Effect of intrauterine exposure of murine fetus to cyclophosphamide on development of thymus

The objective of this study was to demonstrate thymic alterations produced by cyclophosphamide intervention during intrauterine life of murine fetus. Cyclophosphamide (CP) was administered to pregnant mice on day 11 of gestation in a single dose of 10 mg/kg body weight. Fetuses were dissected out on day 19 and studied for various effects on thymus. Thymus of fetuses exposed to cyclophosphamide showed thymic atrophy with retardation of thymic size and a remarkable shrinkage in lobular morphology. Histological studies showed a massive depletion of thymic cortex. Study of thymocytes revealed an increase in apoptotic cell count and percent DNA fragmentation along with a decrease in proliferation. Thymocytes obtained from fetuses of CP-treated mice showed a higher expression of caspase-activated DNase (CAD) indicating that the CP-dependent induction of apoptosis in thymocytes involved caspase pathway. The results of the present study may help in understanding the mechanism of the teratogenic effect of cyclophosphamide on thymus.     

Effect of prenatal exposure to ethanol on the ultrastructure of layer V of mature rat somatosensory cortex

Summary Recent data have shown that the structure and function of layer V pyramidal neurons, e.g. corticospinal neurons, is altered by prenatal exposure to ethanol. We examined the effect of ethanol on the ultrastructure of layer V in somatosensory cortex. Timed pregnant rats were fed a diet containing 6.7% (v/v) ethanol (E) or pair-fed a nutritionally matched control diet (C). Thirty-day-old offspring of these mothers were prepared by standard electron microscopic techniques. The somata of pyramidal and local circuit neurons and the neuropil were analysed.Prenatal exposure to ethanol induced alterations in the somata of both populations of neurons. The parallel stacking of cisternae characteristic of C-treated rats was disorganized in E-treated rats. Moreover, the Golgi complex and lysosomes occupied a larger fraction of the somata of E-treated rats. The number and frequency of symmetric axosomatic synapses, but not asymmetric axosomatic synapses, formed by both types of neurons were significantly greater in E-treated rats. Gesta tional exposure to ethanol produced a variety of changes in the neuropil. Dendrites, particularly dendritic shafts, occupied less space in E-treated rats. In contrast, axons accounted for significantly more of the neuropil in E-treated rats than in controls. This increase in axonal space was due to a significantly greater coverage by non-myelinated axons and a significantly smaller coverage by myelinated axons in E-treated rats than in C-treated rats. Although the overall frequency of synapses was similar in both treatment groups, there were significantly more asymmetric synapses in E-treated rats, and most of these were axospinous synapses.These differences may contribute to documented physiological changes such as the lower rate of glucose utilization in layer V of somatosensory cortex of E-treated rats and they may underlie the mental retardation which is characteristic of children with foetal alcohol syndrome.     

Effect of prenatal propranolol exposure on development of the postnatal rat heart

Maternal propranolol (PRO) treatment has previously been associated with adverse effects on the fetus and neonate. In the present study, pregnant rats were treated with PRO (25 or 50 mg/kg/day s.c.) on gestation days 8-20 to assess its possible effects on the developing heart. Maternal weight gain and pup weight on postnatal day (PND) 1 were reduced in a dose-dependent manner; litter size was unaffected. Pup body weight and heart weight both showed a dose-related decrease at all ages tested (PNDs 5/6, 8/9, 15/16, and 22/23). Since heart protein, but not DNA, was similarly reduced, the decrease seen in heart weight most likely reflects a decrease in cell size instead of cell number. Basal ornithine decarboxylase (ODC), an enzyme associated with growth and development, was unaffected by maternal PRO treatment. Insulin and isoproterenol stimulation of ODC, suggested markers for testing the function of the sympathetic pathway to the heart and of the heart's ODC response system, respectively, also showed no PRO-related response. In conclusion, prenatal PRO exposure resulted in reduced body weight, heart weight, and heart protein, but had little effect on heart DNA or ODC activity. Since PRO treatment also reduced maternal weight gain, the adverse effects seen in the pups may be due to generalized PRO toxicity. The results suggest that when high PRO doses were used clinically, the careful monitoring of maternal weight gain during pregnancy might be useful in predicting adverse fetal effects.     

Effect of prenatal reserpine exposure on development of the postnatal rat heart

Previous studies have suggested that reserpine treatment may result in altered heart development. In order to more fully investigate this possibility, reserpine was administered s.c. at 0, 0.375, or 0.75 mg/kg/day to pregnant rats on gestation days 12-15. Maternal weight gain, as well as pup weight on postnatal day (PND) 1, was significantly reduced in a dose-dependent manner. Litter size was unaffected, but reserpine-treated dams had more dead pups than did control dams. On PND 1, litters were randomly standardized at ten pups each for analysis on PNDs 5, 8, 15, and 22. Pup body weight and heart weight were reduced in a dose-related manner at all ages measured. The decreased heart weights were probably due to decreases in cell number. Beta-adrenergic receptor concentration was significantly reduced only on PND 5, at the low reserpine dose, and was not considered to be a treatment effect. Prenatal reserpine exposure had no effect on levels of basal cardiac ornithine decarboxylase (ODC), an enzyme associated with growth and development. Cardiac ODC stimulation by insulin and isoproterenol also showed no effects of maternal reserpine treatment. The results suggest that maternal reserpine treatment may lead to adverse effects in the developing offspring.     

Effect of prenatal exposure to ethanol on glutamate and GABA immunoreactivity in macaque somatosensory and motor cortices: critical timing of exposure

The present study explored the effects of gestational ethanol exposure on enduring changes in the distribution of projection neurons and local circuit neurons in somatosensory/motor cortex. Critical events in corticogenesis occur during macaque gestation: the first six weeks of gestation include the period of primary stem cell production and the next 18 weeks are marked by the birth, migration, early differentiation, and death of cortical neurons. Monkeys were exposed to ethanol (or saline) one day per week during the first six or during the entire 24 weeks of gestation. Offspring were killed as adolescents. Projection neurons and local circuit neurons were identified immunohistochemically with antibodies directed against glutamate and anti-GABA, respectively. In all animals, both projection neurons and local circuit neurons were distributed in all laminae of both somatosensory and motor cortices. Ethanol did not affect the size of Cresyl Violet-stained, glutamate-positive, or GABA-immunolabeled somata, however, it did decrease neuronal density. The total density of Cresyl Violet-stained neurons was reduced in monkeys treated with ethanol (or saline) one day per week during the first six weeks of gestation and during the entire 24 weeks of gestation. Similar reductions were detected for glutamate- and GABA-positive neurons. The densities of Cresyl Violet-stained and of glutamate- and GABA-expressing neurons were reduced in all cortical layers. The only exception was layer V which was unaffected in monkeys treated with ethanol (or saline) one day per week during the first six weeks of gestation and during the entire 24 weeks of gestation. Thus, the parallel effects on both neuronal subpopulations suggest that ethanol targets a population of undetermined neuronal precursors.     

Effect of prenatal imipramine exposure on development of the postnatal rat heart and brain

Imipramine (IMI) was administered s.c. at 0, 5, or 10 mg/kg/day to pregnant rats on gestation days 8-20 to assess possible alterations in postnatal heart and brain development. Maternal weight gain was significantly reduced in a dose-response manner, but litter size and pup weight on postnatal day (PND) 1 were unaffected. On PND 1, litters were culled to 10 pups for analysis on PNDs 4/5, 7/8, 14/15, and 21/22. Pup body weight was not affected at any age measured, but heart weight was significantly reduced at 10 mg/kg IMI on PNDs 4/5 and 7/8. Brain weight was increased in a dose-related pattern on PNDs 4/5 and 7/8 and was significantly higher at 5 mg/kg IMI on PND 14/15. No significant effect was observed in heart or brain protein and DNA content or in cardiac beta-adrenergic receptor concentration. Prenatal IMI exposure had no effect on basal cardiac ornithine decarboxylase (ODC), an enzyme associated with growth and development, but basal brain ODC was lower at 5 mg/kg IMI at all ages measured. Cardiac ODC stimulation by insulin was unaffected by prenatal exposure to IMI, but isoproterenol-stimulated ODC was increased on PND 21/22 at 5 mg/kg IMI. In conclusion, the IMI-related changes in several parameters suggest that when maternal IMI treatment is used, alterations in postnatal heart and brain development must be considered as possible outcomes.     

Long-term consequences of prenatal exposure to lead on brain development in rats

Administration of singe doses of lead citrate (200 mg/kg) to pregnant rats (on day 18 of pregnancy) was followed by the appearance of destructive changes in brains at age 40 days, with cysts, foci of gliocyte proliferation, pyknotic neurons, and decreases in NADH and NADPH diaphorase activities in neocortical and hippocampal neurons. Decreases in the density of neurons in the cortex and decreases in cortical thickness were also observed. The intensity of free-radical oxidation in the cortex increased three-fold, along with a 3.9-fold increase in the concentration of lipid peroxides, providing evidence of oxidative stress. The possible mechanisms by which these alterations develop are analyzed. __________ Translated from Morfologiya, Vol. 131, No. 1, pp. 27–31, January–February, 2007.     

Modeling the effects of prenatal exposure to aspirin on the postnatal development of rat brain

Three growth models were used to examine the effects of prenatal exposure to aspirin on the postnatal development of brain parts. A total of 60 pregnant rats which were divided into three experimental groups and a control group were exposed to aspirin doses of 12.5, 25, 37.5 mg/kg, and distilled water, respectively. The brain parts of 200 rat pups starting from the first week after birth until the fifth week were weighted and the length and width of the cerebrum and cerebellum were measured to determine the parameters of the growth models. The results indicated that the three models successfully predicted the growth of the different brain parts and that aspirin decreased the total brain weight, cerebrum length and width, and decreased the cerebellum length and width at aspirin dose of 37.5 mg/kg. Further analysis is needed to investigate if aspirin effects were carried out through its role in inhibiting prostaglandin production and consequently affecting the activity of the hypothalamus-pituitary axis.     

Chick embryonic development following exposure to ethanol and pyrazole

The mechanism of alcohol-induced dysmorphogenesis is not clear. Pyrazole is a potent inhibitor of alcohol dehydrogenase. Treatment of chick embryos at 96 h incubation with pyrazole (0.1 mg) and ethanol (0.1 ml, 40-60% v/v) enhanced the embryopathic response, compared with individual treatments. The results suggest that ethanol itself is embryotoxic.     

Adult brain nitrergic activity after concomitant prenatal exposure to ethanol and methyl mercury

Pregnant rats were exposed to ethanol (EtOH) and/or methyl mercury (MeHg) during fetal brain development. Nitrergic activity was quantified by densitometric measurement of formazan deposits in the hippocampus, cerebellum and striatum of two-month-old offspring following histochemical assay for NADPH-diaphorase (NADPH-d) activity. Compared to control subjects, an increase in nitrergic activity was found in the molecular layer of dentate gyrus and in the lacunosum molecular and stratum radiatum of CA1 (cornus amoni 1) in the EtOH+MeHg group, whereas a single administration of EtOH increased the activity in all striatal segments. The cerebellum seems to be less sensitive at this time-point to intoxication, and presented an increase only at the molecular layer of EtOH-exposed animals when compared to the MeHg and EtOH+MeHg groups (ANOVA, one-way followed by Tukey's test, p<0.05 or p<0.01). Taken together, results suggest that developmental exposure to EtOH and MeHg, singularly or in combination, alters nitrergic activity in adult rat in different ways depending on the region and layer of the central nervous system (CNS), and that these alterations might be related to different local metabolic properties.     

Effect of prenatal exposure to diesel exhaust on dopaminergic system in mice

Diesel exhaust (DE) is composed of particles and gaseous compounds. It has been reported that DE causes pulmonary and cardiovascular disease. We have previously reported that fetal exposure to DE had deleterious effects to the reproductive system of mice offspring. However, there is still little known about the effects of prenatal exposure to DE to the central nervous system (CNS). In the present study, we found that prenatal exposure to DE induced reduction of locomotion, furthermore, dopamine (DA) turnover was significantly decreased in the striatum and nucleus accumbens. These results suggest that prenatal exposure to DE has an effect on the CNS. Hypolocomotion could be due to a decrease in DA turnover associated with DA nervous system abnormality. The present study provides the possibility that maternally inhaled DE might influence the development of central dopaminergic system and result in behavior disorder.     

Effect of moderate prenatal exposure to alcohol on cortical capillary ultrastructure in the offspring

Laboratory of Brain Ultrastructure, Brain Research Institute, Academy of Medical Sciences of the USSR, Moscow. (Presented by Academician of the Academy of Medical Sciences of the USSR O. S. Adrianov.) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 113, No. 2, pp. 161–164, February, 1992.     

Effect of monoamine oxidase A knockout on resistance to long-term exposure to ethanol

It was shown that transgenic Tg8 mice with monoamine oxidase A (MAO A) gene knockout demonstrate higher resistance to acute ethanol exposure compared to wild type C3H mice. This difference was observed at the early age (28-30 days). Long-term ethanol treatment changed the resistance to hypnotic, but not hypothermic action of this agent. Seven-day exposure increased the resistance to ethanol-induced narcotic sleep in Tg8 and C3H mice. After 30-day ethanol treatment the duration of narcotic sleep sharply decreased in C3H mice and increased in Tg8 mice, which attested to their decreased tolerance to ethanol.     

Effect of the hydra peptide morphogen on cell proliferation in the thymus of newborn rats exposed to prenatal hypoxia

Female rats were exposed to high-altitude hypoxia on days 14–19 of pregnancy. Thirty min before hypoxia the animals were injected with the hydra peptide morphogen in a dose of 10 μg/kg intraperitoneally. Prenatal exposure to hypoxia suppressed proliferative processes in thymic cortex and medulla in newborn rats and decreased the lymphocyte count in the female—newborn rat pairs and the percent of full-term deliveries. Injection of hydra peptide morphogen prevented the development of posthypoxic disorders in newborn rats. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 124, No. 9, pp. 348–350, September, 1997     

The effects of prenatal exposure to predictable or unpredictable stress on early development in the rat

Pregnant rats were exposed to different schedules of noise and light stress, and the development of their offspring was studied during the first 2 weeks of life. Motor development was measured by different tests: Righting reflex (Days 2-4); cliff avoidance (Days 4-10); turning on an inclined plane (Days 5-10); and swimming behavior (Days 6-10). Development of motivation-involved behavior was measured with a home-seeking test (Days 6-16). Other developmental landmarks such as acoustic response (Days 12-14) and eye-opening (Days 14-17) were also recorded. Thrice-weekly random stress resulted in a delay in the development of all behaviors studied. Daily stress exposure throughout pregnancy resulted in smaller litters with heavier pups, but otherwise normal behavioral and physical development. Rats exposed to daily stress during the last week of pregnancy only produced litters that did not differ in size and body weight, but that displayed accelerated development of all parameters (except for eye-opening) from Day 6 onwards. It is concluded that the unpredictable nature of prenatal stress is responsible for delays in behavior of offspring.     

Immunolocalization of TGF-beta2 in the rat thymus during late stages of prenatal development

The aim of this study was to investigate the immunolocalization of transforming growth factor beta (TGF-beta2) in rat thymic stromal cells and thymocytes and investigate the roles of TGF-beta2 in thymopoiesis during the late stages of fetal development. Twelve adult pregnant female Wistar rats weighing 250-270 g were used in this study. The rats were killed by cervical dislocation on gestation days 16 (GD16), 18 (GD18) and 20 (GD20). Fetal thymus glands were prepared and examined by an immunohistochemical technique to reveal binding of an anti-TGF-beta2 rabbit polyclonal antibody. The thymic primordium was surrounded with a connective tissue capsule at GD16 and at this stage TGF-beta2 immunoreactivity was not observed. At GD18, the connective tissue capsule had formed septa which subdivided the tissue into lobules and at this stage TGF-beta2 immunolocalization was detected in the capsule and in thymocytes. Lobulation was more evident at GD20 and TGF-beta2 immunoreactivity of thymocytes was more extensive than on GD18. Results indicate that TGF-beta2 may play an important role in the organization or development of thymocytes in the late stages of thymopoiesis.     

Effects of prenatal cocaine exposure and postnatal environment on child development

Studies on the long-term developmental effects of in utero cocaine exposure are few and the small number of studies published do not consider the postnatal environment. The present investigation was conducted to quantify the role that postnatal environment played compared to prenatal exposure. Four groups of 25 infants, each assessed at 12 months of age, were included in the study design: 1) noncocaine-exposed children residing with their biological parents in low socioeconomic environments, 2) cocaine-exposed children living with their biological parents in low socioeconomic environments, 3) noncocaine-exposed children adopted at birth in middle to upper-middle socioeconomic environments, and 4) cocaine-exposed children adopted at birth. Infants were assessed by the Uzgiris-Hunt Ordinal Scales of Infant Psychological Development, the Fagan Test of Infant Intelligence, and the Infant Monitoring Questionnaire. Height and head circumference were measured. Gender and ethnicity were controlled statistically. Significant differences were found in cognitive functioning, in fine motor development, and in physical growth between control and prenatally cocaine-exposed children. Adoption enhanced cognitive functioning and fine motor skills among infants not exposed to cocaine prenatally, but had no apparent effect on infants prenatally exposed to cocaine. Am. J. Hum. Biol. 12:417–428, 2000. © 2000 Wiley-Liss, Inc.     

Effect of prenatal alcohol exposure on3H-diazepam binding to cerebral cortical synaptic membranes at various stages of postnatal development

Laboratory of Neurochemical Mechanisms of the Conditioned Reflex, Institute of Higher Nervous Activity and Neurophysiology, Academy of Sciences of the USSR, Moscow. (Presented by Academician of the Academy of Medical Sciences of the USSR V. S. Rusinov.) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 105, No. 5, pp. 558–561, May, 1988.     

酒精对小鼠锥体外系的影响

目的 探讨酒精对锥体外系影响机制。方法 48只8周龄雌性幼鼠随机分成对照组和低、中、高浓度组,分别用不同浓度的酒精(0％、12.5％、25％和50％)灌喂,按10 ml/kg,隔天1次,90 d后,分别对各浓度组小鼠进行灌酒前、后转棒试验。转棒试验结束后快速取出小脑和尾壳核,并测量它们的乙酰胆碱酯酶(AchE)活性。结果 高浓度组小鼠灌酒前、后在棒上停留时间均减少,中浓度组小鼠灌酒后在棒上停留时间也减少;高、中浓度组小脑和尾壳核胆碱酯酶活性降低。结论 酒精致锥体外系功能障碍与小脑、尾壳核的胆碱酯酶活性降低有关。