Concurrent exposure to perfluorooctane sulfonate and restraint stress during pregnancy in mice: effects on postnatal development and behavior of the offspring.

The combined effects of maternal restraint stress and perfluorooctane sulfonate (PFOS) on postnatal development and behavior of the offspring were assessed in mice. Thirty-four plug positive females were randomly divided into two groups. Animals were given by gavage 0 and 6 mg PFOS/kg/day on gestation days 12-18. One-half of the animals in each group was subjected to restraint stress (30 min per session, three sessions per day) during the same period. Neither restraint nor PFOS exposure significantly modified maternal food or water consumption. Pups of dams exposed to 6 mg/kg of PFOS showed a reduced body weight on postnatal days 4 and 8. Moreover, PFOS exposure induced some delay in developmental landmarks and neuromotor maturation. Maternal restraint stress reduced activity in an open-field when combined with 6 mg PFOS/kg/day. In addition, in males prenatal restraint stress impaired motor coordination in a rotarod. The current results indicate that concurrent exposure to PFOS and restraint stress during pregnancy induces opposite effects on developmental parameters in the pups. These effects consist in a general delayed maturation trend induced by PFOS exposure, and a general accelerated maturation pattern induced by prenatal stress. Interactive effects between PFOS and maternal stress were observed in young adult mice. These effects consisted mainly in a diminished activity in an open-field test.     

Concurrent exposure to aluminum and stress during pregnancy in rats: Effects on postnatal development and behavior of the offspring

The present study was conducted to assess the potential combined influence of maternal restraint stress and aluminum (Al) exposure on postnatal development and behavior in the offspring of exposed rats. Female rats were concurrently exposed to 0 (control group), 50 or 100 mg/kg/day of Al administered as Al nitrate nonahydrate in drinking water with citric acid (355 or 710 mg/kg/day) for a period of 15 days prior to mating with untreated males. Aluminum exposure was maintained throughout the gestational, lactational and post-weaning periods. On days 6-20 of gestation, one-half of the pregnant animals in each group were restrained for 2 h/day. Food consumption and maternal body weight were decreased in the groups exposed to restraint only or combined with the highest Al dose. All of the animals were allowed to deliver and wean their offspring. The pups were evaluated for physical development and neuromotor maturation. Moreover, open-field activity, passive avoidance, and spatial learning in a water maze were also determined on postnatal days 30, 35 and 60, respectively. Body weight of pups treated with 100 mg/kg/day of Al was decreased relative to controls from postnatal day 12 through 21, sexual maturation was delayed in Al treated females and in males exposed to 100 mg/kg/day. Forelimb grip strength was reduced in males exposed to 100 mg/Al/kg/day and in females exposed to this Al dose plus prenatal restraint. Learning in a passive avoidance task indicated facilitated performance for Al treated rats at 100 mg/kg/day combined with prenatal restraint as evidenced by longer avoidance latencies, while learning in a water maze task showed a shorter latency to find the platform on acquisition day 2 for Al treated rats. However, no effects of Al on water maze performance were detected during the retention probe trial in which the only effect noted was an increase in the platform quadrant swim time for the prenatal restraint group. In general terms, the results of the present study did not show a notable influence of maternal restraint on the Al-induced postnatal developmental and behavioral effects in the offspring of prenatally Al-exposed rats.     

Fluoxetine administration to pregnant rats increases anxiety-related behavior in the offspring

Rationale

Fluoxetine (Prozac?) is the most frequently prescribed drug to battle depression in pregnant women, but its safety in the unborn child has not yet been established. Fluoxetine, a selective serotonin reuptake inhibitor, crosses the placenta, leading to increased extracellular serotonin levels and potentially neurodevelopmental changes in the fetus.

Objectives

The purpose of this study was to elucidate the long-term consequences of prenatal fluoxetine in rats.

Methods

Pregnant rats were injected daily with 12?mg/kg fluoxetine or vehicle from gestational day?11 until birth, and the behavior of the offspring was monitored.

Results

Plasma fluoxetine transfer from mother to pup was 83%, and high levels of fluoxetine (13.0???g/g) were detected in the pup brain 5?h after the last injection. Fluoxetine-treated dams gave birth to litters 15% smaller than usual and to pups of reduced weight (until postnatal day?7). Furthermore, prenatal fluoxetine exposure significantly increased anxiety in the novelty-suppressed feeding test, the footshock-induced conditioned place aversion test, and the elevated plus maze test (following footshock pre-exposure) during adulthood, and also significantly decreased components of social play behavior at 4?weeks of age, and a strong tendency for increased self-grooming and making less contact in adults. Behavioral despair, anhedonia, and sexual behavior were not different between treatment groups. Finally, the hypothermic response to the 5-HT_1A agonist flesinoxan was observed at a lower dose in prenatally fluoxetine-exposed rats than in controls.

Conclusions

Prenatal fluoxetine exposure in rats leads to detrimental behavioral outcomes in later life, which may partly be due to altered 5-HT_1A receptor signaling.     

Effects of prenatal exposure to manganese on postnatal development and behavior in mice: influence of maternal restraint

Manganese (Mn) is an essential trace element whose deficiency and excess have been reported to cause central nervous system (CNS) disturbances. On the other hand, during pregnancy, maternal stress has been shown to enhance the developmental toxicity of a number of metals. In this study, the maternal toxicity and developmental effects of a concurrent exposure to Mn and restraint stress were evaluated in mice. Pregnant animals were divided into three groups and received subcutaneous injections of manganese chloride tetrahydrate (MnCl2.4H2O) at 0, 1 and 2 mg/kg/day on Gestation Days 6-18. Each group was divided into two subgroups. Mice in one subgroup were subjected to restraint for 2 h/day on Days 6-18 of gestation. Pregnant mice were allowed to deliver, and pups were evaluated for physical and neuromotor maturation. Subsequently, adult mice were also evaluated for activity and learning. A significant increase in perinatal mortality was observed at 2 mg/kg/day Mn. A delay in some developmental landmarks (eye opening, testes descent) due to Mn exposure (2 mg/kg/day) was also seen in both restrained and unrestrained animals. No differences in motor resistance and coordination, or in learning at the passive avoidance test, were noted in adult mice. At the current Mn doses, combined exposure to Mn and stress during the prenatal period did not produce long-lasting effects on adult mice.     

Both prenatal and postnatal factors contribute to the effects of maternal stress on offspring behavior and central 5-hydroxytryptamine receptors in the rat

Litters from stressed and control females were cross-fostered at birth to determine whether the effects of maternal stress on the offspring originated prenatally or during the neonatal period. Offspring of stressed females reared by control mothers from birth showed a reduced behavioral response to injections of the 5-hydroxytryptamine (5-HT) agonist 5-methoxy-N,N-dimethyltryptamine (5-MeODMT), increased 5-HT2 receptor binding in cerebral cortex and increased open field activity when tested at 60 days of age. In contrast, control litters reared by previously stressed females showed an increased behavioral response to 5-MeODMT, increased 5-HT2 receptor binding and only minor changes in open-field activity. These results provide further evidence that adult rat behavior can be significantly altered by exposure to the effects of maternal stress in utero. However, the effect of maternal stress on central 5-HT receptors is also strongly influenced by the postnatal rearing conditions.     

L-NAME prevents anxiety-like and depression-like behavior in rats exposed to restraint stress

Stressful life events contribute to the development of many neuropsychiatric disorders including depression and anxiety. Animal studies based on the relationship of stress and depression or anxiety are scarce and controversial. Moreover, neither the neurobiological basis of anxiety and depression nor the mechanisms responsible for neurochemical regulation by stressful stimuli are well understood. This study was designed to investigate the possible contribution of both acute (2 h) and chronic (2 h X 15 d) restraint stress in the generation of anxiety and depression, and also to find out whether nitric oxide (NO) has a modulatory role in these behavioral reactions. Elevated plus-maze and forced swimming test (FST) were chosen for assessment of anxiety and depression, respectively, and N(G)-nitro L-arginine methyl ester (L-NAME, 10 mg/kg), a NO synthase (NOS) inhibitor, and L-arginine (50 mg/kg), a NO precursor, were used to evaluate the role of nitrergic system in restraint exposed rats. The results showed that acute and chronic stress caused depression-like and anxiety-like behaviors in rats and the acute inhibition of NOS by L-NAME prevented these acute and chronic stress-induced anxiogenesis and depression. These data lead to the conclusion that stress and NO seem to be involved in the generation of anxiety and depression.     

Fucoidan prevents depression-like behavior in rats exposed to repeated restraint stress

Previous studies have demonstrated that repeated restraint stress in rodents increased depression-like behavior and altered the expression of corticotrophin-releasing factor in the hypothalamus. The current study focused on verifying the impact of fucoidan (FCN) administration on repeated restraint stress-induced behavioral responses using the forced swimming test (FST). Additionally, we examined the effect of FCN on the central noradrenergic system by observing changes in neuronal tyrosine hydroxylase (TH) immunoreactivity and brain-derived neurotrophic factor (BDNF) mRNA expression in the rat brains. Male rats received 10, 20, or 50 mg/kg FCN (i.p.) 30 min before daily exposures to repeated restraint stress (2 h/day) for 14 days. Repeated restraint stress increased immobility in the FST. Daily administration of FCN during the repeated restraint stress period significantly inhibited the stress-induced behavioral deficits in this behavioral test. Administration of FCN also significantly blocked the increase in TH expression in the locus coeruleus and the basolateral nucleus of the amygdala, and the decrease in BDNF mRNA expression in the hippocampus. Taken together, these findings indicate that administration of FCN prior to restraint stress significantly improved helpless behavior in rats, possibly through modulating the central noradrenergic system. Therefore, FCN may be a useful agent for treating complex symptoms of depression disorder.     

Investigation of Turnera ulmifolia effects in pregnant rats and offspring

Turnera ulmifolia Linn. (Turneraceae) is an herb commonly found in northeastern Brazil, frequently employed in folk medicine, including by pregnant woman, for many afflictions due to it expectorant, tonic, anti-inflammatory, antiulcerogenic, and antioxidant effects. This work studied the infusion commonly used by the population, obtained by maceration of fresh leaves of T. ulmifolia in filtered water, to evaluate if the same may promote alterations in rat gestation and exposed offspring. Pregnant rats received, by gavage, the aqueous extract (0, 1, 2, or 3 g/kg/day) from gestation day (GD) 1 to GD 21. The treatment was not able to promote maternal toxicity: body weight gain, food and water intake were not altered during gestation period. The offspring presented normal physical and reflexological development. No alterations were observed in the histopathological study and sexual hormone levels of the dams and offspring at 30, 60, and 90 days of age. The sexual behavior was evaluated in male and female offspring at adult age (GD 90) and no alterations were observed. These results suggest that the infusion of T. ulmifolia, employed in folk medicine, at these doses, is not able to promote alterations to pregnant rats, to impair gestation, or to damage the exposed offspring.     

Effects of prenatal exposure to chlorpromazine on postnatal development and behavior of rats

Chlorpromazine was administered to pregnant rats at doses of 1, 3, or 9 mg/kg/day from Days 6 to 15 of gestation. Fetuses from half the dams were examined for terata, and the remaining litters delivered at term. The growth, morphologic and reflex development, and reproductive performance of the offspring were recorded. Selected males from all groups were tested in the postweaning period for rotorod performance and activity in an open field. At sexual maturity selected pups of both sexes were necropsied; mean organ weights were recorded; and histomorphologic and morphometric examinations were performed on coronal sections of the brain of high-dose and control males. There was no prenatal evidence of a teratogenic effect. The growth, physical, and reflex development of F₁ pups was unaffected during the preweaning period. Postweaning growth of female offspring in all dosage groups was comparable to that of the controls. At 3 and 9 mg/kg/day there was a very slight but statistically significant decrease in average body weight gain of males in the postweaning period, but the biological significance of this effect is uncertain. Mating performance of offspring exposed prenatally to chlorpromazine was unaffected. In the postweaning period there were significant increases in activity in an open field and decreases in latency time in male offspring from the 3 and 9-mg/kg/day dosage groups compared to pooled controls. There were no changes in organ weights and the results of histomorphologic and morphometric examination in brain sections from control and 9-mg/kg/day males were comparable.     

Effects of postnatal low-levels of exposure to styrene on behavior and development in rats

Three groups of rats were exposed by inhalation to either clean air (control group) or styrene monomer at 25 and 50 ppm (styrene-exposed groups) for 7 h/day, 6 day/week, from 1 to 48 days of age. Compared to control group, Styrene-exposed groups showed significant delay in the following developmental indices: body weight gain, appearance of pinna detachment and incisor eruption. With respect to open-field activity, the styrene groups indicated longer latency to enter the field, less number of squares crossed and fewer rearings than those of controls. In the avoidance behavior aspect, the styrene groups attained less achievement level in avoidance rates than that of the control group. Dose-related trends were found between the two exposed groups in body weight increment, exploratory and avoidance behavior. Sex differences were seen on these factors also. These results suggest that at postnatal exposure of low-levels to styrene affects behavior and development in rats.     

Pro-oxidant effects in the brain of rats concurrently exposed to uranium and stress

Metal toxicity may be associated with increased rates of reactive oxygen species (ROS) generation within the central nervous system (CNS). Although the kidney is the main target organ for uranium (U) toxicity, this metal can also accumulate in brain. In this study, we investigated the modifications on endogenous antioxidant capacity and oxidative damage in several areas of the brain of U-exposed rats. Eight groups of adult male rats received uranyl acetate dihydrate (UAD) in the drinking water at 0, 10, 20, and 40 mg/kg/day for 3 months. Animals in four groups were concurrently subjected to restraint stress during 2h/day throughout the study. At the end of the experimental period, cortex, hippocampus and cerebellum were removed and processed to examine the following stress markers: reduced glutathione (GSH), oxidized glutathione (GSSG), glutathione reductase (GR), glutathione peroxidase (GPx), superoxide dismutase (SOD), catalase (CAT), thiobarbituric acid reactive substances (TBARS), as well as U concentrations. The results show that U significantly accumulated in hippocampus, cerebellum and cortex after 3 months of exposure. Moreover, UAD exposure promoted oxidative stress in these cerebral tissues. In cortex and cerebellum, TBARS levels were positively correlated with the U content, while in cerebellum GSSG and GSH levels were positively and negatively correlated, respectively, with U concentrations. In hippocampus, CAT and SOD activities were positively correlated with U concentration. The present results suggest that chronic oral exposure to UAD can cause progressive perturbations on physiological brain levels of oxidative stress markers. Although at the current UAD doses restraint scarcely showed additional adverse effects, its potential influence should not be underrated.     

Effects of prenatal exposure to toluene on postnatal development and behavior in rats.

Development and neurobehavioral effects of prenatal exposure to toluene (CAS 108-88-3) were studied after exposing pregnant rats (Mol:WIST) to 1800 ppm of the solvent for 6 h daily on days 7-20 of gestation. Body weights of exposed offspring were lower until day 10 after parturition. Neurobehavioral evaluation of the pups revealed no effects on motor function (rotarod), activity level (open field), acoustic startle, and prepulse inhibition. Measurements of hearing function using auditory brain stem response revealed small effects in male-exposed offspring. Performance in a Morris water maze during initial learning gave some indications of impaired cognitive functions, which was confirmed during further testing, especially in reversal and new learning. Effects on cognitive functions seemed most marked in female offspring.     

The effects of restraint stress on voluntary ethanol consumption in rats

Sixty Wistar rats (Rattus norvegicus) were assigned to 4 groups of 15 rats each: ethanol stress (ES), ethanol no-stress (EN), isocaloric stress (IS) and isocaloric no-stress (IN). The effect of restraint stress on daily intake of ethanol and a 0.72% solution of glucose was examined in an ABA design (stress-no stress-stress). During the stress phases, 2 groups were subjected to daily 15-min restraint stress, whereas 2 groups were placed in different cages for 15 min as a control. All 4 groups were then given 6-hr access to their assigned liquid alone for 4 days followed by a choice between their assigned liquid and water on the 5th day. The ES group significantly increased their ethanol intake (g/kg) compared to the EN group on choice days but not on forced days. Percentage preference for ethanol was significantly greater and increased at a faster rate over the 75-day testing period compared with the EN group. However, total ethanol consumption (g/kg) and percentage preference did not vary as a function of phase. It is notable that the effects of restraint stress on ethanol self-administration persisted even after the stress schedule was removed.     

Effect of ethanol and diazepam given to pregnant rats on the behavior and catecholamine content in the brain of offspring

Effect of separate and combined treatment with ethanol and diazepam applied to pregnant rats upon the behavior of 3- and 6-week old and 3 month old rats, as well as on the content of noradrenaline (NA), 5-hydroxytryptamine (5-HT), and 5-hydroxyindoleacetic acid (5-HIAA) in various brain areas was investigated. It has been shown that separate application of ethanol and diazepam causes slight changes in the behavior and content of amines on the brain of offsprings. Combined application of ethanol and diazepam to pregnant rats exerts marked effects upon the behavior of offsprings and causes a decreased content mainly of 5-HT and 5-HIAA in the investigated areas of the brain.     

氯沙坦对妊娠大鼠及子代的影响

目的探讨血管紧张素Ⅱ受体拮抗剂(ARB)———氯沙坦对♀性大鼠妊娠受孕率、平均产仔数及其子代的影响,为临床妊娠高血压症患者选药提供动物实验依据。方法随机选择20只♀性SD大鼠分为实验组和对照组,分别用0.75%的氯沙坦混悬液和0.6%羧甲基纤维素钠溶液灌胃23 d后,均以♀∶♂=1∶2交配2 d,停止交配后继续灌胃至怀孕大鼠的鼠仔出生直至断乳,考察受孕率,平均产仔数,鼠仔体重、性别及生命质量等指标。结果2组大鼠受孕率均为50%,实验组每只孕鼠平均产仔数为(11.2±5.83)只,对照组每只孕鼠平均产仔数为(12.80±3.11)只,2组产仔数、鼠仔的体重、性别比例均无显著性差异;2组鼠仔均未出现畸胎;鼠仔生存率实验组为85%,对照组为100%;实验组少数鼠仔出现发育不良。结论氯沙坦在37.5mg.kg-1.d-1的给药量对妊娠大鼠受孕率、平均产仔数、子代体重、性别比例无影响;对子代的生存发育有影响,提示妊娠高血压患者要慎用ARB。     

Exposure to allethrin-based mosquito coil smoke during gestation and postnatal development affects reproductive function in male offspring of rat

The threat of zika virus looms throughout the world and the use of allethrin-based mosquito coils to prevent mosquito bites during and postpregnancy is on the rise. The aim of this study was to analyze the toxic effects of exposure to allethrin-based mosquito coil smoke in rats under conditions that reflect human settings. Pregnant female rats were exposed to mosquito coil smoke and same was continued to the male pups up to 111?days postparturition (21-day weaning plus up to 90?days postweaning). Increased oxidative stress, distorted antioxidant enzyme status, downregulation of genes involved in spermatogenesis, sperm maturation and steroidogenesis was observed. Daily sperm production, total sperm count and acrosome reaction was compromised. Results of our study indicate the toxic effects of exposure to allethrin-based mosquito coil smoke in male offspring and calls for preventing mosquito coil use during pregnancy and postnatal development. Community-based programs that will encourage general population to use classical methods such as use of mosquito nets, keeping the surroundings clean and use of natural mosquito repellents should be conducted.     

Neurochemical and behavioral effects of 8-OH-DPAT following exposure to restraint stress in rats

8-Hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), a selective 5-hydroxytryptamine 1A (serotonin; 5-HT1A) agonist was used to evaluate the role of somatodendritic and/or postsynaptic 5-HT1A receptors following exposure to restraint stress. Exposure to an episode of 2-h restraint stress decreased 24 h cumulative food intake. Intensity of 8-OH-DPAT-induced 5-HT syndrome monitored next day was smaller in restrained than unrestrained animals. Hyperphagic effects of 8-OH-DPAT were comparable in the two groups. Restrained animals injected with saline exhibited an increase in 5-HT levels in the hippocampus, hypothalamus and cortex but not in the midbrain and striatum. 5-Hydroxyindolacetic acid (5-HIAA) increased in the hippocampus, midbrain and cortex but not in the hypothalamus and striatum. 8-OH-DPAT injected at a dose of 0.25 mg/kg decreased 5-HT and 5-HIAA levels in different brain regions of unrestrained as well as restrained animals. The decreases were greater in restrained than unrestrained animals, suggesting a supersensitivity of somatodendritic 5-HT1A receptors. The results are discussed in the context of a role of 5-HT1A receptor in restraint-induced behavioral deficits.     

Effects of ethanol on pregnant rats and their offspring

Pregnant rats were intubated with either 1.0 or 2.0 g/kg of ethanol daily throughout gestation. Pair-fed vehicle-treated, and nontreated rats fed ad libitum, served as control groups for ethanol-treated animals. Ethanol treatment reduced food and water consumption and attenuated the gain in body weight of pregnant animals relative to nontreated animals fed ad libitum. Litter size, litter weight, and the mean weight per pup were reduced in both the ethanol-treated and pair-fed control groups. There was no evidence of gross malformations in any of the offspring. Since the reduction in litter size and litter weights did not differ significantly between ethanol-treated and pair-fed controls, the effects of treatment with ethanol appeared to be related to a reduction in maternal intake of calories rather than to the direct effect of ethanol on the developing fetus.There were no significant differences between any of the groups of offspring on one-way shock avoidance learning, water maze escape learning, spontaneous alternation, or brightness discrimination learning in tests beginning at 75 days of age. Thus, at the doses of alcohol used in this study, there was no evidence of behavioral teratogenesis comparable to that reported for higher doses in animals or in man characterized by the fetal alcohol syndrome.     

Long-term effects of prenatal phenytoin exposure on offspring behavior in rats

Pregnant Sprague-Dawley CD rats were administered phenytoin by gavage on days 7-18 of gestation in doses of 0 or 200 mg/kg. The offspring were tested at various ages to determine the duration of postnatal dysfunction and its replicability and generality compared to previous experiments. Phenytoin offspring had increased newborn (5.2%) and preweaning (16.7%) mortality compared to controls (0% and 3.1%, respectively), and an 8.5% reduction in average body weight at 28-70 days. No weight differences were significant at other ages. Phenytoin offspring showed increased activity on multiple tests, swam slower in a straight channel, committed more errors and took more time in the Cincinnati water maze, startled less, and had longer latencies on the Morris hidden platform test. Among phenytoin offspring 42.3% exhibited the abnormal circling defect previously described (14,17). Consequently, data were reanalyzed in terms of circlers, noncirclers, and controls to determine the contribution of this effect to the dysfunctions observed. Circlers accounted for the differences in open-field activity, figure-8 ambulation, hole-board horizontal locomotion, straight channel swimming time, water maze retention errors, tactile prepulse startle inhibition, and some trials of the Morris test. Circlers and noncirclers differed from one another and from controls on measures of figure-8 rearing, water maze errors and times, and some trials of the Morris test, with circlers more affected than noncirclers. Circlers and noncirclers did not differ from one another, but both differed from controls, on measures of early locomotion, hole-board vertical activity, and unmodified startle amplitude. Circling was hypothesized to reflect an underlying vestibular defect, however, the data also support the view that phenytoin has effects beyond those accounted for by possible vestibular effects.