Lead-induced Learning Research Articles

Sesamin: Insights into its protective effects against lead-induced learning and memory deficits in rats

BackgroundLead (Pb) is one of the most hazardous pollutants that induce a wide spectrum of neurological changes such as learning and memory deficits. Sesamin, a phytonutrient of the lignan class, exhibits anti-inflammatory, anti-apoptotic, and neuroprotective properties. The present study was designed to investigate the effects of sesamin against Pb-induced learning and memory deficits, disruption of hippocampal theta and gamma rhythms, inflammatory response, inhibition of blood δ-aminolevulinic acid dehydratase (δ-ALA-D) activity, Pb accumulation, and neuronal loss in rats. MethodsSesamin treatment (30 mg/kg/day; P.O.) was started simultaneously with Pb acetate exposure (500 ppm in standard drinking water) in rats, and they continued for eight consecutive weeks. ResultsThe results showed that chronic exposure to Pb disrupted the learning and memory functions in both passive-avoidance and water-maze tests, which was accompanied by increase in spectral theta power and theta/gamma ratio, and a decrease in spectral gamma power in the hippocampus. Additionally, Pb exposure resulted in an enhanced tumor necrosis factor-alpha (TNF-α) content, decreased interleukin-10 (IL-10) production, inhibited blood δ-ALA-D activity, increased Pb accumulation, and neuronal loss of rats. In contrast, sesamin treatment improved all the above-mentioned Pb-induced pathological changes. ConclusionThis data suggests that sesamin could improve Pb-induced learning and memory deficits, possibly through amelioration of hippocampal theta and gamma rhythms, modulation of inflammatory status, restoration of the blood δ-ALA-D activity, reduction of Pb accumulation in the blood and the brain tissues, and prevention of neuronal loss.

Relationships between lead-induced learning and memory impairments and gut microbiota disturbance in mice

Objective: To explore the effect of lead exposure on the neurobehavior and gut microbiota community structure in mice. Methods: In August 2019, 64 C57BL/6 mice were randomly divided into 4 groups: control group (0 ppm) , low lead exposure group (20 mg/l) , medium lead exposure group (100 mg/l) and high lead exposure group (500 mg/l) . During the experiment, they were free to eat and drink. The drinking water of the lead exposure group was mixed with lead acetate, and sodium acetate was added in the control group. After 10 weeks of exposure, the Morris water maze was used to test the learning and memory ability of each group of mice, and then they were sacrificed for sampling. ICP-MS was used to detect lead content in whole blood and brain tissue. ELISA was used to determine the level of IL-1β in mouse serum. 16S rRNA sequencing was used to detect the structural diversity of the intestinal flora in feces, and then the correlation between the flora and behavior indicators was analyzed. Results: In the Morris water maze experiment, compared with the control group, there was no significant difference in the body weight and swimming speed of the mice in the lead exposure groups. The escape latency of the mice in the 100 mg/l and 500 mg/l dose groups was prolonged, and the number of platform crossings decreased (P<0.05) ; meanwhile, the staying time of the mice in the 500 mg/l Pb-treated group in the target quadrant was lower than that of the control group, and the difference was statistically significant (P<0.05) . Compared with the control group, the blood lead content of the mice in each lead exposure group was significantly increased, and the brain lead content of mice in the 500 mg/l dose group was significantly elevated (P<0.05) . The serum IL-1β levels of mice in each lead exposure group were higher than those of the control group (P<0.05) . At the phylum level, the relative abundance of the Proteobacteria phylum in all of Pb-treated groups was significantly increased (P<0.05) ; at the genus level, Allobaculum, Desulfovibrio, Lachnospiraceae_NK4A136_group, Turicibacter and Ureaplasma were significantly increased (P<0.05) . Among them. The relative abundance of Desuffaoibrio, Turici bacter, and Ureaplasma was negatively correlated with the residence time of mice in the quadrant of the platform (r=-0.32, -0.29, -0.44, P<0.05) . Conclusion: Lead exposure induced learning and memory impairments in mice, which may be related to the disturbance of the gut microbiota.

Amelioration of Prenatal Lead-Induced Learning and Memory Impairments by Methanolic Extract of Zataria Multiflora in Male Rats.

Introduction:This study aimed to evaluate the reliability and validity of an Iranian computerized memory battery modeled after the Betula study.Methods:This study aimed to evaluate the reliability and validity of an Iranian computerized memory battery modeled after the Betula study ( Nilsson et al., 1997). The researchers developed this battery as an assessment tool in the Sepidar prospective cohort study. One hundred and ninety-nine participants aged 19–83 years were tested extensively on different aspects of memory. Exploratory factor analysis of the data demonstrated factors similar to those reported by the Betula study.Results:The authors succeeded to converge the cross-sectional findings of the study and the data from longitudinal studies of memory aging by correcting possible cohort effects. Investigating age differences in episodic and semantic memory factor scores corrected by education and socioeconomic status revealed no significant difference between younger and older adults before ages 53 to 60, though linear age-related declines existed thereafter.Conclusion:The results support the reliability and construct validity of this computerized battery for memory assessment in Iranian adults.

Amelioration of Prenatal Lead-Induced Learning and Memory Impairments by Methanolic Extract of Zataria Multiflora in Male Rats

Introduction:The current study aimed at evaluating the effects of Zataria Multiflora (ZM) on learning and memory of adult male offspring rats with prenatal lead-exposure.Methods:Pregnant rats in the case group received tap water containing 0.2% lead acetate throughout the gestation period. Control rats had free access to lead-free tap water. Two male offspring (two-month-old, weighing 180–200 g) from each mother were randomly selected and treated with either Z. Multiflora (50, 200, 400, and 800 mg/kg/Intraperitoneally (I.P)/20 day) or saline. Spatial memory of the control, saline, and ZM-treated rats was evaluated by a training trial and probe test using Morris water maze (6–8 rat/group).Results:The obtained results showed memory deficits including increased escape latency, and a greater traveled distance, as well as decrements in the frequency of crossings into target quadrants in prenatally lead-exposed male offspring compared with the controls. ZM treatment (200 mg/kg/i.p) ameliorated the memory deficits in male offspring by increasing the time spent and traveled distance in the trigger zone (P<0.01 vs. saline).There was no significant difference in swimming speed between the groups.Conclusion:The results showed memory deficits in prenatally lead-exposed male offspring. ZM treatment (especially 200 mg/kg) had beneficial effects on cognitive behavior and was indicated as the improvement of lead-induced memory deficits in prenatally lead-exposed male rats. The exact mechanism(s) is not determined yet, but it could be mediated through the anticholinesterase and antioxidant effects and also alterations in Central Nervous System (CNS) and neurotransmission in the central nervous system.

Gene-environment interaction between lead and Apolipoprotein E4 causes cognitive behavior deficits in mice

BackgroundAlzheimer’s disease (AD) is characterized by progressive cognitive decline and memory loss. Environmental factors and gene-environment interactions (GXE) may increase AD risk, accelerate cognitive decline, and impair learning and memory. However, there is currently little direct evidence supporting this hypothesis.MethodsIn this study, we assessed for a GXE between lead and ApoE4 on cognitive behavior using transgenic knock-in (KI) mice that express the human Apolipoprotein E4 allele (ApoE4-KI) or Apolipoprotein E3 allele (ApoE3-KI). We exposed 8-week-old male and female ApoE3-KI and ApoE4-KI mice to 0.2% lead acetate via drinking water for 12 weeks and assessed for cognitive behavior deficits during and after the lead exposure. In addition, we exposed a second (cellular) cohort of animals to lead and assessed for changes in adult hippocampal neurogenesis as a potential underlying mechanism for lead-induced learning and memory deficits.ResultsIn the behavior cohort, we found that lead reduced contextual fear memory in all animals; however, this decrease was greatest and statistically significant only in lead-treated ApoE4-KI females. Similarly, only lead-treated ApoE4-KI females exhibited a significant decrease in spontaneous alternation in the T-maze. Furthermore, all lead-treated animals developed persistent spatial working memory deficits in the novel object location test, and this deficit manifested earlier in ApoE4-KI mice, with female ApoE4-KI mice exhibiting the earliest deficit onset. In the cellular cohort, we observed that the maturation, differentiation, and dendritic development of adult-born neurons in the hippocampus was selectively impaired in lead-treated female ApoE4-KI mice.ConclusionsThese data suggest that GXE between ApoE4 and lead exposure may contribute to cognitive impairment and that impaired adult hippocampal neurogenesis may contribute to these deficits in cognitive behavior. Together, these data suggest a role for GXE and sex differences in AD risk.

Protective Effect of Microporous Natural Clinoptilolite on Lead-Induced Learning and Memory Impairment in Rats

Background: Lead poisoning impairs memory and learning. Objectives: The protective effect of natural zeolite clinoptilolite on memory and learning impairment in rats exposed to lead acetate was investigated. Materials and Methods: 60 male Wistar rats in six groups treated for 2 months with diets contained different ratios of natural zeolite(i.e. 5% or 12.5%), and %0.2 lead acetate (LA) concentrations. behavioral test was evaluated by passive avoidance learning method in shuttle box at 6, 12, 24, 48 hours, and one week after the shock test. Results: digestive exposure with 0.2% lead acetate in the presence of zeolite additive had no effect on the rats’ memory performance (P < 0.05). Adding 5 and 12.5%w/w of natural zeolite to the rats’ feed improved short-term, medium-term, and long-term memory performance (P < 0.05) compared to the control group. Conclusion: observed improvement in memory function can be considered in part as the indirect effects of cation exchange or adsorption property of zeolites.

Protective Effect of Microporous Natural Clinoptilolite on Lead-Induced Learning and Memory Impairment in Rats

Background: Lead poisoning impairs memory and learning. Objectives: The protective effect of natural zeolite clinoptilolite on memory and learning impairment in rats exposed to lead acetate was investigated. Materials and Methods: 60 male Wistar rats in six groups treated for 2 months with diets contained different ratios of natural zeolite(i.e. 5% or 12.5%), and %0.2 lead acetate (LA) concentrations. behavioral test was evaluated by passive avoidance learning method in shuttle box at 6, 12, 24, 48 hours, and one week after the shock test. Results: digestive exposure with 0.2% lead acetate in the presence of zeolite additive had no effect on the rats’ memory performance (P < 0.05). Adding 5 and 12.5%w/w of natural zeolite to the rats’ feed improved short-term, medium-term, and long-term memory performance (P < 0.05) compared to the control group. Conclusion: observed improvement in memory function can be considered in part as the indirect effects of cation exchange or adsorption property of zeolites.

The Role of α-synuclein and Tau Hyperphosphorylation-Mediated Autophagy and Apoptosis in Lead-induced Learning and Memory Injury

Lead (Pb) is a well-known heavy metal in nature. Pb can cause pathophysiological changes in several organ systems including central nervous system. Especially, Pb can affect intelligence development and the ability of learning and memory of children. However, the toxic effects and mechanisms of Pb on learning and memory are still unclear. To clarify the mechanisms of Pb-induced neurotoxicity in hippocampus, and its effect on learning and memory, we chose Sprague-Dawley rats (SD-rats) as experimental subjects. We used Morris water maze to verify the ability of learning and memory after Pb treatment. We used immunohistofluorescence and Western blotting to detect the level of tau phosphorylation, accumulation of α-synuclein, autophagy and related signaling molecules in hippocampus. We demonstrated that Pb can cause abnormally hyperphosphorylation of tau and accumulation of α-synuclein, and these can induce hippocampal injury and the ability of learning and memory damage. To provide the new insight into the underlying mechanisms, we showed that Grp78, ATF4, caspase-3, autophagy-related proteins were induced and highly expressed following Pb-exposure. But mTOR signaling pathway was suppressed in Pb-exposed groups. Our results showed that Pb could cause hyperphosphorylation of tau and accumulation of α-synuclein, which could induce ER stress and suppress mTOR signal pathway. These can enhance type II program death (autophgy) and type I program death (apoptosis) in hippocampus, and impair the ability of learning and memory of rats. This is the first evidence showing the novel role of autophagy in the neurotoxicity of Pb.

Selection of Nutrients for Prevention or Amelioration of Lead-Induced Learning and Memory Impairment in Rats

We carried out animal experiments based on the orthogonal design L(8)(2(7)) setting seven factors with two different levels of each and 10 groups of rats. The nutrients tested were tyrosine, glycine, methionine, taurine, ascorbic acid, thiamine and zinc. The objective of this study was to explore the optimal combinations of nutrients for prevention or amelioration of lead-induced learning and memory impairment. Rats were supplemented with nutrients by gavage once a day in two experiments: one was simultaneous nutrient supplementation with lead acetate administration (800 mg l(-1)) for 8 weeks (prophylactic supplementation) and the other was nutrient supplementation for 4 weeks after the cessation of 4 weeks of lead administration (remedial supplementation). Morris water maze was initiated at ninth week. Rats were terminated for assays of levels of Pb in blood, activities of superoxide dismutase (SOD) and nitric oxide synthase (NOS) in hippocampus, levels of nitric oxide (NO) in hippocampus and expressions of Ca2+/calmodulin-dependent protein kinase II (CaMKII) and cyclic adenosine monophosphate (cAMP) response element-binding protein messenger RNA in hippocampus. Results showed that in prophylactic supplementation, methionine, taurine, zinc, ascorbic acid and glycine were the effective preventive factors for decreasing prolonged escape latency, increasing SOD and NOS activities and NO levels in the hippocampus, respectively. On the other hand, in remedial supplementation, taurine was the effective factor for reversing Pb-induced decrease in activities of SOD, NOS and levels of NO. In conclusion, the optimum combinations of nutrients appear to be methionine, taurine, zinc, ascorbic acid and glycine for the prevention of learning and memory impairment, while taurine and thiamine appear to be the effective factors for reversing Pb neurotoxicity.

Use of Bullfrog Tadpoles (Rana catesbeiana) to Examine the Mechanisms of Lead Neurotoxicity

SYNOPSIS. Sublethal exposure to lead elicits changes in behavior, particularly learning. Previously, we had shown that bullfrog tadpoles exposed to 1 mg Pb/liter for 7 days exhibit learning deficits in a discriminate avoidance learning assay. The precise mechanisms involved in these lead-induced learning deficits are not understood, but CNS monoamine neurotransmitter systems have been implicated in the learning process. In the present study, we exposed bullfrog tadpoles to 1.7 ± 0.2 mg Pb/liter for 7 days and then compared concentrations of neurotransmitters from whole brain samples with those of controls. Serotonin or 5-hydroxytryptamine (5-HT) was significantly decreased in the lead exposed group while the serotonin metabolite, 5-hydroxyindoleacetic acid, (5-HIAA) was similar to controls. No changes were observed in the catecholamines epinephrine and norepinephijine following lead exposure. The ratio of 5-HIAA/5-HT was significantly increased in lead exposed animals as a result of the decrease in 5-HT, suggesting a decrease in 5-HT biosynthesis rather than an increase in 5-HT metabolism. These findings are the first to suggest that lead exposure in bullfrog tadpoles affects the monoamine neurotransmitters that are implicated in the learning process. The results of the present study, in conjunction with previous evidence of learning deficits following lead exposure, offer the possibility of correlating lead exposure with learning deficits and alterations in CNS neurotransmitters in bullfrog tadpoles. The use of this tadpole model shows promise as a means to examine and understand the mechanisms involved in lead neurotoxicity.

Relationships between lead-induced learning impairments and changes in dopaminergic, cholinergic, and glutamatergic neurotransmitter system functions.

Behavioral consequences of low-level lead (Pb) exposure include impairments in learning processes and in Fixed-Interval schedule-controlled operant behavior. Although the neurobiological bases of these effects remain undetermined, current evidence suggests that inhibitory effects of Pb on the NMDA receptor complex may play a preferential role in the learning deficits. In contrast, alterations in dopaminergic systems, consistent with a decrease in dopamine availability, appear to be related to the changes in Fixed-Interval performance. Hypocholinergic function has also been described, but its relationship to the behavioral changes is not yet known. Explication of these relationships will require more efforts involving direct rather than correlative methods. The answers are critical for understanding risks associated with exposure and for the development of behavioral or chemical therapeutic strategies for dealing with lead neurotoxicity.

Relationships Between Lead-Induced Learning Impairments and Changes in Dopaminergic, Cholinergic, and Glutamergic Neurotransmitter System Functions

Due to the massive data sets available for drug candidates, modern drug discovery has advanced to the big data era. Central to this shift is the development of artificial intelligence approaches to implementing innovative modeling based on the dynamic, ...Read More

The role of dopaminergic and glutamatergic systems in lead-induced learning impairments: CORY-SLECHTA, D.A., Department of Environmental Medicine, University of Rochester School of Medicine, Rochester, NY

The role of dopaminergic and glutamatergic systems in lead-induced learning impairments: CORY-SLECHTA, D.A., Department of Environmental Medicine, University of Rochester School of Medicine, Rochester, NY

The nature of lead-induced learning impairments and neurotransmitter system involvement: D. A. Cory-Slechta. University of Rochester School of Medicine, Rochester, NY

The nature of lead-induced learning impairments and neurotransmitter system involvement: D. A. Cory-Slechta. University of Rochester School of Medicine, Rochester, NY

Splenomegaly and adrenal weight changes in isolated adult mice chronically exposed to lead

Inorganic lead is an environmental contaminant of continuing toxicological concern. Since the effects of chronic lead ingestion are most pronounced in neonatal or very young animals, investigations relating to the mental health effects of lead on children have to date been of prime importance. As the perspective of lead toxicity has widened, however, concern about the effects of lead exposure in adults has also been expressed, and several studies have now documented lead-induced learning abnormalities in adult animals. Recently research has shown that lead-treated adult mice fail to develop the isolation-induced aggressiveness typical of untreated control animals. Animal aggression has both neural and endocrine substrates, and with regard to the latter, it is well known that many mammals exhibit changes of adrenal weight and function when subjected to irritable aggression associated with the pressure of population density. Although impairment of adrenal gland functioning has been reported for lead-poisoned humans, few animal studies have yet investigated the effects of chronic lead exposure on the pituitary-adrenal axis. In this paper, changes are described in adrenal weights for mice subjected to isolation and lead exposure. In addition, since it is well known that lead exposure can reduce the survival time of red bloodmore » cells, the possibility that the spleen, the disposal center for discarded red cells, might also be affected by lead exposure was investigated.« less