Environmental inequality and disparities in school readiness: The role of neurotoxic lead.

Developmental science has increasingly scrutinized how environmental hazards influence child outcomes, but few studies examine how contaminants affect disparities in early skill formation. Linking research on environmental inequality and early childhood development, this study assessed whether differences in exposure to neurotoxic lead explain sociodemographic gaps in school readiness. Using panel data tracking a representative sample of 1266 Chicago children (50% female, 16% White, 30% Black, 49% Hispanic, µage = 5.2 months at baseline, collected 1994-2002), analyses quantified the contribution of lead contamination to class and racial disparities in vocabulary skills and attention problems at ages 4 and 5. Results suggested that lead contamination explains 15%-25% and 33%-66% of the disparities in each outcome, respectively, although imprecise estimates preclude drawing firm inferences about attention problems.

Chronic developmental lead exposure increases µ-opiate receptor levels in the adolescent rat brain.

Childhood lead (Pb2+) intoxication is a global public health problem best known for producing deficits in learning and poor school performance. Human and preclinical studies have suggested an association between childhood Pb2+ intoxication and proclivity to substance abuse and delinquent behavior. While environmental factors have been implicated in opioid addiction, less is known about the role of exposure to environmental pollutants on the brain opioid system. Opioid receptors are involved in the biological effects of opioids and other drugs of abuse. In this study, we examine the effect of chronic developmental Pb2+ exposure (1500 ppm in the diet) on µ-opioid receptor (MOR) levels in the rat brain using [3H]-d-Ala2-MePhe4-Gly-ol5 enkephalin ([3H]-DAMGO) quantitative receptor autoradiography at different developmental stages (juvenile, early-adolescent, late adolescent and adult) in male and female rats. Our results indicate that chronic developmental Pb2+ exposure increases the levels of [3H]-DAMGO specific binding to MOR in juvenile and early adolescent Pb2+-exposed male and female rat brain with no changes in late-adolescent (PN50) and minor changes in Pb2+-exposed adult male rats (PN120). Specifically, at PN14, Pb2+-exposed males had an increase in MOR binding in the lateral posthalamic nuclei (LPTN), and Pb2+-exposed females had increased MOR binding in LPTN, medial thalamus, and hypothalamus. At PN28, Pb2+-exposed males had increased MOR levels in the striatum, stria medullaris of the thalamus, LPTN, medial thalamus, and basolateral amygdala, while Pb2+-exposed females showed an increase in nucleus accumbens core, LPTN, and medial thalamus. No changes were detected in any brain region of male and female rats at PN50, and at PN120 there was a decrease in MOR binding of Pb2+-exposed males in the medial thalamus. Our findings demonstrate age and gender specific effects of MOR levels in the rat brain as a result of chronic developmental Pb2+ exposure. These results indicate that the major changes in brain MOR levels were during pre-adolescence and early adolescence, a developmental period in which there is higher engagement in reward and drug-seeking behaviors in humans. In summary, we show that chronic exposure to Pb2+, an ubiquitous and well-known environmental contaminant and neurotoxicant, alters MOR levels in brain regions associated with addiction circuits in the adolescent period, these findings have important implications for opioid drug use and abuse.

Intraventricular infusion of quinolinic acid impairs spatial learning and memory in young rats: a novel mechanism of lead-induced neurotoxicity.

BACKGROUND: Lead (Pb), a heavy metal, and quinolinic acid (QA), a metabolite of the kynurenine pathway of tryptophan metabolism, are known neurotoxicants. Both Pb and QA impair spatial learning and memory. Pb activates astrocytes and microglia, which in turn induce the synthesis of QA. We hypothesized increased QA production in response to Pb exposure as a novel mechanism of Pb-neurotoxicity. METHODS: Two experimental paradigms were used. In experiment one, Wistar rat pups were exposed to Pb via their dams' drinking water from postnatal day 1 to 21. Control group was given regular water. In the second protocol, QA (9 mM) or normal saline (as Vehicle Control) was infused into right lateral ventricle of 21-day old rats for 7 days using osmotic pumps. Learning and memory were assessed by Morris water maze test on postnatal day 30 or 45 in both Pb- and QA-exposed rats. QA levels in the Pb exposed rats were measured in blood by ELISA and in the brain by immunohistochemistry on postnatal days 45 and 60. Expression of various molecules involved in learning and memory was analyzed by Western blot. Means of control and experimental groups were compared with two-way repeated measure ANOVA (learning) and t test (all other variables). RESULTS: Pb exposure increased QA level in the blood (by ~ 58%) and increased (p < 0.05) the number of QA-immunoreactive cells in the cortex, and CA1, CA3 and dentate gyrus regions of the hippocampus, compared to control rats. In separate experiments, QA infusion impaired learning and short-term memory similar to Pb. PSD-95, PP1, and PP2A were decreased (p < 0.05) in the QA-infused rats, whereas tau phosphorylation was increased, compared to vehicle infused rats. CONCLUSION: Putting together the results of the two experimental paradigms, we propose that increased QA production in response to Pb exposure is a novel mechanism of Pb-induced neurotoxicity.

Enhanced taupathy and AD-like pathology in aged primate brains decades after infantile exposure to lead (Pb).

Late Onset Alzheimer Disease (LOAD) constitutes the majority of AD cases (∼90%). Amyloidosis and tau pathology, which are present in AD brains, appear to be sporadic in nature. We have previously shown that infantile lead (Pb) exposure is associated with a change in the expression and regulation of the amyloid precursor protein (APP) and its beta amyloid (Aß) products in old age. Here we report that infantile Pb exposure elevated the mRNA and protein levels of tau as well as its transcriptional regulators namely specificity protein 1 and 3 (Sp1 and Sp3) in aged primates. These changes were also accompanied by an enhancement in site-specific tau phosphorylation as well as an increase in the mRNA and protein levels of cyclin dependent kinase 5 (cdk5). There was also a change in the protein ratio of p35/p25 with more Serine/Threonine phosphatase activity present in aged primates exposed to Pb as infants. These molecular alterations favored abundant tau phosphorylation and immunoreactivity in the frontal cortex of aged primates with prior Pb exposure. These findings provide more evidence that neurodegenerative diseases may be products of environmental influences that occur during the development.

Cumulative exposure to lead and cognition in persons with Parkinson's disease.

Dementia is an important consequence of Parkinson's disease (PD), with few known modifiable risk factors. Cumulative exposure to lead, at levels experienced in the community, may exacerbate PD-related neural dysfunction, resulting in impaired cognition. Among 101 persons with PD ("cases") and, separately, 50 persons without PD ("controls"), we evaluated cumulative lead exposure, gauged by tibia and patella bone lead concentrations, in relation to cognitive function, assessed using a telephone battery developed and validated in a separate sample of PD patients. We also assessed the interaction between lead and case-control status. After multivariable adjustment, higher tibia bone lead concentration among PD cases was associated with worse performance on all of the individual telephone tests. In particular, tibia lead levels corresponded to significantly worse performance on a telephone analog of the Mini-Mental State Examination and tests of working memory and attention. Moreover, higher tibia bone lead concentration was associated with significantly worse global composite score encompassing all the cognitive tests (P = 0.04). The magnitude of association per standard deviation increment in tibia bone lead level was equivalent to the difference in global scores among controls in our study, who were approximately 7 years apart in age. The tibia lead-cognition association was notably stronger within cases than within controls (P(difference) = 0.06). Patella bone lead concentration was not consistently associated with performance on the tests. These data provide evidence suggesting that cumulative exposure to lead may result in worsened cognition among persons with PD.

Saturnismo, a propósito de un caso / Lead poisoning. A case report

Profesora de pintura sobre vidrio y restauración de vidrieras de 65 años acude a la Unidad Médica de Valoración de Incapacidades del Instituto Nacional de la Seguridad Social (INSS) con diagnóstico de exposición laboral a plomo. La paciente ha permanecido en Incapacidad Temporal por astenia durante varios meses, y se le detecta tras una reincorporación al trabajo plumbemia elevada, asociada a otros síntomas típicos de la intoxicación por plomo, por lo que se la separa de su ambiente de trabajo. Finalmente, el Equipo de Valoración de Incapacidades, reunido para valorar su caso resuelve Incapacidad Laboral Permanente Total derivada de enfermedad profesional para trabajos en que haya exposición a plomo y otros ototóxicos, exposición a ruidos de riesgo, y para aquellos trabajos en que sea necesaria una comunicación verbal fluida en frecuencias conversacionales normales. Con este caso clínico pretendemos revisar los síntomas del cuadro clínico de saturnismo, así como hacer una reflexión sobre los efectos de la prevención de riesgos para el trabajador (AU)

Lead poisoning is most commonly caused by occupational exposure. We report a case of a 65-year-old woman, paint teacher, which was working in reparation of stained glass window. She consults the Medical Incapacity Valoration Unit of National Institute of Social Security with diagnosis of lead occupational intoxication. The patient was not able to word for several months because of presenting asthenia. After reporting for work high lead blood levels were detected, in association with physical symptoms. She was evaluated by a tribunal which settled total long sick-leave due to occupational lead exposure and was restricted for loud works and other ones that need verbal communication in conversational frequencies. With this clinical case we try to check the symptoms of lead poisoning, as well as to think about the effects of prevention of occupational hazards (AU)

Asociación de meningioma y aneurisma cerebral en un paciente con intoxicación crónica por plomo / Association between meningioma and brain aneurysm in a patient with chronic lead poisoning

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Developmental lead exposure attenuates methamphetamine dose-effect self-administration performance and progressive ratio responding in the male rat.

Perinatal (gestation/lactation) lead exposure modifies the reinforcement efficacy of various psychoactive drugs (e.g., cocaine, opiates) across the phases of initial selection, use, and abuse [Nation J.R., Cardon A.L., Heard H.M., Valles R., Bratton G.R. Perinatal lead exposure and relapse to drug-seeking behavior in the rat: a cocaine reinstatement study. Psychopharmacol 2003;168: 236-243.; Nation J.R., Smith K.R., Bratton G.R. Early developmental lead exposure increases sensitivity to cocaine in a self-administration paradigm. Pharmacol Biochem Behave 2004; 77: 127-13; Rocha A., Valles R., Cardon A.L., Bratton G.R., Nation J.R. Enhanced acquisition of cocaine self-administration in rats developmentally exposed to lead. Neuropsychopharmacol 2005; 30: 2058-2064.]. However, changes in sensitivity to methamphetamine across the phases of drug abuse have not been examined in animals perinatally exposed to lead. Because the mainstream popularity of methamphetamine in the United States is increasing and lead exposure continues to be widespread, an examination of this drug and how it may be modified by perinatal exposure to lead is warranted. The studies reported here examined the effects of perinatal lead exposure on adult self-administration of intravenous (i.v.) methamphetamine across the maintenance phase of drug addiction. Experiment 1 examined dose-effect patterns in control and lead-exposed animals. Experiment 2 evaluated control and lead-exposed animals in a progressive ratio task. Female rats were administered a 16-mg lead or a control solution for 30 days prior to breeding with non-exposed males. Exposure continued through pregnancy and lactation and was discontinued at weaning (postnatal day [PND] 21). Animals born to control or lead-exposed dams received indwelling jugular catheters as adults (PND 70) and subsequently were randomly assigned to one of the two studies, using only one male rat per litter for each study. The data showed a general attenuation of the reinforcement efficacy of methamphetamine in animals perinatally exposed to lead, as compared to control animals.

The environment, epigenetics and amyloidogenesis.

Alzheimer's Disease (AD) is a progressive, irreversible neurodegenerative disease. Despite several genetic mutations (Haass et al., J. Biol. Chem. 269:17741-17748, 1994; Ancolio et al., Proc. Natl. Acad. Sci. USA 96:4119-4124, 1999; Munoz and Feldman, CMAJ 162:65-72, 2000; Gatz et al., Neurobiol. Aging 26:439-447, 2005) found in AD patients, more than 90% of AD cases are sporadic (Bertram and Tanzi, Hum. Mol. Genet. 13:R135-R141, 2004). Therefore, it is plausible that environmental exposure may be an etiologic factor in the pathogenesis of AD. The AD brain is characterized by extracellular beta-amyloid (Abeta) deposition and intracellular hyperphosphorylated tau protein. Our lab has demonstrated that developmental exposure of rodents to the heavy metal lead (Pb) increases APP (amyloid precursor protein) and Abeta production later in the aging brain (Basha et al., J. Neurosci. 25:823-829, 2005a). We also found elevations in the oxidative marker 8-oxo-dG in older animals that had been developmentally exposed to Pb (Bolin et al., FASEB J. 20:788-790, 2006) as well as promotion of amyloidogenic histopathology in primates. These findings indicate that early life experiences contribute to amyloidogenesis in old age perhaps through epigenetic pathways. Here we explore the role of epigenetics as the underlying mechanism that mediates this early exposure-latent pathogenesis with a special emphasis on alterations in the methylation profiles of CpG dinucleotides in the promoters of genes and their influence on both gene transcription and oxidative DNA damage.

Avaliação dos efeitos tóxicos sobre o sistema nervoso periférico, decorrentes da exposição ocupacional ao chumbo / Evaluation of toxic effects on the peripheral nervous system, as a consequence of the occupational exposure to lead

Após descrever a interação do homem com meio ambiente, em particular nas atividades laborativas, se destaca a extração e o processamento dos minérios de chumbo como importante fonte de exposição ocupacional a este metal, que gerou no passado grandes casuísticas de intoxicação. Em seguida é feito um relato de como ocorreu a exposição ocupacional ao chumbo em Santo Amaro da Purificação na Bahia, e uma revisão da toxicologia deste metal, identificando-se a necessidade de se trabalhar com indicadores, parâmetros, que melhor reflitam os efeitos cumulativos, como os que ocorrem no sistema nervoso periférico. Analisar e discutir as alterações do sistema nervoso periférico pós exposição ocupacional, em um grupo de ex-empregados de uma metalurgia primária de chumbo; e identificar marcadores que melhor reflitam os efeitos da bioacumulação deste metal. A partir de dados secundários, foi construída uma serie de casos, na qual se analisou o passado clínico e toxicológico, e a relação com os achados neurofisiológicos. Os dados analisados, demonstraram a ocorrência, de um leque de neuropatias periféricas em todo o grupo, mas as alterações da condução motora em membros superiores, que tem sido melhor relacionadas aos efeitos tóxicos do chumbo, não foram tão consistentes. Ficou comprovado ser a media acumulada do chumbo no sangue um marcador biológico mais fidedigno, para avaliações de efeitos de longo prazo como as alterações sobre o sistema nervoso periférico.

A review of chronic lead intoxication: an unrecognized cause of chronic kidney disease.

Chronic lead nephropathy occurs as a result of years of lead exposure. This disease has been prevalent throughout human history. It is important that primary care providers and internists recognize this disorder because it can contribute to progressive loss of kidney function. Diagnosis is made by a thorough history in combination with physical examination. A history of lead intoxication often requires knowledge of the various sources of lead exposure. Laboratory tests, many previously known and some newly described, are available to further support this diagnosis. Therapy to reduce lead burden may be useful when employed early in the disease; new data sheds more light on which patients should be treated and when such patients should undergo chelation therapy. In particular, treatment with calcium EDTA chelation may benefit certain patients with chronic kidney disease by slowing the progression to end-stage renal disease.

Neonatal lead exposure potentiates sickness behavior induced by Listeria monocytogenes infection of mice.

The effects of lead (Pb) administration on infection-induced decreases in water intake, food intake, and body weight gain have been assessed as manifestations of sickness behavior using a BALB/c mouse model. Pb acetate (0.5 mM) was administered via drinking water to dams from Day 0 postpartum to weaning and to mouse pups after weaning until sacrifice. At 22 days after birth, young mice were infected with Listeria monocytogenes. Mice with blood Pb levels of less than 25 microg/dl exhibited enhanced and prolonged sickness behavior compared to mice not exposed to Pb. With this mouse model, after infection, serum levels of interleukin (IL)-1beta and IL-6 were enhanced in Pb-exposed mice. Compared with control infected mice, significant reductions in the number of thymic CD4(+)CD8(+), CD4(+), CD8(+), and CD4(-)CD8(-) T cells were observed in Pb-exposed mice. As a substitute for the infection, mice were injected with IL-1 and/or IL-6; Pb exacerbated sickness behavior only in mice injected peripherally with IL-1 and IL-6. Our data in young mice suggest that children with blood Pb levels during bacterial infection may exhibit enhanced and prolonged sickness behavior due to Pb/cytokine-dependent processes and that Pb appears to influence sickness behavior depending on the types and amounts of cytokines generated.

Past adult lead exposure is associated with longitudinal decline in cognitive function.

OBJECTIVE: To determine whether adults with past exposure to neurotoxicants have progressive declines in cognitive function years after exposure has ceased, and whether tibia lead is a predictor of the magnitude of change. METHODS: A total of 535 former organolead manufacturing workers with a mean age of 55.6 years, a mean duration of 16 years since last occupational lead exposure, and low blood lead levels at the first study visit and 118 controls were evaluated with neurobehavioral tests two to four times over 4 years. "Peak" tibia lead levels, estimated from current levels measured by X-ray fluorescence, were used to predict changes in cognitive function over time. RESULTS: In former lead workers, peak tibia lead ranged from -2.2 to 98.7 microg Pb/g bone mineral. Compared to controls, former lead workers performed worse over time for three tests of visuo-constructive ability and verbal memory and learning (p < 0.05). In former lead workers, peak tibia lead predicted declines for six tests of verbal memory and learning, visual memory, executive ability, and manual dexterity (p < 0.05 for four tests and < 0.10 for two additional tests). On average, for these six tests, an increase of 15.7 microg/g of peak tibia lead was equivalent in its effects on annual test decline to 5 more years of age at baseline. CONCLUSIONS: These are the first data to suggest that cognitive function can progressively decline due to past occupational exposures to a neurotoxicant.

Amyotrophic lateral sclerosis in a secluded region in Mexico possibly related to lead toxicity / Esclerosis lateral amiotrofica posiblemente relacionada con intoxicación de plomo una area aislada de México

La esclerosis lateral amiotrófica (ELA) es un padecimiento con una distribución relativamente uniforme en el mundo. La relación entre la ELA y diversos factores ambientales tóxicos se ha documentado en múltiples estudios. Uno de los aspectos más relevantes para el estudio de dichos factores ambientales es el hallazgo de "brotes" de la enfermedad en sujetos cuyo único punto en común es compartir el mismo medio ambiente. El objetivo de éste estudio es investigar la presencia de un "brote" de ELA en la comunidad de Tetela del Río en Guerrero. Se realizó un cuestionario para recolectar posibles casos de la enfermedad así como factores de riesgo, además de mediciones de plomo en quince sujetos control de la comunidad. El cuestionario se aplicó casa por casa en la comunidad, se detectaron 5 posibles casos con disartria, disfagia y atrofia de las extremidades. Los niveles promedio de plomo en los controles fueron de 22.4 ug/dl, los cuales fueron significativamente mayores a los de una población control en Hidalgo (p<0.00001). En este estudio sólo se confirmó un caso definitivo de ELA, pero el testimonio de los pobladores de la comunidad apuntaron hacia otros 5 posibles casos. El estudio de los brotes de FLA provee de información muy valiosa para la detección de factores ambientales relacionados al desarrollo de la enfermedad, lo cual puede ayudar en la búsqueda de opciones terapéuticas.