a higher incidence of morphological abnormalities, as well as an increase in lacI mutation frequency, compared with embryos cultured in 10 mmol/l glucose with no abnormalities and a lower frequency of lacI mutations. We also used a transgenic lacI rat system to evaluate the relationship between abnormal embryonic development and DNA mutation frequency in day 11 embryos of severely diabetic rats (serum glucose >20 mmol/l). Compared with control embryos, the embryos from diabetic rats displayed significantly more malformations, shorter crown-rump lengths, fewer somites, and more than six times greater genomic DNA mutation frequency. Genetic analysis of the mutated lacI gene from both in vitro cultured mouse embryos and in vivo developed rat embryos revealed that the majority of mutations were due to base substitutions (transitions and transversions), but that the rate of large DNA mutations tended to increase in embryos exposed to a diabetic environment. Our results support the interrelationship between increased rates of congenital malformations and DNA mutations in the offspring of diabetic pregnancy.

Animals↗
PubMed1999

Developmental damage, increased lipid peroxidation, diminished cyclooxygenase-2 gene expression, and lowered prostaglandin E2 levels in rat embryos exposed to a diabetic environment.

Previous experimental studies suggest that diabetic embryopathy is associated with an excess of radical oxygen species (ROS), as well as with a disturbance of prostaglandin (PG) metabolism. We aimed to investigate the relationship between these pathways and used hyperglycemia in vitro (embryo culture for 24-48 h) and maternal diabetes in vivo to affect embryonic development. Subsequently, we assessed lipid peroxidation and gene expression of cyclooxygenase (COX)-1 and -2 and measured the concentration of prostaglandin E2 (PGE2) in embryos and membranes. Both hyperglycemia in vitro and maternal diabetes in vivo caused embryonic dysmorphogenesis and increased embryonic levels of 8-epi-PGF2alpha, an indicator of lipid peroxidation. Addition of N-acetylcysteine (NAC) to the culture medium normalized the morphology and 8-epi-PGF2alpha concentration of the embryos exposed to high glucose. Neither hyperglycemia nor diabetes altered COX-1 expression, but embryonic COX-2 expression was diminished on gestational day 10. The PGE2 concentration of day 10 embryos and membranes was decreased after exposure to high glucose in vitro or diabetes in vivo. In vitro addition of NAC to high glucose cultures largely rectified morphology and restored PGE2 concentration, but without normalizing the COX-2 expression in embryos and membranes. Hyperglycemia/diabetes-induced downregulation of embryonic COX-2 gene expression may be a primary event in diabetic embryopathy, leading to lowered PGE2 levels and dysmorphogenesis. Antioxidant treatment does not prevent the decrease in COX-2 mRNA levels but restores PGE2 concentrations, suggesting that diabetes-induced oxidative stress aggravates the loss of COX-2 activity. This may explain in part the antiteratogenic effect of antioxidant treatment.

Abnormalities, Drug-Induced↗
PubMed1998

Maternal antioxidant treatments prevent diabetes-induced alterations of mitochondrial morphology in rat embryos.

Previous studies have suggested that production of reactive oxygen species by embryonic mitochondria may have a role in the induction of both high-amplitude mitochondrial swelling and embryonic dysmorphogenesis in diabetic pregnancy. The present study analyzed the relationships between a putative metabolite-induced production of free oxygen radicals, mitochondrial lipid peroxidation, and high-amplitude mitochondrial swelling in embryos during organogenesis. For studies in vitro, day 9 embryos of normal rats were cultured for 48 h with a high concentration of glucose in the absence or presence of alpha-cyano-4-hydroxycinnamic acid (CHC), a mitochondrial pyruvate transport inhibitor. The morphology of mitochondria in the neuroepithelium of the embryos was studied with the aid of transmission electron microscopy. For studies in vivo, normal and diabetic pregnant rats were fed a diet supplemented with the antioxidants alpha-tocopherol (vitamin E) or 2,6-di-tert-butyl-4-methylphenol (BHT), and the ultrastructure of mitochondria in the embryonic neuroepithelium and in the visceral yolk sac was investigated on gestational day 11. Exposure to a high concentration of glucose in vitro or to maternal diabetes in vivo induced high-amplitude swelling of mitochondria in the neuroepithelium of the embryos. The swelling of mitochondria was prevented by addition of CHC to the culture media or by maternal ingestion of antioxidant-supplemented food. In diabetic pregnancy, embryonic mitochondria during organogenesis produce free oxygen radicals that cause mitochondrial lipid peroxidation and swelling and furthermore embryonic dysmorphogenesis. Dietary supplementation with antioxidants to the mother may prevent embryonic malformations in diabetic pregnancy by inhibition of mitochondrial dysfunction.

Animals↗
PubMed1998

Maternal diabetes alters extracellular matrix protein levels in rat placentas.

OBJECTIVES: The aim of this study was to determine whether maternal diabetes affects placental levels of the extracellular matrix components fibronectin, laminin, and collagen-IV. STUDY DESIGN: Fibronectin, laminin, and collagen-IV deposition in term (day 20) rat placentas from normal and diabetic pregnancies was detected by use of Western blot, slot-blot, and immunohistochemical studies. RESULTS: Increased placental and decreased fetal wet weight were found in offspring of manifestly diabetic rats compared with offspring of normal pregnancies. Laminin deposition was reduced whereas fibronectin levels were increased in placentas from diabetic rats. No diabetes-induced changes of collagen-IV expression and deposition were found. CONCLUSION: The diabetes-induced alterations of laminin and fibronectin protein levels in the fetal-maternal interface may affect placental development and alter gas exchange and nutrient transfer to the offspring. This may in turn contribute to the abnormal fetal development in diabetic pregnancy.

Animals↗
PubMed1998

Metabolic alteration in neural tissue of rat embryos exposed to beta-hydroxybutyrate during organogenesis.

Hyperketonemia has been identified as an important factor in diabetic pregnancy affecting growth and development of the offspring. In order to assess the immediate metabolic alterations in embryos caused by excess ketone bodies, we studied rat embryonic neural tissue exposed to a high concentration of beta-hydroxybutyrate in vitro. Beta-hydroxybutyrate inhibited oxygen uptake of the neural tissue of day 9 and day 10 embryos by 12.8% and 1 1.2%, but did not affect that of day 11 and day 12 tissue. In contrast, glucose utilization of the neural tissue of day 9 and day 10 embryos was not altered. However, a 30% decrease in glucose utilization was observed in the neural tissue of day 11 and day 12 embryos exposed to beta-hydroxybutyrate. Thus, beta-hydroxybutyrate induced different metabolic alterations in the embryonic neural tissue during early and late organogenesis, which suggests different modes of teratogenic action of ketone bodies in different parts of gestation.

3-Hydroxybutyric Acid↗