Beneficial effects of garlic on learning and memory deficits and brain tissue damages induced by lead exposure during juvenile rat growth is comparable to the effect of ascorbic acid.

OBJECTIVE: The neuroprotective effects of both garlic and ascorbic acid (AA) have been documented. In this study the effects of garlic and ascorbic acid on memory deficits and brain tissue oxidative damages induced by lead exposure was investigated. METHODS: The juvenile rats were divided and treated: (1) Control, (2) Lead (lead acetate in drinking water, 8 weeks), (3) Lead - Ascorbic Acid (Lead-AA), (4) Lead - Garlic (100 mg/kg, daily, gavage) (Lead-Gar). RESULTS: In Morris water maze (MWM), the escape latency and traveled path in the Lead group were significantly higher while, the time spent in the target quadrant (Q1) was lower than Control. Both Lead-Gar and Lead-AA groups spent more times in Q1than to lead group. There were no significant differences in swimming speed between the groups. In passive avoidance (PA) test, the time latency for entering the dark compartment by Lead group was lower than Control. Treatment of the animals by AA and garlic significantly increased the time latency. In Lead group, the total thiol concentration in brain tissues was significantly lower while, MDA was higher than Control. Treatment by both garlic and AA increased total thiol concentrations and decreased MDA. Both garlic and AA decreased the lead content of brain tissues. CONCLUSION: It is suggested that treatment with garlic attenuates the learning and memory impairments due to lead exposure during juvenile rat growth which is comparable to AA. The possible mechanism may be due to its protective effects against brain tissues oxidative damage as well the lowering effects of brain lead content.

Early chronic lead exposure reduces exploratory activity in young C57BL/6J mice.

Research has suggested that chronic low-level lead exposure diminishes neurocognitive function in children. Tests that are sensitive to behavioral effects at lowest levels of lead exposure are needed for the development of animal models. In this study we investigated the effects of chronic low-level lead exposure on exploratory activity (unbaited nose poke task), exploratory ambulation (open field task) and motor coordination (Rotarod task) in pre-adolescent mice. C57BL/6J pups were exposed to 0 ppm (controls), 30 ppm (low-dose) or 230 ppm (high-dose) lead acetate via dams' drinking water administered from birth to postnatal day 28, to achieve a range of blood lead levels (BLLs) from not detectable to 14.84 µg dl(-1) ). At postnatal day 28, mice completed behavioral testing and were killed (n = 61). BLLs were determined by inductively coupled plasma mass spectrometry. The effects of lead exposure on behavior were tested using generalized linear mixed model analyses with BLL, sex and the interaction as fixed effects, and litter as the random effect. BLL predicted decreased exploratory activity and no threshold of effect was apparent. As BLL increased, nose pokes decreased. The C57BL/6J mouse is a useful model for examining effects of early chronic low-level lead exposure on behavior. In the C57BL/6J mouse, the unbaited nose poke task is sensitive to the effects of early chronic low-level lead exposure. This is the first animal study to show behavioral effects in pre-adolescent lead-exposed mice with BLL below 5 µg dl(-1).

Early childhood lead exposure and academic achievement: evidence from Detroit public schools, 2008-2010.

OBJECTIVES: We assessed the long-term effect of early childhood lead exposure on academic achievement in mathematics, science, and reading among elementary and junior high school children. METHODS: We linked early childhood blood lead testing surveillance data from the Detroit Department of Health and Wellness Promotion to educational testing data from the Detroit, Michigan, public schools. We used the linked data to investigate the effect of early childhood lead exposure on academic achievement among school-aged children, both marginally and adjusted for grade level, gender, race, language, maternal education, and socioeconomic status. RESULTS: High blood lead levels before age 6 years were strongly associated with poor academic achievement in grades 3, 5, and 8. The odds of scoring less than proficient for those whose blood lead levels were greater than 10 micrograms per deciliter were more than twice the odds for those whose blood lead levels were less than 1 micrograms per deciliter after adjustment for potential confounders. CONCLUSIONS: Early childhood lead exposure was negatively associated with academic achievement in elementary and junior high school, after adjusting for key potential confounders. The control of lead poisoning should focus on primary prevention of lead exposure in children and development of special education programs for students with lead poisoning.

Developmental lead exposure and adult criminal behavior: A 30-year prospective birth cohort study.

Using a variety of research designs and measures of lead absorption, numerous studies link childhood lead exposure to a range of cognitive and behavioral deficits, including low IQ, impulsivity, juvenile delinquency, and criminal behavior in adolescence and early adulthood. In this study, we tested the association between multiple measures of blood lead concentration assessed in childhood with criminal behavior in adulthood and across the life-course. Prospective data from the Cincinnati Lead Study (CLS) included blood lead measures quarterly across the first 78 months of life and the number of times a person was arrested across the life-course (from age 18 to 33 years) and in later adulthood (age 27 to 33 years). Childhood blood lead concentration prospectively predicted variation in adult arrests and arrests over the life-course, indicating lead absorption is implicated in the etiology of crime-especially in geographic areas where environmental sources of lead are more prevalent and concentrated. Efforts to decrease lead exposure in both developed and developing countries should be part of a comprehensive strategy to reduce social dislocation and crime.

Altered functional activations of prefrontal brain areas during emotional processing of fear in Inuit adolescents exposed to environmental contaminants.

Exposure to mercury, lead and polychlorinated biphenyls (PCBs) have been associated with emotional dysregulation, but their neuronal correlates have yet to be examined. Inuit from Nunavik (Northern Quebec, Canada) face internalizing problems and are among the most exposed individuals to these environmental contaminants in the world. The aim of this study was to examine the link between pre- and postnatal exposure to these contaminants and brain fear-circuitry in Inuit adolescents. Facial expression stimuli were presented to participants (mean age = 18.3 years) in a magnetic resonance imaging (MRI) scanner. Fear conditioning and extinction tasks included neutral faces as the conditioned threat and safety cues and a fearful face paired with a shrieking scream as the unconditioned stimulus. Functional MRI data were gathered at the conditioning phase (n = 71) and at the extinction phase (n = 62). Mercury, lead and PCB 153 concentrations were measured in blood samples at birth (cord blood) and at the time of the adolescent testing to estimate pre- and postnatal exposure, respectively. For each time point, exposures were categorized in tertiles (low, moderate and high exposed groups). Mixed analyses of variance were conducted for each contaminant of interest controlling for sex, age, socioeconomic status, drug/alcohol use, food insecurity and contaminant co-exposure. Results revealed greater differential activation during the conditioning phase in the right orbitofrontal cortex in participants with moderate and high concentrations of cord blood PCB 153 compared to those in the low exposure group. During the extinction phase, the high prenatal mercury exposed group showed a lower differential activation in the right and left anterior cingulate cortex compared to those in the low-exposed group; whereas there was a higher differential activation in right dorsolateral prefrontal cortex in the high postnatal lead exposed group compared to the moderate- and low-exposed groups. Our study is the first to show alterations in the prefrontal brain areas in fear conditioning and extinction tasks in relation to environmental contaminant exposures. The observed brain correlates may advance our understanding of the emotional problems associated with environmental chemical toxicity.

Lead and conduct problems: a meta-analysis.

This meta-analysis examined the association between conduct problems and lead exposure. Nineteen studies on 8,561 children and adolescents were included. The average r across all 19 studies was .19 (p < .001), which is considered a medium effect size. Studies that assessed lead exposure using hair element analysis yielded considerably larger effect sizes than those that assessed lead exposure using blood, tooth, or bone lead levels. Excluding the 3 hair analysis studies, the average r was .15 (p < .001). The age of the participants did not significantly moderate the relation between lead exposure and conduct problems. Overall, the relation between lead exposure and conduct problems was strikingly similar in magnitude to the relation between lead exposure and decreased IQ.

Blood lead levels in Egyptian children from high and low lead-polluted areas: impact on cognitive function.

OBJECTIVES: Many children are harmed by low-level lead exposure which impairs cognitive development with subsequent poor scholastic achievement. We investigated blood lead levels in children in relation to cognitive function. MATERIALS AND METHODS: Blood lead levels were measured in 100 children recruited from high (n = 50) and low (n = 50) lead-polluted areas. RESULTS: Blood lead levels ranged between 3 and 28 microg/dl (median 9, interquartile range 6 microg/dl). In addition, 43% of children had levels > or =10 microg/dl, of whom 90.1% were living in high-risk areas for lead pollution. Cognitive dysfunction was found in 37% of children. Children with cognitive dysfunction had significantly higher blood lead and lower hemoglobin than those without (P < 0.001). CONCLUSIONS: Increased blood lead level in many children is one of the health problems in Egypt which may be the reason, at least in part, for cognitive dysfunction with subsequent poor scholastic achievement. Thus, interventions to control lead exposure are mandatory.

Association between hair lead levels and autism spectrum disorder in children: A systematic review and meta-analysis.

A number of studies measured lead levels in hair from children with autism spectrum disorder (ASD) to detect the relationship between cumulated lead exposure and the development of ASD, but results are inconsistent. We aimed to conduct a systematic review and meta-analysis using the published studies to explore the actual association of hair lead levels with ASD in children. We searched PubMed, Embase, PsycINFO, and Cochrane Library databases (up to December 11, 2018). The random-effects model was applied to summarize effect sizes. Subgroup and meta-regression analyses were performed simultaneously. Twenty eligible studies involving 1787 participants (941 autistic children and 846 healthy subjects) were included. Our results of primary analysis showed that there were no statistically significant differences in the levels of hair lead between children with ASD and healthy individuals (Hedges's g = 0.251; 95% confidence interval: -0.121, 0.623; P = 0.187). We identified 2 sources of between-study heterogeneity: analytical technology and the sample size of patients. Additionally, no publication bias was observed in this meta-analysis. In conclusion, this study does not support the association of hair lead levels with ASD in children, and the involvement of cumulated lead exposure in the occurrence of ASD.

Elevated lead levels from e-waste exposure are linked to sensory integration difficulties in preschool children.

Exposure to lead is associated with adverse effects on neurodevelopment. However, studies of the effects of lead on sensory integration are few. The purpose of this research is to investigate the effect of lead exposure on child sensory integration by correlating the blood lead levels of children with sensory processing measures. A total of 574 children, from 3 to 6 years of age, 358 from an electronic waste (e-waste) recycling town named Guiyu, and 216 from Haojiang, a nearby town with no e-waste recycling activity, were recruited in this study. The median blood lead level in Guiyu children was 4.88 µg/dL, higher than the 3.47 µg/dL blood lead level in Haojiang children (P < 0.001). 47.2% of Guiyu children had blood lead levels exceeding 5 µg/dL. The median concentration of serum cortisol, an HPA-axis biomarker, in Guiyu children was significantly lower than in Haojiang, and was negatively correlated with blood lead levels. All subscale scores and the total score of the Sensory Processing Measure (Hong Kong Chinese version, SPM-HKC) in Guiyu children were higher than Haojiang children, indicating greater difficulties, especially for touch, body awareness, balance and motion, and total sensory systems. Sensory processing scores were positively correlated with blood lead, except for touch, which was negatively correlated with serum cortisol levels. Simultaneously, all subscale scores and the total SPM-HKC scores for children with high blood lead levels (blood lead > 5 µg/dL) were higher than those in the low blood lead level group (blood lead < 5 µg/dL), especially for hearing, touch, body awareness, balance and motion, and total sensory systems. Our findings suggest that lead exposure in e-waste recycling areas may result in a decrease in serum cortisol levels and an increase in child sensory integration difficulties. Cortisol may be involved in touch-related sensory integration difficulties.

Neurotoxicity of low-level lead exposure: History, mechanisms of action, and behavioral effects in humans and preclinical models.

Lead is a neurotoxin that produces long-term, perhaps irreversible, effects on health and well-being. This article summarizes clinical and preclinical studies that have employed a variety of research techniques to examine the neurotoxic effects of low levels of lead exposure. A historical perspective is presented, followed by an overview of studies that examined behavioral and cognitive outcomes. In addition, a short summary of potential mechanisms of action is provided with a focus on calcium-dependent processes. The current level of concern, or reference level, set by the CDC is 5 µg/dL of lead in blood and a revision to 3.5 µg/dL has been suggested. However, levels of lead below 3 µg/dL have been shown to produce diminished cognitive function and maladaptive behavior in humans and animal models. Because much of the research has focused on higher concentrations of lead, work on low concentrations is needed to better understand the neurobehavioral effects and mechanisms of action of this neurotoxic metal.

Latent subgroups of cognitive performance in lead- and manganese-exposed Uruguayan children: Examining behavioral signatures.

OBJECTIVES: Lead (Pb) and manganese (Mn) are confirmed neurotoxins but it is unclear to what extent low-level exposure produces a unique behavioral signature. The objective of this study was to investigate latent cognitive profiles among children (6-8 years) from Montevideo, Uruguay co-exposed to these metals. METHOD: Among 345 children, blood Pb and hair Mn were measured using atomic absorption spectroscopy and ICP-MS, respectively. Sixteen measures, reflecting multiple domains of cognitive functioning were gathered: (1) three tests from Cambridge Neuropsychological Test Automated Battery (CANTAB): Intra-Extra Dimensional Shift (IED), Spatial Span (SSP) and Stockings of Cambridge (SOC), (2) ten tasks from Woodcock-Muñoz Achievement Battery, Revised (WM): Visual-Motor Integration, Verbal Comprehension (Vocabulary, Synonyms, Antonyms, Analogies), Visual-Auditory Comprehension, Concept Formation, Visual Spatial Thinking, Number Inversion and Spatial Relations, (3) Bender Gestalt task, and (4) Weschler block design task. Scores were modeled using latent profile analysis (LPA). Association between blood Pb and hair Mn on performance profiles was assessed using ordinal regression, controlling for confounders. An interaction between Pb and Mn was tested. RESULTS: Mean ± SD of blood Pb was 4.1 ± 2.1 µg/dL and 35% of children had blood Pb ≥ 5 µg/dL. Median [5%, 95%] hair Mn level was 0.8 [0.3, 4.1] ppb. Three latent cognitive performance profiles were identified: high (n = 46, 13%), average (n = 209, 61%) and low (n = 90, 26%). Each one-unit increase in blood Pb was associated with a 28% greater likelihood of belonging to a poorer-performing profile. The association was non-linear, with the effect of Pb on profile membership strongest at lower levels of exposure. There was no meaningful interaction between Pb and Mn. CONCLUSIONS: A behavioral signature for low-level Pb & Mn exposure was not identified, but the likelihood of membership in low-performing profile was higher at lowest levels of blood Pb. There was no effect measure modification between Pb and Mn. Future research should address how complex environments created by chemical exposures and the social context relate to cognitive performance in young children.

Reduced regional volumes associated with total psychopathy scores in an adult population with childhood lead exposure.

Childhood lead exposure has been correlated to acts of delinquency and criminal behavior; however, little research has been conducted to examine its potential long term influence on behavioral factors such as personality, specifically psychopathic personality. Neuroimaging studies have demonstrated that the effects of childhood lead exposure persist into adulthood, with structural abnormalities found in gray and white matter regions involved in behavioral decision making. The current study examined whether measurements of adult psychopathy were associated with neuroanatomical differences in structural brain volumes for a longitudinal cohort with measured childhood lead exposure. We hypothesized that increased total psychopathy scores and increased blood lead concentration at 78 months of age (PbB78) would be inversely associated with volumetric measures of gray and white matter brain structures responsible for executive and emotional processing. Analyses did not display a direct effect between total psychopathy score and gray matter volume; however, reduced white matter volume in the cerebellum and brain stem in relation to increased total psychopathy scores was observed. An interaction between sex and total psychopathy score was also detected. Females displayed increased gray matter volume in the frontal, temporal, and parietal lobes associated with increased total psychopathy score, but did not display any white matter volume differences. Males primarily displayed reductions in frontal gray and white matter brain volume in relation to increased total psychopathy scores. Additionally, reduced gray and white matter volume was associated with increased blood lead levels in the frontal lobes; reduced white matter volume was also observed in the parietal and temporal lobes. Females demonstrated gray and white matter volume loss associated with increased PbB78 values in the right temporal lobe, as well as reduced gray matter volume in the frontal lobe. Males displayed reduced white matter volumes associated with increased PbB78 values in the frontal, temporal, and parietal lobes. Comparison of the two primary models revealed a volumetric decrease in the white matter of the left prefrontal cortex associated with increased total psychopathy scores and increased blood lead concentration in males. The results of this study suggested that increased psychopathy scores in this cohort may be attributable to the neuroanatomical abnormalities observed and that childhood lead exposure may be influential to these outcomes.

Blood lead levels and specific attention effects in young children.

The detrimental effects of early exposure to lead are credible and persistent, but there is presently no agreement on a safe threshold for circulating lead levels. Although several research groups have found significantly poorer cognitive performance in children who have whole blood levels as low as 5 microg/dL, most government agencies, including the EPA and the CDC, continue to use 10 microg/dL as the criterion for concern in public health advisories. Prior research has consistently indicated a negative relation between lead levels and attention. Similarly, the results of the present study show a relation between blood lead level and neurobehavioral outcome in 7-year-old children (N=506). Higher lead levels were associated significantly with decreased scores on measures of intelligence (i.e., overall, performance and verbal IQ), lengthened reaction time, hyperactivity, and social and delinquent behavior problems. Importantly, the present study documents a significant negative impact of blood lead levels on attention, but not impulsivity, in early elementary age children, further delineating the specific aspects of attention related to blood lead concentrations. Analyses were also conducted to identify a "safe" blood lead level threshold. Visual inspection of non-parametric regression plots suggested a gradual linear dose-response relationship for each endpoint. None of the neurobehavioral outcomes assessed showed evidence of a threshold under which lead levels appear to "safe". In light of the consistency of these findings with those of several other groups, it is advisable to consider whether the threshold for an acceptable blood lead level should be reduced.

Systemic Lead Toxicity.

A 4-year-old girl with slow mentation had increasing knee tenderness and limping gait.

Bone lead levels and language processing performance.

The relation between bone lead absorption and language processing abilities in 156 randomly selected 11- to 14-year-old boys who were asymptomatic for lead toxicity is examined. Tibial lead concentrations were measured by X-ray fluorescence spectroscopy. The language processing outcome variables consisted of the least and most difficult subtests from the Nonword Repetition Task, Competing Language Processing Task, and the Revised Token Test. Participants were classified by quartiles according to bone lead concentrations, and analysis of variance and analysis of covariance measured the impact on language processing scores. Results showed that children in the highest bone lead quartile displayed decreased language processing performance on the most difficult language processing tasks but not on the easier tasks.

Impaired neuropsychological functioning in lead-exposed children.

Neuropsychological functions were assessed in 174 children participating in a longitudinal study of low-level lead exposure. At age 5 1/2 years, children were administered the Working Memory and Planning Battery of the Cambridge Neuropsychological Testing Automated Battery. Measures of sociodemographic characteristics of the family, prenatal and perinatal risk, quality of caregiving and crowding in the home, and maternal and child intelligence were used as covariates to test the hypothesis that children with higher lifetime average blood lead concentrations would perform more poorly on tests of working memory, attentional flexibility, and planning and problem solving. The lifetime average blood lead level in this sample was 7.2 micrograms per deciliter (mug/dL; range: 0-20 mug/dL). Children with greater exposure performed more poorly on tests of executive processes. In both bivariate and multivariate analyses, children with higher lifetime average blood lead concentrations showed impaired performance on the tests of spatial working memory, spatial memory span, intradimensional and extradimensional shifts, and an analog of the Tower of London task. Many of the significant associations remained after controlling for children's intelligence test scores, in addition to the other covariates. These findings indicate that the effects of pediatric lead exposure are not restricted to global indexes of general intellectual functioning, and executive processes may be at particular risk of lead-induced neurotoxicity.

Effect modification in epidemiologic studies of low-level neurotoxicant exposures and health outcomes.

Little attention has been invested in exploring the possibility that the nature or magnitude of a neurotoxicant's health impact on children depends on host characteristics (e.g., sex, age) or contextual factors (e.g., socioeconomic status, other chemical exposures). Such effect modification is a property of a true association, and should be distinguished from confounding. In epidemiologic studies of children, most efforts to identify effect modification have been unsystematic, pursued as part of data analysis rather than of study design. As a result, most samples have insufficient statistical power to characterize effect modification with adequate precision. This may contribute to an inconsistency in results across studies. Failure to assess effect modification adequately may also lead to invalid inferences. If the magnitude of an association between a neurotoxicant exposure and a particular end point varies across strata of a third factor, an estimate that summarizes the association across strata of this factor will be inappropriate, overestimating the association in a stratum in which the association is absent, and underestimating it in a stratum in which it is present. Until such dependencies are identified, our understanding of the mechanism(s) of a compound's neurotoxicity will remain incomplete, as will the knowledge base required to formulate public policy that adequately protects the most sensitive subgroups of the population.

Neurodevelopmental effects of postnatal lead exposure at very low levels.

This study is among the first to examine specific neurobehavioral deficits in children exposed at very low lead levels. A systematic analysis for the presence of a threshold of lead exposure was conducted. The sample consisted of 246 African American, inner-city children from whom blood lead concentrations were assessed at 7.5 years of age. The results consistently show neurobehavioral deficits in relation to low levels of lead in the areas of intelligence, reaction time, visual-motor integration, fine motor skills, attention, including executive function, off-task behaviors, and teacher-reported withdrawn behaviors. Effects were identified in the specific domains of attention, executive function, visual-motor integration, social behavior, and motor skills, which have been previously suggested as part of lead's "behavioral signature". Visual inspection of nonparametric regression plots suggested a gradual linear dose-response relation for most endpoints. No threshold discontinuity was evident. Regression analyses in which lead exposure was dichotomized at 10 microg/dl were no more likely to be significant than analyses dichotomizing exposure at 5 microg/dl. Given that associations were found between lead levels as low as 3 microg/dl for multiple outcomes, these data provide additional evidence that there is no apparent lower bound threshold for postnatal lead exposure.

Epigenetic histone modification regulates developmental lead exposure induced hyperactivity in rats.

Lead (Pb) exposure was commonly considered as a high environmental risk factor for the development of attention-deficit/hyperactivity disorder (ADHD). However, the molecular basis of this pathological process still remains elusive. In light of the role of epigenetics in modulating the neurological disease and the causative environment, the alterations of histone modifications in the hippocampus of rats exposed by various doses of lead, along with concomitant behavioral deficits, were investigated in this study. According to the free and forced open field test, there showed that in a dosage-dependent manner, lead exposure could result in the increased locomotor activity of rats, that is, hyperactivity: a subtype of ADHD. Western blotting assays revealed that the levels of histone acetylation increased significantly in the hippocampus by chronic lead exposure, while no dramatic changes were detected in terms of expression yields of ADHD-related dopaminergic proteins, indicating that histone acetylation plays essential roles in this toxicant-involved pathogenesis. In addition, the increased level of histone acetylation might be attributed to the enzymatic activity of p300, a typical histone acetyltransferase, as the transcriptional level of p300 was significantly increased upon higher-dose Pb exposure. In summary, this study first discovered the epigenetic mechanism bridging the environmental influence (Pb) and the disease itself (ADHD) in the histone modification level, paving the way for the comprehensive understanding of ADHD's etiology and in further steps, establishing the therapy strategy of this widespread neurological disorder.

Evaluation of lead levels in biological samples of mentally retarded children in different stages using advanced extraction method.

In present study the lead (Pb) levels has been assessed by analyzing the scalp hair and blood samples of mentally retarded/intellectual disabled (MR/ID) children of both genders, age ranged 3-8 years. For comparative purpose, healthy age matched children were also selected. The cloud point extraction of Pb from digested biological samples was carried out by complexed with ammonium pyrrolidinedithiocarbamate. The complexed analyte was subsequently isolated from the aqueous matrix in the micelles of a non-ionic surfactant (Triton X-114). Dilution of the surfactant-rich phase with acidified ethanol was performed after phase separation, and the Pb content was measured by flame atomic absorption spectrometer. Factors affecting the cloud point extraction were evaluated and optimized. The proposed procedure allowed the determination of lead in certified standard and real samples with detection limits of 0.834µgL(-) and enhancement factor 55. The results were compared with those of healthy children have same age, socioeconomic status and residential areas.