Biomedical subjects

U J Eriksson

Publications and source records attributed to U J Eriksson.

At least 37 records · Page 2Linked to original sources

PubMed1998

Apoptosis in embryos of diabetic rats.

The aim of the present study was to determine whether maternal diabetes affects rat embryo and yolk sac apoptosis during the postimplantation period. Severely malformed and growth-retarded embryos of gestational day 12 from diabetic rats exhibited pronounced DNA laddering on agarose gels. On the other hand, no DNA laddering could be observed in any of the non-malformed embryos from control and diabetic rats, or in their corresponding yolk sacs. Analysis of embryos of gestational day 10 revealed only a few scattered TUNEL positive cells mainly located in the allantois, the foregut epithelium, the cranial neuroepithelium and in the cranial mesenchyme. Embryonic tissue of gestational day 12 showed numerous aggregates of TUNEL-positive cells, indicating developmental remodelling of multiple organs. Analysis of non-malformed embryos of day 10 and 12 revealed a distribution and frequency of TUNEL positive cells unaffected by the diabetic state of the mother on both days. In vitro incubation (2-8 hr) of normal day-12 yolk sacs resulted in strong DNA laddering, but not in the corresponding embryos. Dispersed yolk sac cells generated higher levels of reactive oxygen species than dispersed embryonic cells. Reactive oxygen species levels in both embryonic and yolk sac cells were unaffected by the diabetic state of the mother. Moreover, immunoblot analysis showed high Bcl-2 and undetectable caspase-1 levels in embryos from both normal and diabetic rats and low Bcl-2 and high caspase-1 levels in the corresponding yolk sacs. Immunohistochemical analysis of embryos demonstrated caspase-1-reactivity in a small subpopulation of cells located in proximity to TUNEL-positive cells. We conclude that the inherent capacity of embryonic cells to enter apoptosis in vitro is low as compared to yolk sac cells, and that wide-spread apoptosis is not likely to play a major role in diabetes-induced dysmorphogenesis but rather in early phases of resorption of severely malformed and developmentally retarded embryos.

Animals↗

PubMed1998

The paternal allele of the H19 gene is progressively silenced during early mouse development: the acetylation status of histones may be involved in the generation of variegated expression patterns.

Transcriptional silencing can reflect heritable, epigenetic inactivation of genes, either singly or in groups, during the life-time of an organism. This phenomenon is exemplified by parent-of-origin-specific inactivation events (genomic imprinting) for a subset of mammalian autosomal genes, such as H19. Very little is known, however, about the timing and mechanism(s) of silencing of the paternal H19 allele during mouse development. Using a novel in situ approach, we present evidence that the silencing of the paternal H19 allele is progressive in the trophectodermal lineage during early mouse development and generates variegated expression patterns. The silencing process apparently involves recruitment of histone deacetylases since the mosaic paternal-specific H19 expression reappears in trichostatin A-treated mouse conceptuses, undergoing in vitro organogenesis. Moreover, the paternal H19 alleles of PatDup.d7 placentas, in which a region encompassing the H19 locus of chromosome 7 is bipaternally derived, partially escape the silencing process and are expressed in a variegated manner. We suggest that allele-specific silencing of H19 share some common features with chromatin-mediated silencing in position-effect variegation.

Acetylation↗

PubMed1998

Appearance of glucose-induced insulin release in fetal rat beta-cells.

Fetal rat pancreatic cells were isolated from pancreatic primordia on days 12-14 of pregnancy and cultured for 48 h in the presence of 5 mmol/l glucose. Insulin accumulation in the medium over the next 24 h was measured. Cultured cells from day 12 fetuses secreted about 1 fmol insulin per pancreas in response to 5 or 15 mmol/l glucose irrespective of whether 1 mmol/l tolbutamide, 400 mumol/l diazoxide, 5 mmol/l theophylline or 10 mmol/l mannoheptulose was present. In contrast, insulin released from day 13 cultured cells increased significantly from 3.0 +/- 0.6 to 6.2 +/- 2.2 fmol per pancreas, when the glucose concentration was raised. Tolbutamide increased, diazoxide and mannoheptulose decreased and theophylline had no effect on insulin release. Even more pronounced effects were found on insulin release from day 14 cultured cells, in which theophylline also increased the release. In addition, insulin release from cells from pregnancy day 14 was 75 +/- 16 amol/min per pancreas when the cells were perifused for 15-20 min in the presence of 5 mmol/l glucose within 3 h of isolation. Increasing the glucose concentration to 15 mmol/l or adding tolbutamide increased, whereas diazoxide decreased, insulin release in the freshly isolated cells. The insulin content of rat pancreata from pregnancy day 13 was 0.06 +/- 0.01 pmol per pancreas and increased approximately 10-fold every second day up to 6.7 +/- 0.9 pmol on day 17 of pregnancy. Between day 17 and 19 the pancreatic insulin content increased about fivefold to 39 +/- 2 pmol. The present data suggest that critical components of the insulin-secretory machinery, including ATP-regulated K+ channels, glucokinase and adenylate cyclase activities, are present in the developing beta-cell earlier than hitherto thought.

Animals↗

PubMed1998

Beta-hydroxybutyrate increases reactive oxygen species in late but not in early postimplantation embryonic cells in vitro.

Embryonic dysmorphogenesis has been blocked by antioxidant treatment in vivo and in vitro, suggesting that embryonic excess of reactive oxygen species (ROS) has a role in the teratogenic process of diabetic pregnancy. We report that the basal levels of ROS in dispersed rat embryonic cells in vitro, as determined by fluorescence of dichlorofluorescein (DCF), were not different in cells from control and diabetic pregnancy at day 10 or 12. Beta-hydroxybutyrate (beta-HB) and succinic acid monomethyl ester both augmented DCF fluorescence in cells from day 12 embryos of normal and diabetic rats but not from day 10 embryos. Cells of day 10 and day 12 embryos from normal and diabetic rats responded to increasing glucose concentrations with a dosage-dependent alleviation of DCF fluorescence. Day 10 embryonic cells exhibited high glucose utilization rates and high pentose phosphate shunt rates, but low mitochondrial oxidation rates. Moreover, in vitro culture of embryos between gestational days 9 and 10 in the presence of 20% oxygen induced an increased and glucose-sensitive oxidation of glucose compared with embryos not cultured in vitro. At gestation day 12, however, pentose phosphate shunt rates showed a decrease, whereas the mitochondrial beta-HB oxidation rates were increased compared with those at gestation day 10. This was paralleled by a lower expression of glucose 6-phosphate dehydrogenase- and phosphofructokinase-mRNA levels at day 12 than at day 10. On the other hand, H-ferritin mRNA expression at day 12 was high compared with day 10. None of the mRNA species investigated were affected by the diabetic state of the mother. It was concluded that beta-HB-induced stimulation of mitochondrial oxidative events may lead to the generation of ROS at gestational day 12, but probably not at day 10, when only a minute amount of mitochondrial activity occurs. Thus our results do not support the notion of diabetes-induced mitochondrial oxidative stress before the development of a placental supply of oxygen.

3-Hydroxybutyric Acid↗

PubMed1998

Teratogenicity of 3-deoxyglucosone and diabetic embryopathy.

The increased rate of embryonic dysmorphogenesis in diabetic pregnancy is correlated with the severity and duration of the concurrent hyperglycemia during early gestation. Whole embryo culture was used to investigate a possible association of hyperglycemia-induced disturbances of embryo development with tissue levels of the three alpha-oxoaldehydes: glyoxal, methylglyoxal, and 3-deoxyglucosone (3-DG). Rat embryos exposed to high glucose levels in vitro showed severe dysmorphogenesis and a 17-fold increased concentration of 3-DG compared with control embryos cultured in a low glucose concentration. Exogenous 3-DG (100 micromol/l) added to the medium of control cultures yielded an increased embryonic malformation rate and a 3-DG concentration similar to that of embryos cultured in high glucose. Addition of superoxide dismutase (SOD) to the culture medium decreased the malformation rates of embryos exposed to either high glucose or high 3-DG levels, but it did not decrease the high embryonic 3-DG concentrations caused by either agent. Our results implicate the potent glycating agent 3-DG as a teratogenic factor in diabetic embryopathy. In addition, the anti-teratogenic effect of SOD administration appears to occur downstream of 3-DG formation, suggesting that 3-DG accumulation leads to superoxide-mediated embryopathy.

Animals↗

PubMed1998

Antioxidants diminish developmental damage induced by high glucose and cyclooxygenase inhibitors in rat embryos in vitro.

Previous studies have suggested that the metabolism of arachidonic acid and radical oxygen species (ROS) are altered in diabetes and that these disturbances may induce severe embryonic dysmorphogenesis in diabetic pregnancy. We tested this hypothesis by studying whether an inhibition of the rate-limiting enzyme of prostaglandin biosynthesis, cyclooxygenase (COX), caused developmental disturbances analogous to those seen in embryos exposed to high glucose concentration. Whether antioxidants could prevent such developmental alterations was also investigated. Whole embryo culture was used in which day-9 embryos were exposed to high concentrations of glucose, arachidonic acid, prostaglandin (PG)E2, COX inhibitors, and antioxidants for 48 h. Increased glucose concentration (from 10 to 30 mmol/l) caused embryonic dysmorphogenesis, and addition of either 60 pmol/l arachidonic acid or 280 nmol/l PGE2 largely protected the embryo from this maldevelopment. Furthermore, exposure to the COX inhibitors indomethacin (200 micromol/l) or acetylsalicylic acid (700 micromol/l) in 10 mmol/l glucose concentration yielded embryonic dysmorphogenesis similar to that caused by 30 mmol/l glucose. Supplementation of either arachidonic acid or PGE2 to the culture medium with COX inhibitors in low glucose rectified the embryonic development, and PGE2 supplementation also normalized the development of embryos cultured with COX inhibitors in high glucose concentration. Interestingly, the antioxidants superoxide dismutase (SOD) and N-acetylcysteine (NAC) were each able to diminish the dysmorphogenesis induced by the COX inhibitors, at doses previously shown to diminish glucose-induced embryonic damage in the same in vitro culture system. In conclusion, the present study shows that a high glucose concentration disturbs embryonic development and that this disturbance may be partly mediated via altered metabolism of arachidonic acid and ROS in the embryo.

Acetylcysteine↗

PubMed1997

Increase of bikunin and alpha1-microglobulin concentrations in urine of rats during pregnancy is due to decreased tubular reabsorption.

Bikunin and alpha1-microglobulin are two plasma proteins of about 25 kDa which are made in the liver from a common precursor. The concentration of bikunin in human urine has been shown to increase several fold during various conditions of stress. The mechanism behind this increase is unknown. We have studied pregnant rats and found that the bikunin and alpha1-microglobulin levels in their urine increased 3-fold towards the end of the pregnancy, whereas those of albumin and orosomucoid did not. There were no significant changes in either the bikunin/alpha1-microglobulin mRNA level or the concentrations of the two proteins in serum. These findings imply that the synthesis and the clearance rates of bikunin and alpha1-microglobulin are normal during pregnancy but that the tubular reabsorption of these proteins is decreased.

Alpha-Globulins↗

PubMed1997

Decreased catalase activity in malformation-prone embryos of diabetic rats.

The risk for congenital malformation is increased in diabetic pregnancy. An excess of radical oxygen species (ROS) in the embryo has been suggested as a major teratogenic mechanism. We have used 2 rat strains, denoted H and U, with different catalase isoenzymes to study if the type of ROS scavenging enzyme may be of importance for the embryonic dysmorphogenesis in diabetic pregnancy. Rats were mated H x H and U x U, and about half of the females had streptozotocin-induced diabetes. Embryos were harvested from female rats on day 11 and day 20 of pregnancy. On day 11, the H embryos showed larger crown-rump length (3.9 mm) than the U embryos (2.9 mm), a difference that remained in the embryos of diabetic rats (3.1 mm and 2.5 mm in the H and U strains, respectively). H embryos displayed higher activity of catalase (1.8 +/- 0.1 U/micrograms DNA) than U embryos (1.1 +/- 0.1 U/micrograms DNA), and the difference increased further when the H and U mothers were diabetic (H: 2.1 +/- 0.2 U/micrograms DNA, U: 0.6 +/- 0.1 U/micrograms DNA). In the day-20 fetuses, diabetes in the mother caused increased resorption rate in both strains (from 3.2% to 10.6% in H rats, from 6.8% to 39.5% in U rats), and high rate of congenital malformations in the U strain (H: 0% malformations, U: 20% malformations). We found a strain-related difference in embryo catalase activity with higher activity in the teratogenically resistant H embryos compared to the malformation-prone U embryos. Provided that this difference between the strains signifies a genetic difference of functional antioxidative importance, the results may suggest that catalase enzyme activity has a protective role in opposing embryonic dysmorphogenesis in diabetic rat pregnancy.

Abnormalities, Drug-Induced↗

PubMed1997

Teratogenic effect of diabetic serum is prevented by supplementation of superoxide dismutase and N-acetylcysteine in rat embryo culture.

Congenital malformations are more common in offspring of diabetic mothers than offspring of non-diabetic mothers. The precise cell biological mechanism leading to the increased incidence of congenital malformations in diabetic pregnancy is not known. In previous studies increased glucose and beta-hydroxybutyrate concentrations were found to cause embryonic dysmorphogenesis. We have previously shown that rat embryos, cultured in serum from insulin-treated diabetic rats, develop malformations, despite normalisation of glucose and beta-hydroxybutyrate concentration, thereby suggesting a multifactorial teratological nature of the diabetic environment. In the present study, therefore, we aimed to characterise the teratogenic activity of various components of diabetic serum and in addition to study the possible anti-teratogenic effects of supplementation of superoxide dismutase and N-acetylcysteine in rat embryo culture. We found that diabetic serum has a teratogenic effect on embryo development, a capacity residing in the alteration of several serum components in addition to glucose. Improving the embryonic capability to scavenge oxygen radicals, either by increasing superoxide dismutase activity or by supplying a rate-limiting precursor (N-acetylcysteine) for the enhanced synthesis of reduced glutathione, blocks the embryonic dysmorphogenesis.

Acetylcysteine↗

PubMed1997

Vitamin C supplementation of the maternal diet reduces the rate of malformation in the offspring of diabetic rats.

An excess of reactive oxygen species (ROS) has been associated with the increased rate of congenital malformations in experimental diabetic pregnancy. Previous in vitro and in vivo studies show that antioxidants can protect the embryonic development in a diabetic environment. In the present investigation we examined the antiteratogenic capacity of vitamin C, an antioxidative agent not previously evaluated as a dietary supplement in diabetic pregnancy. Normal and streptozotocin diabetic rats were either fed a standard diet or a diet enriched with 0.9, 1.8 or 4% sodium ascorbate throughout pregnancy. On gestational day 20, the litters of normal and diabetic rats without vitamin C supplement contained 9 and 12% early resorptions, 2 and 17% late resorptions and 1 and 27% malformations, respectively. Vitamin C treatment reduced the rates of late resorptions and malformations in the diabetic groups in proportion to the dose administered. Thus, in the diabetic group with 4% ascorbate treatment we found unchanged numbers of early resorptions, but only 7% late resorptions (p < 0.05 vs untreated diabetic pregnancy) and 8% malformations (p < 0.05 vs untreated diabetic pregnancy). Maternal diabetes did not alter tissue levels of ascorbic acid in the fetuses at term, whereas vitamin C treatment caused accumulation of ascorbic acid in the placenta, maternal and fetal liver. Vitamin C supplementation yielded increased alpha-tocopherol concentration in the placenta and caused a reduction of the high concentrations of thiobarbituric acid reactive substances (TBARS) in serum of pregnant diabetic rats. Vitamin C treatment reduces the rates of congenital malformations and late resorptions, thereby supporting that ROS are involved in the embryonic dysmorphogenesis of diabetic pregnancy.

Animals↗

PubMed1997

Altered metabolism and superoxide generation in neural tissue of rat embryos exposed to high glucose.

Oxygen uptake and glucose utilization of embryonic and fetal neural tissue of normal and diabetic rat pregnancy were studied. Exposure to 50 mM glucose inhibited oxygen uptake of embryonic neural tissue of normal rats by 28% at gestational day 9 (P < 0.001) and 20% at days 10-12 and 15 (P < 0.001) and stimulated glucose utilization by 132% at day 9 (P < 0.001), 50% at days 10 and 11 (P < 0.01), 168% at day 12 (P < 0.001), and 338% at day 15 (P < 0.001), indicating a Crabtree effect. The glucose-altered metabolism led to production of superoxide by the tissue, which was 1.8 to 2.4 nmol.h-1.microgram DNA-1 at days 9-12 and 1.2 nmol.h-1.microgram DNA-1 at day 15. The embryonic neural tissue of diabetic rats showed a diminished metabolic sensitivity to high glucose exposure, suggesting an impaired mitochondrial function. Consequently, the glucose-induced superoxide production was not detected in the tissue of embryos of diabetic rats. The data suggest that high concentration of glucose alters embryonic and fetal metabolism and causes generation of superoxide. Prolonged duration of the glucose-induced metabolic changes may impair cellular function and lead to embryonic dysmorphogenesis.

Animals↗

PubMed1997

In vitro regulation of insulin release and biosynthesis of fetal rat pancreatic cells explanted on pregnancy day 16.

Although the morphological development of the fetal pancreatic B cell has been studied in considerable detail, knowledge about the functional maturation, particularly in early stages of development, is still poor. The present paper describes a method for monolayer culture of fetal rat islet cells which allows a study of the regulation of insulin biosynthesis, release and content during critical stages of embryonic and fetal development. Suspensions of pancreatic cells were prepared from rat fetuses on pregnancy day 16 and cultured for 3 days. During the initial 2 days cultures were performed in the presence of 5 or 15 mmol/l glucose. During this initial period, culture at 5 mmol/l glucose was carried out in the presence or absence of either 10 mmol/l nicotinamide (NA) or 5 or 100 ng/ml nerve growth factor (NGF). After changing the media the cells were further exposed for 24 h to either 5 or 15 mmol/l glucose or 15 mmol/l glucose plus 5 mmol/l theophylline before measuring the insulin concentration in the culture medium. Cells that had initially been cultured for 2 days in 5 mmol/l glucose showed an increased insulin release, when subsequently cultured in 15 mmol/l glucose for 24 h. Theophylline potentiated the response and caused a decrease in cellular insulin content. Cells initially cultured in the presence of 15 mmol/l glucose showed unchanged insulin release during the subsequent 24-hour exposure to 15 mmol/l glucose, irrespective of the presence or absence of theophylline. The presence of NGF (100 ng/ml) during the initial 2-day culture period increased the insulin release in the presence of 15 mmol/l glucose and theophylline during the subsequent 24-hour culture period as compared to cells cultured in the absence of NGF. When cells were first exposed to either NA or NGF followed by exposure to 5 mmol/l glucose alone in the last 24-hour culture period, there was an increased insulin content. Rates of insulin biosynthesis remained unchanged irrespective of the glucose concentration in the culture medium. It is concluded that, already in early fetal development, B cells show glucose stimulation of insulin release albeit less pronounced than in the postnatal state.

Animals↗

PubMed1997

Vitamin E decreases the occurrence of malformations in the offspring of diabetic rats.

An association between excess oxygen radical activity and disturbed embryogenesis in diabetic pregnancy has been suggested. In the present study, the protective capacity of vitamin E with different treatment regimens was investigated in early and late pregnancy of streptozotocin-induced diabetic rats. Daily gavaging of 0.2 g/kg or 0.8 g/kg of vitamin E exerted moderate protective effects. In contrast, treatment with a diet enriched with 2% (wt/wt) of vitamin E, yielding an approximate daily dosage of 2 g/kg of vitamin E, clearly restored both embryonic and fetal morphology. High-performance liquid chromatography measurement showed that maternal diabetes decreased embryonic content of vitamin E. When pregnant diabetic animals were supplemented with vitamin E, increased concentrations of the vitamin were found in maternal, embryonic, and fetal tissues. Thus, despite marked accumulation of vitamin E in maternal tissues, the compound apparently reached the conceptus. Thiobarbituric acid reactive substances (TBARS) were estimated as a measure of lipid peroxidation, and no changes were observed in maternal tissue, embryonic tissue, placenta, and fetal brain in the untreated diabetic group. In contrast, a fivefold increase of TBARS was found in fetal liver, a rise that was reduced with vitamin E treatment of the diabetic pregnant rats and completely normalized with 2% vitamin E in the diet. Congenital malformations caused by experimental diabetes can be prevented by antioxidants in vivo. These findings further corroborate the notion that an imbalance in the metabolism of free oxygen radicals is involved in the embryonic maldevelopment of diabetic pregnancy, and suggest a direction for prophylactic treatment in the future.

Animals↗

PubMed1996

Cyanide detoxification in rats exposed to acetonitrile and fed a low protein diet.

Different neurological syndromes have been associated with exposure to cyanide. Dietary cyanide exposure from cassava roots combined with a low intake of the sulfur amino acids necessary for cyanide detoxification has been implicated in the causation of konzo, an upper motoneuron disease identified in Africa. We have investigated the effect of a low protein diet on the capacity for cyanide detoxification. Rats were fed normal chow containing 18% protein or a low protein diet with 5% protein. To expose rats to cyanide the drinking water was supplemented with 40 or 80 mM acetonitrile (CH3CN) for up to 4 weeks. Weight gain was monitored and 24-hr urines were collected for analyses of total sulfur, inorganic sulfate, thiocyanate, and 2-aminothiolazine-4-carboxylic acid (ATC). Blood was collected for analyses of cyanide and cyanate. Rats on a normal diet grew throughout the experiment, while those on a low protein diet initially lost weight and then stabilized at a constant weight. Rats exposed to acetonitrile all progressively lost weight, those on a low protein diet at the highest rate. Signs of neurological damage were not observed. Rats not exposed to acetonitrile excreted < 0.2% of sulfur as thiocyanate and those on a low protein diet reduced their total sulfur excretion to one-third that of rats of the normal diet. Rats on the normal diet did not change total sulfur excretion during exposure to acetonitrile, although thiocyanate now contributed more than two-thirds of excreted sulfur. Rats on a low protein diet exposed to acetonitrile increased both total sulfur and thiocyanate excretion to the levels of rats on a normal diet. Rats exposed to acetonitrile had manyfold increases of circulating concentrations of cyanide and cyanate and of urinary excretion of ATC. There was a positive correlation between blood cyanide concentrations and the plasma concentration of cyanate. It is concluded that the rat has a high capacity for detoxification of cyanide. During adaptation to a low protein intake, sulfur is conserved but cyanide detoxification is still possible at the cost of extensive protein catabolism. It is thus possible that subclinical cyanide exposure could interfere with normal growth and development. The observation of a relationship between circulating cyanide on the one hand and circulating cyanate and urinary excretion of ATC on the other highlights the possibility that cyanide metabolites may mediate neurotoxic effects of cyanide.

Acetonitriles↗

PubMed1996

Lifelong consequences of metabolic adaptations in utero?

Dr. Phillips argues that insulin resistance in adult life may be the price the developing fetus has to pay in return for a short-term successful adaptation to undernutrition in utero. The concept is interesting, and, indeed, challenging. There is, however, a strong need for expansion of the existing knowledge of the possible developmental mechanisms involved, especially against the background of the obvious diagnostic and therapeutic gains in this particular group of patients.

Adult↗

PubMed1996

High glucose concentration inhibits migration of rat cranial neural crest cells in vitro.

Cranial neural crest cells give rise to a large part of the facial structures, and disturbed development of these cells may therefore cause congenital malformations affecting the head and face. We studied the effects of increased glucose concentration on the migration and development of cranial neural crest cells, maintained in vitro for 48 h. Pre-migratory cranial neural crest cells were removed from embryos of normal and diabetic rats on gestational day 9. After 24 h in 10 mmol/l glucose the cells were exposed to glucose concentrations of 10, 30, or 50 mmol/l for another 24 h. The cultures were photographed at 24 h and 48 h in a phase-contrast microscope to evaluate cell morphology, cell number, and cell migration. Exposure to 50 mmol/l glucose reduced the total number of neural crest cells, their mean migratory distance and migratory area expansion compared to cells cultured in 10 mmol/l glucose. To investigate the effect of antioxidant agents, high glucose cultures were studied after addition of N-acetylcysteine (NAC), or superoxide dismutase (SOD). Addition of NAC diminished the inhibitory effect of high glucose, whereas SOD did not offer any improvement in cell development. Neural crest cell culture from embryos of diabetic rats showed reduced cell migration in vitro at all glucose concentrations compared to normal cells. In addition, the cells from embryos of diabetic rats showed reduced migratory area expansion after culture in the basal 10 mmol/l glucose concentration, indicating that maternal diabetes permanently influences the future development of premigratory cranial neural crest cells. These findings indicate that high glucose concentration inhibits cranial neural crest development in vitro, and that antioxidant therapy may diminish this inhibition. Free radical oxygen species may be involved in the induction of malformations and antioxidants may therefore have a role in future attempts to block the teratogenic effects of diabetic pregnancy.

Animals↗

PubMed1996

Effect of butylated hydroxytoluene on alpha-tocopherol content in liver and adipose tissue of rats.

Female rats were fed an antioxidant supplemented diet containing butylated hydroxytoluene (BHT; 0.5% and 1.0%) with or without vitamin E acetate (0.4%) for 4 weeks, after which the contents of BHT and alpha-tocopherol in the liver and abdominal adipose tissue were analysed. The body weight gain was similar in all groups independent of the diet after the first week of treatment. At the end of the experiment the liver weights of the BHT-supplemented rats were increased compared to the liver weights of the control groups, and this difference was unaffected by vitamin E treatment. The liver concentration of alpha-tocopherol was decreased and inversely proportional to the BHT concentration in the diet. This attenuating effect of BHT on the hepatic alpha-tocopherol concentration was present both in animals with and without vitamin E supplementation. In contrast, BHT treatment did not alter the concentration of alpha-tocopherol in abdominal adipose tissue. The results show that BHT has adverse effects in the liver. BHT is metabolized by the cytochrome P450 system in the liver and may be converted to prooxidative compounds during this process. Adipose tissue lacks the cytochrome P450 system. Therefore, the decreased hepatic concentration of alpha-tocopherol may be a consequence of a BHT-induced, free oxygen radical mediated, depletion of this antioxidant.

Adipose Tissue↗

PubMed1996

The pathogenesis of diabetes-associated congenital malformations.

Congenital malformations convey a major financial and social burden to society. Epidemiologic, clinical, and animal studies indicate that these malformations occur in early pregnancy, are influenced by an aberrant metabolic fuel milieu, and seem to result from a combination of more than one factor acting synchronously. Unfortunately, during the critical period of organogenesis, the pregnancy is hardly recognizable, making evaluation and study of relevant maternal embryonic parameters extremely difficult. Additionally, there are obvious limitations to human study for technical and ethical reasons. Animal experimentation, however, has demonstrated that these malformations can be produced in many vertebrates and are similar to those seen in humans. The mechanism for induction of dysmorphogenesis in experimental diabetic pregnancy has been shown to include generation of free oxygen radicals and are associated with alterations in the embryonic levels of arachidonic acid, prostaglandins, and myo-inositol. Most of the earlier experimental studies focused on defects at the level of the embryo excluding the extraembryonic membranes. Current investigations provide evidence that the yolk sac has an integral role in diabetic embryopathy. The experimental use of several different compounds, such as arachidonic acid, myo-inositol, and antioxidants, offers significant promise for the future in possibly serving as a pharmacologic prophylaxis against diabetic embryopathy.

Animals↗