Influence of gut microbiota on the development of most prevalent neurodegenerative dementias and the potential effect of probiotics in elderly: A scoping review.

Dementia is one of today's greatest public health challenges. Its high socio-economic impact and difficulties in diagnosis and treatment are of increasing concern to an aging world population. In recent years, the study of the relationship between gut microbiota and different neurocognitive disorders has gained a considerable interest. Several studies have reported associations between gut microbiota dysbiosis and some types of dementia. Probiotics have been suggested to restore dysbiosis and to improve neurocognitive symptomatology in these dementias. Based on these previous findings, the available scientific evidence on the gut microbiota in humans affected by the most prevalent dementias, as well as the probiotic trials conducted in these patients in recent years, have been here reviewed. Decreased concentrations of short-chain fatty acids (SCFA) and other bacterial metabolites appear to play a major role in the onset of neurocognitive symptoms in Alzheimer disease (AD) and Parkinson disease dementia (PDD). Increased abundance of proinflammatory taxa could be closely related to the more severe clinical symptoms in both, as well as in Lewy Bodies dementia. Important lack of information was noted in Frontotemporal dementia behavioral variant. Moreover, geographical differences in the composition of the gut microbiota have been reported in AD. Some potential beneficial effects of probiotics in AD and PDD have been reported. However, due to the controversial results further investigations are clearly necessary.

Metals linked with the most prevalent primary neurodegenerative dementias in the elderly: A narrative review.

The ageing population has been steadily increasing worldwide, leading to a higher risk of cognitive decline and dementia. Environmental toxicants, particularly metals, have been identified as modifiable risk factors for cognitive impairment. Continuous exposure to metals occurs mainly through dietary sources, with older adults being particularly vulnerable. However, imbalances in the gut microbiota, known as dysbiosis, have also been associated with dementia. A literature review was conducted to explore the potential role of metals in the development of cognitive decline and the most prevalent primary neurodegenerative dementias, as well as their interaction with the gut microbiota. High levels of iron (Fe) and copper (Cu) are associated with mild cognitive impairment (MCI) and Alzheimer's disease (AD), while low selenium (Se) levels are linked to poor cognitive status. Parkinson's disease dementia (PDD) is associated with elevated levels of iron (Fe), manganese (Mn), and zinc (Zn), but the role of copper (Cu) remains unclear. The relationship between metals and Lewy body dementia (LBD) requires further investigation. High aluminium (Al) exposure is associated with frontotemporal dementia (FTD), and elevated selenium (Se) levels may be linked to its onset. Challenges in comparing studies arise from the heterogeneity of metal analysis matrices and analytical techniques, as well as the limitations of small study cohorts. More research is needed to understand the influence of metals on cognition through the gut microbiota (GMB) and its potential relevance in the development of these diseases.

Behavioural effects of PNU-282987 and stress in an animal model of Alzheimer's disease.

BACKGROUND: Cholinergic deficits play an important role in both cognitive and behavioural alterations in Alzheimer's disease. This study was aimed at evaluating the possible therapeutic role of PNU-282987 (PNU), an α7 nicotinic cholinergic receptor agonist, and the possible effects of stress in precipitating the onset of behavioural deficits in animals with susceptibility to Alzheimer's disease. METHODS: B6C3-Tg mice with susceptibility to Alzheimer's disease and wild-type mice either with or without restraint stress received 0- or 1-mg/kg PNU. At 12 months old, mice were evaluated for activity levels, anxiety-like levels, and spatial learning and memory. RESULTS: Data did not show the effects of PNU on activity and anxiety-like behaviour. No effect of PNU on acquisition of a spatial learning task was detected, but a reversal of stress effects on retention in the Morris water maze was observed in transgenic mice. CONCLUSIONS: Further studies are needed in order to better understand the role of α7 nicotinic cholinergic receptor agonists in motor activity, anxiety, and spatial learning and memory and to develop more accurate pharmacological treatment of psychopathological diseases.

Validation of the Spanish version of the multifaceted empathy test: comparison between cannabis use effects and controls in social cognition.

OBJECTIVE: While social cognition is shown to be impaired in several mental disorders, the effects of cannabis on social cognition are still not clear. Past studies have used the multifaceted empathy test (MET) to study social cognition. This study aims to test the validity of the MET Spanish version and to evaluate the effects of cannabis use on social cognition. METHODS: In total 116 participants from a Cannabis Social Club (CSC) completed the MET and the reading the mind in the eyes test (RMET) under the effects of cannabis and were compared to 86 university students (control group). Internal consistency and convergent validity were assessed. Cognitive empathy (CE) and emotional empathy (EE) were tested in both groups. RESULTS: The MET CE scale shows low internal consistency, while the EE scale shows high internal consistency. Items showed similar difficulty for both groups. Cannabis users showed deficient overall emotional recognition, with reduced scores associated with positive stimuli. Overall scores for EE were similar for both groups, but the experimental group scored lower with negative stimuli when compared to controls. CONCLUSION: This study validates the MET Spanish version for its use in future studies. Results confirmed deficient emotional recognition in cannabis users and a dampened reaction to negative stimuli for the first time.

Recognition memory and ß-amyloid plaques in adult Tg2576 mice are not modified after oral exposure to aluminum.

The role of aluminum (Al) in Alzheimer disease is highly controversial. However, this element has been detected in neuritic plaques and neurofibrillary tangles in patients with Alzheimer disease. Its presence in neuritic plaques in hippocampus is especially relevant, as this is an area closely related to spatial learning and memory. In this study, the diet of wild-type and Tg2576 mice (animals overexpressing the human amyloid precursor protein) was supplemented with Al lactate (1 mg/g). General neurotoxic Al effects were evaluated using a functional observational battery and a novel object recognition task. Four experimental groups were used: Control-wild, Al-wild, Control-Tg, and Al-Tg mice. The results show a decreased home-cage activity and an increase in piloerection in all Al-exposed animals, and an increased sensorimotor reactivity in Tg2576 mice given Al. Neither Al treatment nor genotype had any noticeable effect on corticosterone levels and Al concentrations in frontal cortex and cerebellum of the mice. Recognition memory was impaired in Tg2576 mice, whereas ß-amyloid plaque depositions were observed in all these animals. However, Al did not alter the recognition memory and ß-amyloid plaque loads of Tg2576 mice.

Modifiable Risk Factors for Dementia: The Role of Gut Microbiota.

Dementia is a syndrome resulting from chronic or progressive brain disease. Around 40% of worldwide dementia can be prevented or delayed by modifying 12 risk factors: low educational attainment in early life, mid-life hypertension, mid-life obesity, hearing loss, traumatic brain injury, excessive alcohol consumption, smoking, depression, physical inactivity, social isolation, diabetes mellitus, and air pollution. There is growing evidence that gastrointestinal tract microbiota may significantly contribute to dementia pathogenesis. In particular, gut dysbiosis can trigger metabolic diseases and the progression of low-grade systemic inflammation, being involved in much of the major modifiable risk factors. In this review, we focus on studies that have evaluated the association between modifiable risk factors for dementia and the role of gut microbiota. We also suggest clinical implications for researchers in dementia-gut microbiota related fields.

Does living close to a petrochemical complex increase the adverse psychological effects of the COVID-19 lockdown?

The petrochemical industry has made the economic development of many local communities possible, increasing employment opportunities and generating a complex network of closely-related secondary industries. However, it is known that petrochemical industries emit air pollutants, which have been related to different negative effects on mental health. In addition, many people around the world are being exposed to highly stressful situations deriving from the COVID-19 pandemic and the lockdowns adopted by national and regional governments. The present study aims to analyse the possible differential effects on various psychological outcomes (stress, anxiety, depression and emotional regulation strategies) stemming from the COVID-19 pandemic and consequent lockdown experienced by individuals living near an important petrochemical complex and subjects living in other areas, nonexposed to the characteristic environmental pollutants emitted by these kinds of complex. The sample consisted of 1607 subjects who answered an ad hoc questionnaire on lockdown conditions, the Perceived Stress Scale (PSS), the Hospital Anxiety and Depression Scale (HADS), the Barratt Impulsivity Scale (BIS) and the Emotional Regulation Questionnaire (ERQ). The results indicate that people living closer to petrochemical complexes reported greater risk perception [K = 73.42, p < 0.001, with a medium size effect (η2 = 0.061)]. However, no significant relationship between psychological variables and proximity to the focus was detected when comparing people living near to or far away from a chemical/petrochemical complex. Regarding the adverse psychological effects of the first lockdown due to COVID-19 on the general population in Catalonia, we can conclude that the conditions included in this survey were mainly related to changes in the participants' impulsivity levels, with different total impulsivity scores being obtained if they had minors in their care (p<0.001), if they had lost their jobs, if they were working (p<0.001), if they were not telecommuting (p<0.001), if they went out to work (p<0.001) or if they established routines (p = 0.009). However, we can also be fairly certain that the economic effects are going to be worse than those initially detected in this study. More research will be necessary to corroborate our results.

Randomized Phase III Trial of Prophylactic Cranial Irradiation With or Without Hippocampal Avoidance for Small-Cell Lung Cancer (PREMER): A GICOR-GOECP-SEOR Study.

PURPOSE: Radiation dose received by the neural stem cells of the hippocampus during whole-brain radiotherapy has been associated with neurocognitive decline. The key concern using hippocampal avoidance-prophylactic cranial irradiation (HA-PCI) in patients with small-cell lung cancer (SCLC) is the incidence of brain metastasis within the hippocampal avoidance zone. METHODS: This phase III trial enrolled 150 patients with SCLC (71.3% with limited disease) to standard prophylactic cranial irradiation (PCI; 25 Gy in 10 fractions) or HA-PCI. The primary objective was the delayed free recall (DFR) on the Free and Cued Selective Reminding Test (FCSRT) at 3 months; a decrease of 3 points or greater from baseline was considered a decline. Secondary end points included other FCSRT scores, quality of life (QoL), evaluation of the incidence and location of brain metastases, and overall survival (OS). Data were recorded at baseline, and 3, 6, 12, and 24 months after PCI. RESULTS: Participants' baseline characteristics were well balanced between the two groups. The median follow-up time for living patients was 40.4 months. Decline on DFR from baseline to 3 months was lower in the HA-PCI arm (5.8%) compared with the PCI arm (23.5%; odds ratio, 5; 95% CI, 1.57 to 15.86; P = .003). Analysis of all FCSRT scores showed a decline on the total recall (TR; 8.7% v 20.6%) at 3 months; DFR (11.1% v 33.3%), TR (20.3% v 38.9%), and total free recall (14.8% v 31.5%) at 6 months, and TR (14.2% v 47.6%) at 24 months. The incidence of brain metastases, OS, and QoL were not significantly different. CONCLUSION: Sparing the hippocampus during PCI better preserves cognitive function in patients with SCLC. No differences were observed with regard to brain failure, OS, and QoL compared with standard PCI.

Combined effects of perfluorooctane sulfonate (PFOS) and maternal restraint stress on hypothalamus adrenal axis (HPA) function in the offspring of mice.

Although it is known that prenatal exposure to perfluorooctane sulfonate (PFOS) can cause developmental adverse effects in mammals, the disruptive effects of this compound on hormonal systems are still controversial. Information concerning the effects of PFOS on hypothalamus adrenal (HPA) axis response to stress and corticosterone levels is not currently available. On the other hand, it is well established that stress can enhance the developmental toxicity of some chemicals. In the present study, we assessed the combined effects of maternal restraint stress and PFOS on HPA axis function in the offspring of mice. Twenty plug-positive female mice were divided in 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 were also subjected to restraint stress (30 min/session, 3 sessions/day) during the same period. Five plug-positive females were also included as non-manipulated controls. At 3 months of age, activity in an open-field and the stress response were evaluated in male and female mice by exposing them to 30 min of restraint stress. Male and female offspring were subsequently sacrificed and blood samples were collected to measure changes in corticosterone levels at four different moments related to stress exposure conditions: before stress exposure, immediately after 30 min of stress exposure, and recuperation levels at 60 and 90 min after stress exposure. Results indicate corticosterone levels were lower in mice prenatally exposed to restraint. In general terms, PFOS exposure decreased corticosterone levels, although this effect was only significant in females. The recuperation pattern of corticosterone was mainly affected by prenatal stress. Interactive effects between PFOS and maternal stress were sex dependent. The current results suggest that prenatal PFOS exposure induced long-lasting effects in mice.

Maternal exposure to mixtures of dienestrol, linuron and flutamide. Part II: Endocrine-related gene expression assessment on male offspring rat testes.

Exposure to endocrine-disrupting compounds (EDCs) during pregnancy and early development can lead to adverse developmental outcomes in offspring. One of the endpoints of concern is feminization. The present study aimed to investigate for any possible correlations with endocrine sensitive parameters in the testes of male rat offspring following dam exposure to three EDCs by assessing the expression of endocrine-related genes. Dienestrol (DIES) [0.37-6.25 µg/kg bw/day], linuron (LIN) [1.5-50 mg/kg bw/day], flutamide (FLU) [3.5-50 mg/kg bw/day] as well as their binary mixtures were administered to sexually mature female rats from gestation day (GD) 6 until postnatal day (PND) 21. Gene expression analysis of Star, Cyp11a1, Cyp17a1, Hsd3b2, Pgr and Insl3 was performed by RT-qPCR. Administration of the anti-androgen FLU alone significantly upregulated Cyp11a1 and Cyp17a1 gene expression while administration of LIN and DIES alone did not alter significantly gene expression. The effects of the binary mixtures on gene expression were not as marked as those seen after single compound administrations. Deregulation of Cyp17a1 in rat pup testis, following administration of FLU alone or in mixtures to dams, was significantly correlated with the observed feminization endpoints in male pups.

Maternal exposure to mixtures of dienestrol, linuron and flutamide. Part I: Feminization effects on male rat offspring.

Exposure to endocrine-disrupting compounds (EDCs) during pregnancy can result in negative health effects in later generations, including sex changes and feminization. The present study assessed the feminization effects on male offspring rats of three EDCs: Dienestrol (DIES), Linuron (LIN), and Flutamide (FLU). Sexually mature female rats were exposed from gestation day (GD) 6 until postnatal day (PND) 21 to: 0.37, 0.75, 1.5, 3.12 or 6.25 µg/kg/day of DIES, 1.5, 3, 6, 12.5, 25 or 50 mg/kg/day of LIN, 3.5, 6.7, 12.5, 25 or 50 mg/kg/day of FLU, and the following mixtures: FLU + DIES (mg/kg/day+µg/kg/day), 3.5 + 0.37, or 3.5 + 3, 25 + 0.37, or 25 + 3; FLU + LIN (mg/kg/day + mg/kg/day), 3.5 + 12.5, or 25 + 12.5; and DIES + LIN (µg/kg/day + mg/kg/day), 0.37 + 12.5, or 3 + 12.5. Anogenital distance (AGD), nipple retention (NR) and cryptorchidism were evaluated. FLU produced a decrease of AGD, an increase of NR, and an increase of cryptorchidism at the highest dose. None of these three endpoints were significantly affected by LIN or DIES treatments alone. Combinations of FLU + LIN and FLU + DIES increased NR, and decreased AGD, while DIES + LIN did not produce any effects in male pups. Results show that FLU is able to induce feminization in male pups, while binary combinations of LIN and DIES did not modify the effects produced by FLU.

Oxidative stress in testes of rats exposed to n-butylparaben.

This study was aimed at determining if oxidative stress imbalance in testes of rats occurs after n-butylparaben (n-ButP) exposure. Young male Sprague-Dawley rats were subcutaneously treated with n-ButP during one spermatogenic cycle (57 days) at 0 (control-oil), 150, 300 and 600 mg/kg/d with peanut oil as vehicle. A non-vehicle control group was also included. Antioxidant enzyme activities (superoxide dismutase, catalase, glutathione reductase, and glutathione peroxidase) and levels of reduced and oxidized glutathione were measured in testes. Lipid peroxidation and H2O2 concentrations were also assessed. Results showed an increase of oxidative stress in oil-treated groups, excepting 600 mg/kg/d, suggesting oxidative stress due to peanut oil. A possible antioxidant effect due to n-ButP and its metabolites was suggested at 600 mg/kg/d, the only group not showing oxidative stress. An increase of calcium concentration in testes was also observed. On the other hand, a physiologically-based pharmacokinetic (PBPK) model was developed and the concentrations of n-ButP and its metabolites were simulated in plasma and testes. The peak concentration (Cmax) in testes was found slightly higher than that in plasma. The current results indicate that peanut oil can cause oxidative stress while high doses of n-ButP can act as antioxidant agent in testes.

Oral exposure of rats to dienestrol during gestation and lactation: Effects on the reproductive system of male offspring.

This study was aimed at determining whether dienestrol (DIES) affects reproduction in male offspring of rats following oral maternal exposure during gestation and lactation. Pregnant rats were treated from GD 6 to PND 21. Animals received 0 (control-vehicle), 0.75, 1.5, 3.12, 6.25, 12.5, 50, 75 µg/kg bw/d of DIES. A control group -without vehicle-was also included. High DIES concentrations caused abortions at 75 and 50 µg/kg bw/d, while at 12.5 µg/kg bw/d had still miscarriages. Ten male rats per group were kept alive until PND 90 to ensure sexual maturity. Body and organ weights, anogenital distance (AGD) at PNDs 21 and 90, biochemical and sperm parameters like motility, viability, morphology, spermatozoa and resistant spermatid counts, and histopathology for sexual organs and liver were determined. An increase in organ weight (liver and sexual organs) and a decrease in AGD due to vehicle were found. A reduction of sperm motility and viability, and an increase of abnormal sperm morphology were caused by DIES, which provoked a dose-dependent prostatitis. Maternal exposure to DIES induced toxicity on the reproductive system of the male offspring, which could affect the capacity of fertilization.

Behavioral deficits in the cuprizone-induced murine model of demyelination/remyelination.

The neurotoxicant cuprizone has been used extensively to create a mouse model of demyelination. However, the effects on behavior of cuprizone treatment have not been previously reported. We have analyzed the behavioral changes of mice given a diet containing 0.2% cuprizone for 6 weeks followed by 6 weeks of recovery. Behavior was assessed using a range of tests: the functional observation battery, the open-field test and the rota-rod test. Concurrent with the start of demyelination, at 3 and 4 weeks of 0.2% cuprizone treatment, the animals exhibited an increase in central nervous system activity and an inhibited anxiogenic response to the novelty challenge test. At 5 weeks of treatment (the period of maximal demyelination) equilibrium was altered and sensorimotor reactivity was also affected. Further, rota-rod analysis demonstrated that the treated group had poorer motor co-ordination than control animals. This effect was not reversed 6 weeks after cuprizone withdrawal. The animals in the recovery period also exhibited difficulties in the rota-rod progressive learning task. Our results indicate that behavioral deficits follow the course of demyelination-remyelination induced by administration of 0.2% cuprizone, and that some of the changes persist even after 6 weeks on normal diet.

[Effectiveness of dog-assisted therapy in the elderly. A preliminary study]. / Estudio preliminar de la efectividad de la terapia asistida con perros en personas de la tercera edad.

INTRODUCTION: Animal-assisted therapy is increasingly present in several educational and health areas. The aim of this study is to assess the effectiveness of such interventions in the elderly population living in residential settings. MATERIALS AND METHODS: A 12-week dog-assisted intervention program was designed, with 16 participants from a nursing home divided into an experimental group and a control group. RESULTS: Several physical and psychological variables were assessed before and after the intervention. While there were no significant differences in the control group, the experimental group improved significantly after participating in the program. DISCUSSION: The results support the hypothesis that animal-assisted interventions may be beneficial for residents in elderly care homes.

Behavioral effects of adult rats concurrently exposed to high doses of oral manganese and restraint stress.

The behavioral effects of concurrent exposure of high doses of manganese (Mn) and restraint stress were assessed in adult rats. Male Sprague-Dawley rats (250-300 g) received 0, 275 and 550 mg/kg/day of Mn in the drinking water for 19 weeks. Each group was divided into two subgroups. Animals in one subgroup were restrained for 2h/day. During the treatment period, food and water intake, and body weight were weekly recorded. At the end of the treatment period, activity levels were monitored in an open-field. Learning was evaluated by a water-maze task during five consecutive days. A trial probe was also conducted to assess the time spent in the platform quadrant. Body weight and food consumption were significantly reduced in the group receiving 550 mg/kg/day of Mn. A two-way analysis of variance (ANOVA) revealed an overall effect of Mn on the total distance traveled. Differences on spatial learning were observed in the acquisition period, in which rats given 550 mg/kg/day of Mn (alone or restrained) were impaired in comparison with the control and the restrained only groups. In the probe trial, there was an impaired retention in the group treated with Mn at 550 mg/kg/day. The results of this investigation in the open-field and water maze suggest that it would be plausible that restraint stress and a high exposure to Mn interact at common neurotransmitter levels but inducing opposite effects.

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.

Metal concentrations in hair and cognitive assessment in an adolescent population.

The objective of this study was to establish the potential relationship between the levels of various metals in hair and cognitive functions in children living in zones of Tarragona (Catalonia, Spain) with different metal pollution levels. Thirty-nine boys and 61 girls (12-14 yr old) from various schools were selected for the study. The concentrations of cadmium (Cd), chromium (Cr), mercury (Hg), lead (Pb), manganese (Mn), nickel (Ni), and tin (Sn) in scalp hair were determined by inductively coupled plasma- mass spectrometry (ICP-MS). Attention, visuospatial capabilities, and abstract reasoning were assessed as indicators of cognitive impairment. Three categories of attention were defined: low, medium, and high. A significant negative correlation (p=0.019) between Pb levels in hair and attention was observed. Significant differences between Pb levels in hair in low- and medium-performance groups and those in the high-performance group were also found. Moreover, a positive correlation (p=0.048) between Hg hair concentrations and visuospatial capabilities was also noted.

Interactions of caffeine and restraint stress during pregnancy in mice.

The maternal and developmental toxicity of combined exposure to restraint stress and caffeine was assessed in mice. On gestational Days 0-18, three groups of plug-positive females (n = 13-15) were given by gavage caffeine at 30, 60, and 120 mg/kg/day. Three additional groups received the same caffeine doses and were restrained for 2 hr/day. Control groups included restrained and unrestrained plug-positive mice not exposed to caffeine. All animals in the group concurrently exposed to 120 mg/kg/day of caffeine and restraint died during the experimental period. In the remaining groups, cesarean sections were performed on Day 18 of gestation, and the fetuses were weighed and examined for external, internal, and skeletal malformations and variations. Although maternal and embryo/fetal toxicity were observed at all caffeine doses, the adverse maternal and developmental effects were significantly enhanced in the groups concurrently exposed to caffeine and restraint. It was especially remarkable at 60 and 120 mg/kg/day. The results of this study suggest that maternal and developmental toxic effects might occur if high amounts of caffeine were consumed by women under a notable stress during pregnancy.

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.