Effects of oral meso-2,3-dimercaptosuccinic acid (DMSA) administration on late gestation and postnatal development in the mouse

The present study was conducted to evaluate the effects of meso-2,3-dimercaptosuccinic acid (DMSA) on late gestation and postnatal viability and growth in the mouse. DMSA was given po to four groups of pregnant Swiss mice at 0, 200, 400, and 800 mg/kg/day from day 14 of pregnancy until postnatal day 21. At birth, the following data were recorded: length of gestation, number of live, dead, and abnormal pups, sex, and individual pup weights. Each pup was weighed again on day 4, 14, and 21 of lactation. Pinna detachment, incisor eruption and eye opening were also monitored. No treatment-related signs of toxicity were noted in any of the dams during the study. No adverse effects on offspring survival or development were evident in the 200 or 400 mg DMSA/kg/day groups. However, on days 14 and 21 of lactation a significant decrease in pup body weight was observed in the 800 mg/kg/day group. Also, a significant increase in the relative weight of the brain was seen in this group. The "no observable effect level" (NOEL) for health hazards to the developing pup was greater than 400 mg/kg/day. This dose is higher than the amounts of DMSA usually given in the treatment of human heavy metal intoxications.     

Effects of vanadium on reproduction, gestation, parturition and lactation in rats upon oral administration

Sodium metavanadate was tested for its effects on fetal development, reproduction, gestation and lactation in Sprague Dawley rats. Male rats were administered NaVO3 po at doses of 0, 5, 10 and 20 mg/kg/day for sixty days before mating with females which had received the same doses from 14 days previous to mating. These females received 0, 5, 10 and 20 mg NaVO3/kg/day during the periods of gestation and lactation. No significant adverse effects could be observed on: number of corpora lutea, implantations, live and dead fetuses, and resorptions. Significant decreases were observed in the development of the pups in all the vanadium -treated groups. All the doses used produced toxic effects in the offspring.     

Effects of lithocholic acid exposure throughout pregnancy on late prenatal and early postnatal development in rats

The effects of lithocholic acid (LCA) on late prenatal and early postnatal development were studied. LCA was given in the diet (0.8% by weight) or administered in the drinking water (0.8%) throughout the entire period of pregnancy. The addition of LCA to the drinking water caused a significant reduction in the weight of 20-day-old fetuses as well as their placentas and livers. Feeding LCA to pregnant rats affected postnatal growth of the offspring: their weight was significantly lower than control values until 6 weeks of age. The pattern of postnatal growth was similar in the experimental and control rats. The retardation in growth and development of the offspring was accompanied by microscopic and biochemical changes in their livers.     

The effect of rapamycin on DNA synthesis in multiple tissues from late gestation fetal and postnatal rats

Rapamycin is a potent antiproliferative agent that arrests cells in the G1 phase of the cell cycle through a variety of mechanisms involving the inhibition of the mammalian target of rapamycin (mTOR) pathway. The majority of normal cells in culture are sensitive to the cytostatic effects of rapamycin, whereas the growth of many malignant cells and tumors is rapamycin resistant. We had shown previously that hepatic DNA synthesis in the late gestation rat fetus is rapamycin resistant even though signaling through the mTOR/S6 kinase (S6K) pathway is attenuated. On the basis of this finding, we went on to characterize the response to rapamycin in a spectrum of tissues during late gestation and the early postnatal period in the rat. We found that rapamycin had no effect on DNA synthesis in major organs such as heart, intestine, and kidney in the fetal and early postnatal rat despite a marked attenuation in the phosphorylation of ribosomal protein S6. In contrast, the proliferation of mature hepatocytes during liver regeneration was highly sensitive to rapamycin. These data indicate that basal cellular proliferation in a wide variety of tissues is rapamycin resistant and occurs independently of mTOR/S6K signaling. Furthermore, the well-characterized effects of rapamycin in tissue culture systems are not recapitulated in the asynchronous cell proliferation that accompanies normal growth and tissue remodeling.     

Embryotoxic and teratogenic effects of aluminum nitrate in rats upon oral administration

In order to determine the embryotoxic and teratogenic potential of aluminum, pregnant Sprague-Dawley rats were treated by gavage with a daily dose of 180, 360, or 720 mg/kg of aluminum nitrate from the sixth through to the fourteenth day of gestation. Fetal examinations were performed on day 20. The number of corpora lutea, total implants, and resorptions as well as the number of live and dead fetuses in the treated animals were not significantly different from the control group. Therefore, embryolethality of aluminum cannot be induced (as a measure of percent dead and resorbed fetuses). However, exposure of rats to aluminum nitrate resulted in decreased fetal body weight and increased the incidence and types of external, visceral, and skeletal malformations and variations in all the treated groups. Consequently, teratogenic effects of aluminum-nitrate administration may result in rats given high oral doses that induce concomitant maternal toxicity.     

The effect of chronic oral alcoholization upon late fetal development in mice

The late fetal effect of chronic alcoholization in two strains of mice (RAP and RAP female x CBAT6 male) was controlled. Unilateral ocular anomalies (retinal folding, various degrees of ocular disorganization) were detected in 16% of the alcoholized RAP female x CBAT6 male group. The findings are discussed in connection with other experimental models of alcohol embryo and fetopathy.     

Alcohol exposure during late gestation adversely affects myocardial development with implications for postnatal cardiac function

Prenatal exposure to high levels of ethanol is associated with cardiac malformations, but the effects of lower levels of exposure on the heart are unclear. Our aim was to investigate the effects of daily exposure to ethanol during late gestation, when cardiomyocytes are undergoing maturation, on the developing myocardium. Pregnant ewes were infused with either ethanol (0.75 g/kg) or saline for 1 h each day from gestational days 95 to 133 (term ～145 days); tissues were collected at 134 days. In sheep, cardiomyocytes mature during late gestation as in humans. Within the left ventricle (LV), cardiomyocyte number was determined using unbiased stereology and cardiomyocyte size and nuclearity determined using confocal microscopy. Collagen deposition was quantified using image analysis. Genes relating to cardiomyocyte proliferation and apoptosis were examined using quantitative real-time PCR. Fetal plasma ethanol concentration reached 0.11 g/dL after EtOH infusions. Ethanol exposure induced significant increases in relative heart weight, relative LV wall volume, and cardiomyocyte cross-sectional area. Ethanol exposure advanced LV maturation in that the proportion of binucleated cardiomyocytes increased by 12%, and the number of mononucleated cardiomyocytes was decreased by a similar amount. Apoptotic gene expression increased in the ethanol-exposed hearts, although there were no significant differences between groups in total cardiomyocyte number or interstitial collagen. Daily exposure to a moderate dose of ethanol in late gestation accelerates the maturation of cardiomyocytes and increases cardiomyocyte and LV tissue volume in the fetal heart. These effects on cardiomyocyte growth may program for long-term cardiac vulnerability.     

Vitamin D-dependent calcium-binding protein. Changes during gestation, prenatal and postnatal development in rats

During the perinatal period, calcium metabolism is stressed. As intestinal Ca-binding protein is considered as a molecular expression of the hormonal effect of 1,25-dihydroxycholecalciferol (1,25(OH)2D3), Ca-binding protin measurements may document the vitamin D roles during this period. We describe the variations of Ca-binding protein concentrations in the rat during the last 5 days of gestation, in the maternal duodenum, placentas, fetal membranes and fetal intestines. We also report intestinal Ca-binding protein changes from birth until weaning. The evolution of the maternal intestinal Ca-binding protein, which increases on day 19.5 of gestation, is consistent with that of calcium intestinal absorption and may be explained by increased 1,25(OH)2D3 production. Placental Ca-binding protein rises from day 17.5 until the end of gestation, and may be related to the profile of calcium transfer from mother to fetuses. It is noteworthy that the placental Ca-binding protein is predominantly found in the fetal part of the organ where materno-fetal exchanges occur. The yolk sac synthesizes substantial amounts of Ca-binding protein. In the fetal membranes, Ca-binding protein plateaus from day 17.5 until day 20.5 and decreases on day 21.5. The Ca-binding protein presence in the fetal placenta and in the yolk sac may suggest that these tissues are also targets for vitamin D. In the fetus the intestinal Ca-binding protein s is detected as early as day 17.5 of gestation and increases markedly during the last day of gestation. From birth and during the first 3 weeks of postnatal life, the intestinal Ca-binding protein concentration does not change. It undergoes a sharp rise just at the time of weaning. We have also shown that the specific distribution of Ca-binding protein along the intestine is acquired during intrauterine life and does not change with sucking or weaning. The two main changes of intestinal Ca-binding protein, observed just before birth and at weaning, may reflect the intestinal maturation and/or variations in vitamin D metabolism.     

Behavioral effects of bovine lactoferrin administration during postnatal development of rats

We tested the hypothesis that rats consuming bovine lactoferrin (bLf) during postnatal development would show better performance of stressful tasks during adolescence. In the first study, we orally administered bLf (750 mg/kg) once daily between postnatal days 16–34. Rats then underwent a battery of behavioral tests: open field (forced exploration of risky environment), light–dark emergence (voluntary exploration of risky environment), baited holeboard (working and reference memory), food neophobia (preference for familiar versus novel food), forced swim (test for antidepressant efficacy), and shuttle-box escape (learning to escape footshock). bLf-supplemented rats showed less exploration of the risky environment, greater preference for the familiar food odor, and faster escape responses. The effect of bLf on forced-swim behavior depended on sex: immobility increased for males and decreased for females. In the next study, we replaced the forced-swim test with an escape-swim test in which rats learned to use a visual cue to locate an escape platform, and we tested the dose response of bLf on this and the shuttle-box escape test, with subjects receiving vehicle or bLf at 500, 1,000, or 2,000 mg/kg. Under this modified testing battery, improvement of escape from footshock was not observed at any dose. However, males, but not females, showed a significant dose-dependent effect of bLf on acquisition of the water-escape task. On average, males receiving a higher dose mastered the task 20–25 % sooner than rats receiving a lower dose or vehicle. These results offer preliminary evidence that bLf supplementation during development can improve subsequent cognitive performance during stress.     

Cardiac cytochrome-c oxidase deficiency occurs during late postnatal development in progeny of copper-deficient rats

Although cytochrome-c oxidase (CCO) is a copper-dependent enzyme, the effect of maternal copper deficiency on the expression of CCO activity during postnatal development of the neonatal rat heart has not been investigated extensively. Here, we show that CCO activity in heart mitochondria isolated from neonates of copper-deficient dams did not exhibit significant reductions until postnatal days (PND) 15 and 21. In addition, immunoblot analysis indicated that the CCO subunit (Cox-1) was reduced on postnatal Days 10 and 21, and that Cox-4 was reduced on PND 21 in heart mitochondria of the neonates from copper-deficient dams. These findings indicate that the impairment of CCO activity in neonatal heart by maternal copper deficiency occurs late in the postnatal heart development. Furthermore, the concurrent reductions in Cox-1 and Cox-4 suggest that the impaired CCO activity reflects a CCO deficiency in heart mitochondria. CCO activity and Cox-1 in heart mitochondria were not fully restored by 6 weeks of postweaning copper repletion in the pups of copper-deficient dams. This indicates that prolonged maternal intake of moderately low dietary copper produces CCO deficiency in cardiac mitochondria of neonates during late postnatal heart development, after terminal differentiation of cardiomyocytes occurs. The resistance of CCO deficiency to repair by dietary copper supplementation may be related to the relatively slow turnover of the affected mitochondria in the terminally differentiated heart.     

Adrenocorticotropin administration during early gestation on conceptus development in swine

The purpose of this study was to examine the effect of exogenous adrenocorticotropin (ACTH), administered to gilts during early stages of gestation, upon fetal survival and various maternal and conceptus parameters. Forty-eight gilts of approximately 6-7 months of age were bred by means of artificial insemination after detection of the second estrus and randomly allotted to one of 12 treatment-period groups. Treatment consisted of a daily intramuscular injection of 0, 40 or 80 U.S.P. units of a long acting ACTH preparation for a period of five days. The injection periods were 1-5, 6-10, 11-15 or 16-20 days of gestation with day one corresponding to 48 hours post-estrus detection. All gilts were slaughtered at approximately 37 days of gestation. Forty-two of the 48 inseminated gilts conceived. Conception rate was not different (P>.10) among the 12 treatment-period combinations. Percent fetal survival was greater (P<.09) in gilts receiving 80 U.S.P. units of ACTH (82 +/- 4.3%; X +/- SEM ) than in gilts receiving 40 U.S.P. units of ACTH (68.8 +/- 4.5%). The percent fetal survival in the control group (71.7 +/- 3.9%) was not different (P>.10) from either of the two ACTH treatment groups. A significant (P<.05) treatment by period interaction for percent fetal survival was observed. The lowest percent fetal survival (48.0 +/- 9.0%) was observed in gilts receiving 40 U.S.P. units of ACTH on day 11-15 of gestation. No significant (P>.10) differences were detected among the 12 treatment-period combinations for any of the maternal or conceptus parameters measured.     

Effects of anandamide on gestation in pregnant rats

The present study was to test whether the recently described endogenous ligand for the cannabinoid receptor; arachidonyl-ethanolamide (anandamide, ANA), may produce similar effects on pregnancy as the main psychoactive component of marihuana: Δ⁹-tetrahydrocannabinol (THC) in rats. ANA, THC (0.02 mg/kg i.p./day, respectively) or vehicle were injected daily over the third week of pregnancy. The pregnant rats were either killed on day 21 of pregnancy or followed up to delivery. Results show a significant increase in the duration of pregnancy after both THC and ANA treatment. Both drugs caused an increase in the frequency of stillbirths. The mothers' hormone contents in tissues and sera were measured. Decreased LH content was observed in the serum of treated animals. No changes in FSH content were observed either in the pituitary or in the sera. Pituitary prolactin (PRL) levels was lower in ANA treated animals as compared both to controls or THC treated subjects. The serum PRL content decreased in all experimental groups. Decrease in serum progesterone was more prominent in treated rats. Serum levels of prostaglandins (PGF 1 and PGF 2) were significantly decreased after THC and ANA treatment. We conclude that ANA has the same tendency to change reproductory parameters in pregnant rats as THC, although in some cases the effects of ANA were slightly different from that of THC. Both endogenous and exogenous cannabinoids inhibit PG synthesis in pregnant rats and this maybe responsible for the delay constitute the mechanism in the onset of labour.     

Effects of oral administration of benzylamine on glucose tolerance and lipid metabolism in rats

Repeated administration of benzylamine plus vanadate have been reported to exhibit anti-hyperglycemic effects in different models of diabetic rats. Likewise oral treatment withMoringa oleifera extracts which contain the alkaloïd moringine, identical to benzylamine, has also been shown to prevent hyperglycemia in alloxan-induced diabetic rats. With these observations we tested whether prolonged oral administration of benzylamine could interact with glucose and/or lipid metabolism. Seven week old male Wistar rats were treated for seven weeks with benzylamine 2.9 g/l in drinking water and were submitted to glucose tolerance tests. A slight decrease in water consumption was observed in benzylamine-treated animals while there was no change in body and adipose tissue weights at the end of treatment. Blood glucose and plasma insulin, triacylglycerol or cholesterol levels were not modified. However, benzylamine treatment resulted in a decrease in plasma free fatty acids in both fed and fasted conditions. Benzylamine treatment improved glucose tolerance as shown by the reduction of hyperglycemic response to intra-peritoneal glucose load. Oral benzylamine treatment did not alter the response of adipocytes to insulin nor to insulin-like actions of benzylamine plus vanadate, viain vitro activation of glucose transport or inhibition of lipolysis. This work demonstrates for the first time that oral administration of benzylamine alone influences glucose and lipid metabolism. However, these results obtained in normoglycemic rats require to be confirmed in diabetic models.     

Effects of age and biotin status on postnatal development of plasma biotinidase activity in rats

Biotinidase activity was measured in plasmas of 1-, 7-, 14-, and 21-day-old rats from control dams and dams that had been fed a biotin-depleting diet from Day 15 of gestation. Biotinidase activity increased significantly in the plasma of rats from control and depleted mothers until Postnatal Day 14, after which there was a small but significant decline at Day 21. Differences between the mean activities of the two groups of pups on each sampling day were not significant and there were no significant differences in activity levels attributable to sex. Plasma albumin concentrations increased from birth until Day 21, and plasma biotinidase activity and albumin concentration were significantly correlated (r = +/- 0.43). We suggested that these two proteins may be controlled by a common mechanism in the early postnatal period, and that biotin deficiency does not affect the development of biotinidase activity. Because biotin-depleted neonatal pups show developmental changes in biotinidase activity similar to those of human newborns, and they can be produced reliably by depleting dams from Day 15 of gestation, they may be useful models for studying the developmental abnormalities associated with human biotinidase deficiency.     

Effects of prenatal X-irradiation on the 14th-18th days of gestation on postnatal growth and development in the rat

Thirty-nine pregnant adult Wistar strain rats were randomly assigned to one of three exposure groups: 0, 0.75, or 1.50 Gy X-radiation total exposure. Animals were exposed from the 14th to the 18th days of gestation at 0, 0.15, or 0.30 Gy per day. At term, 15 rats were killed and morphologic analyses were completed. Twenty-four rats were allowed to deliver their offspring. On the first day of postnatal life, litters were reduced to a maximum of eight pups per litter, with equal numbers of male and female offspring wherever possible. A total of 187 pups were observed for the age of acquisition of five reflexes (air righting, surface righting, visual placing, negative geotaxis, auditory startle) and the appearance of four physiologic markers (pinna detachment, eye opening, vaginal opening, testes descent). There was significant dose-related weight reduction in term fetuses and offspring throughout the 86-day postnatal period. Postnatal growth rate (g gained/day) was unaffected. Adult offspring brain and gonadal weight and organ weight:body weight ratios were reduced. Using the PAC50 methodology, dose-related alterations occurred in the acquisition of several reflexes. All physiologic markers exhibited a dose-related delay in appearance. These results indicate that fractionated exposure to X-radiation during the fetal period in the rat results in dose-dependent alterations in postnatal growth and physiologic development. These studies are important for our understanding of the long-range effects of prenatal exposure to ionizing radiation late in gestation.     

Effect of quercetin on some indicators of the proteinase-proteinase inhibitor system in rats upon administration of cobalt chloride to them

The results of quercetin effect on some changes of proteinase--proteinase inhibitor system parameters in rats under cobalt chloride injection are shown. It was established that preliminary quercetin administration prevened neutral proteinase activation and alpha-2-macroglobulin activity decreasing after 2 h of cobalt chloride influence.     

Effects of change of maternal environment during early postnatal development on behaviour in cataleptic rats

Pinch-induced catalepsy was compared at an age of 2 weeks and at weaning in cataleptic GC and control Wistar rats reared by their biological mothers or subjected to reciprocal in-or cross-fostering. Besides, some open-field parameters were studied in the same groups of rats at an age of 2 months. Significant interstrain differences in all the behavioural parameters studied were found. Reciprocal cross-fostering tended to diminish interstrain differences in most parameters. It brought about a decrease of duration of pinch-induced catalepsy at 2 weeks and at weaning in GC rats, and an increase of duration of catalepsy at weaning in Wistar females. Besides, cross-fostering decreased the duration of freezing in the open-field test in GC rats at 2 months.