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1.
Toxicology ; 390: 146-158, 2017 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-28916327

RESUMEN

Lead (Pb) is an environmental neurotoxin which particularly affects the developing brain but the molecular mechanism of its neurotoxicity still needs clarification. The aim of this paper was to examine whether pre- and neonatal exposure to Pb (concentration of Pb in rat offspring blood below the "threshold level") may affect the brain's energy metabolism in neurons and astrocytes via the amount of available glycogen. We investigated the glycogen concentration in the brain, as well as the expression of the key enzymes involved in glycogen metabolism in brain: glycogen synthase 1 (Gys1), glycogen phosphorylase (PYGM, an isoform active in astrocytes; and PYGB, an isoform active in neurons) and phosphorylase kinase ß (PHKB). Moreover, the expression of connexin 43 (Cx43) was evaluated to analyze whether Pb poisoning during the early phase of life may affect the neuron-astrocytes' metabolic cooperation. This work shows for the first time that exposure to Pb in early life can impair brain energy metabolism by reducing the amount of glycogen and decreasing the rate of its metabolism. This reduction in brain glycogen level was accompanied by a decrease in Gys1 expression. We noted a reduction in the immunoreactivity and the gene expression of both PYGB and PYGM isoform, as well as an increase in the expression of PHKB in Pb-treated rats. Moreover, exposure to Pb induced decrease in connexin 43 immunoexpression in all the brain structures analyzed, both in astrocytes as well as in neurons. Our data suggests that exposure to Pb in the pre- and neonatal periods results in a decrease in the level of brain glycogen and a reduction in the rate of its metabolism, thereby reducing glucose availability, which as a further consequence may lead to the impairment of brain energy metabolism and the metabolic cooperation between neurons and astrocytes.


Asunto(s)
Astrocitos/efectos de los fármacos , Encéfalo/efectos de los fármacos , Metabolismo Energético/efectos de los fármacos , Glucógeno/metabolismo , Intoxicación del Sistema Nervioso por Plomo en la Infancia/etiología , Neuronas/efectos de los fármacos , Compuestos Organometálicos/toxicidad , Efectos Tardíos de la Exposición Prenatal , Factores de Edad , Animales , Animales Recién Nacidos , Astrocitos/metabolismo , Astrocitos/patología , Encéfalo/metabolismo , Encéfalo/patología , Comunicación Celular/efectos de los fármacos , Conexina 43/metabolismo , Femenino , Edad Gestacional , Glucosa/metabolismo , Glucógeno Fosforilasa de Forma Encefálica/genética , Glucógeno Fosforilasa de Forma Encefálica/metabolismo , Glucógeno Sintasa/genética , Glucógeno Sintasa/metabolismo , Intoxicación del Sistema Nervioso por Plomo en la Infancia/genética , Intoxicación del Sistema Nervioso por Plomo en la Infancia/metabolismo , Intoxicación del Sistema Nervioso por Plomo en la Infancia/patología , Neuronas/metabolismo , Neuronas/patología , Fosforilasa Quinasa/genética , Fosforilasa Quinasa/metabolismo , Embarazo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas Wistar
2.
Int J Clin Exp Pathol ; 8(6): 7277-81, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26261627

RESUMEN

Lead is a widely used heavy metal that can affect children's nervous system development. ALAD gene polymorphism is associated with lead neurotoxicity. This study aimed to clarify the relationship among maternal blood lead, ALAD gene polymorphism, and neonatal neurobehavioral development through detecting maternal blood lead and ALAD gene polymorphism. 198 maternal and neonatal were selected as the research object. Graphite furnace atomic absorption method was applied to detect the maternal blood lead concentration. PCR-RFLP was used to detect ALAD genotype distribution. Neonatal NANB score was treated as effect indicator. SPSS was used for statistical analysis. The ALAD genotype was 181 cases (91.4%) for ALAD11 and 17 cases (8.6%) for ALAD12. ALAD allele frequency distribution accords with genetics Hardy-Weinberg balance (P > 0.05). Blood lead level in maternal with ALAD12 genotype was significantly higher than with ALAD11 genotype (P < 0.01). NANB score in high blood lead neonatal group was obviously lower than the low blood lead group (P < 0.05). Newborn's NANB score from the maternal with ALAD11 genotype was lower than from the maternal with ALAD12 genotype (P < 0.01). After ruling out the confounding factors influence by multiple linear regressions, ALAD gene polymorphisms had no significant correlation with neonatal NANB score (P > 0.05). ALAD gene polymorphism is associated with the blood lead level. Low level lead exposure in utero may cause newborn early neurobehavioral maldevelopment. Maternal ALAD gene polymorphism can affect early neonatal neurobehavioral development by influencing the blood lead level.


Asunto(s)
Desarrollo Infantil/efectos de los fármacos , Discapacidades del Desarrollo/genética , Intoxicación del Sistema Nervioso por Plomo en la Infancia/genética , Plomo/sangre , Exposición Materna , Intercambio Materno-Fetal , Polimorfismo Genético , Porfobilinógeno Sintasa/genética , Efectos Tardíos de la Exposición Prenatal , Adulto , Factores de Edad , Discapacidades del Desarrollo/sangre , Discapacidades del Desarrollo/diagnóstico , Discapacidades del Desarrollo/enzimología , Femenino , Predisposición Genética a la Enfermedad , Humanos , Recién Nacido , Plomo/efectos adversos , Intoxicación del Sistema Nervioso por Plomo en la Infancia/sangre , Intoxicación del Sistema Nervioso por Plomo en la Infancia/diagnóstico , Intoxicación del Sistema Nervioso por Plomo en la Infancia/enzimología , Modelos Lineales , Fenotipo , Porfobilinógeno Sintasa/metabolismo , Embarazo , Factores de Riesgo , Espectrofotometría Atómica
4.
Toxicology ; 325: 189-99, 2014 Nov 05.
Artículo en Inglés | MEDLINE | ID: mdl-25242007

RESUMEN

The aim of this study was to explore the mechanisms of lead neurotoxicity by focusing on the alteration of D-serine metabolism in the hippocampus of mice at the early life. Mother mice and their offspring were exposed to 0, 0.5, 1.0 and 2.0 g/L lead in lead acetate via drinking water from the first day of gestation until the postnatal day (PND) 40. Morris water maze was used to measure the spatial learning and memory ability of PND 40 mice. Expressions of serine racemase (SR), D-amino acid oxidase (DAAO), alanine-serine- cysteine transporter-1 (asc-1) and subunits of N-methyl-D-aspartate receptor (NMDAR) in the hippocampus of PND 10, 20 and 40 mice were examined by western blot and real time RT-PCR. Findings from this study disclosed that the spatial learning ability of mice tested by place trial could be significantly impaired by 0.5 g/L lead exposure, and the spatial memory ability tested by probe trail could be impaired by 1.0 g/L lead exposure. Exposure to 2.0 g/L lead in the water could significantly inhibit the protein and mRNA expression of SR; conversely enhance the expression of DAAO protein and mRNA in the hippocampus during the early developmental stages. However, the protein expressions of DAAO and asc-1 in the hippocampus were significantly enhanced by 0.5 g/L lead exposure at different developmental stages. On the other hand, the protein and mRNA expressions of both NR1 and NR2A were inhibited significantly by 1.0 g/L lead exposure since PND 10, and by 0.5 g/L lead exposure since PND 20. Noteworthy, the protein expression of NR2B was inhibited significantly by 0.5 g/L lead exposure in PND 10 mice, and by 1.0 g/L lead exposure in PND 20 mice, but there was no significant group difference in PND 40 mice. Meanwhile, expressions of asc-1 and NR2B mRNA were not affected obviously by lead exposure. In conclusion, chronic lead exposure during brain development might affect D-serine metabolism by enhancing its degradation, which might be related to the inhibited expression of NMDAR subunits, and furthermore contribute to deficits in learning and memory ability in mice.


Asunto(s)
Hipocampo/efectos de los fármacos , Intoxicación del Sistema Nervioso por Plomo en la Infancia/etiología , Compuestos Organometálicos/toxicidad , Efectos Tardíos de la Exposición Prenatal , Serina/metabolismo , Factores de Edad , Sistema de Transporte de Aminoácidos y+/genética , Sistema de Transporte de Aminoácidos y+/metabolismo , Animales , Conducta Animal/efectos de los fármacos , D-Aminoácido Oxidasa/genética , D-Aminoácido Oxidasa/metabolismo , Relación Dosis-Respuesta a Droga , Femenino , Edad Gestacional , Hipocampo/crecimiento & desarrollo , Hipocampo/metabolismo , Intoxicación del Sistema Nervioso por Plomo en la Infancia/genética , Intoxicación del Sistema Nervioso por Plomo en la Infancia/metabolismo , Intoxicación del Sistema Nervioso por Plomo en la Infancia/fisiopatología , Memoria/efectos de los fármacos , Ratones , Embarazo , ARN Mensajero/metabolismo , Racemasas y Epimerasas/genética , Racemasas y Epimerasas/metabolismo , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/metabolismo , Aprendizaje Espacial/efectos de los fármacos
5.
Toxicol Lett ; 225(1): 78-85, 2014 Feb 10.
Artículo en Inglés | MEDLINE | ID: mdl-24291742

RESUMEN

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.


Asunto(s)
Trastorno por Déficit de Atención con Hiperactividad/inducido químicamente , Conducta Animal/efectos de los fármacos , Epigénesis Genética/efectos de los fármacos , Hipocampo/efectos de los fármacos , Histonas/metabolismo , Hipercinesia/inducido químicamente , Intoxicación del Sistema Nervioso por Plomo en la Infancia/etiología , Actividad Motora/efectos de los fármacos , Compuestos Organometálicos/toxicidad , Efectos Tardíos de la Exposición Prenatal , Acetilación , Factores de Edad , Animales , Trastorno por Déficit de Atención con Hiperactividad/genética , Trastorno por Déficit de Atención con Hiperactividad/metabolismo , Trastorno por Déficit de Atención con Hiperactividad/fisiopatología , Trastorno por Déficit de Atención con Hiperactividad/psicología , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Relación Dosis-Respuesta a Droga , Femenino , Interacción Gen-Ambiente , Hipocampo/metabolismo , Hipocampo/fisiopatología , Hipercinesia/genética , Hipercinesia/metabolismo , Hipercinesia/fisiopatología , Hipercinesia/psicología , Intoxicación del Sistema Nervioso por Plomo en la Infancia/genética , Intoxicación del Sistema Nervioso por Plomo en la Infancia/metabolismo , Intoxicación del Sistema Nervioso por Plomo en la Infancia/fisiopatología , Intoxicación del Sistema Nervioso por Plomo en la Infancia/psicología , Masculino , Exposición Materna , Embarazo , Procesamiento Proteico-Postraduccional/efectos de los fármacos , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores de Dopamina D4/efectos de los fármacos , Receptores de Dopamina D4/metabolismo , Factores de Transcripción p300-CBP/genética , Factores de Transcripción p300-CBP/metabolismo
6.
Epigenomics ; 4(6): 665-74, 2012 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-23244311

RESUMEN

The epigenetic machinery plays a pivotal role in the control of many of the body's key cellular functions. It modulates an array of pliable mechanisms that are readily and durably modified by intracellular or extracellular factors. In the fast-moving field of neuroepigenetics, it is emerging that faulty epigenetic gene regulation can have dramatic consequences on the developing CNS that can last a lifetime and perhaps even affect future generations. Mounting evidence suggests that environmental factors can impact the developing brain through these epigenetic mechanisms and this report reviews and examines the epigenetic effects of one of the most common neurotoxic pollutants of our environment, which is believed to have no safe level of exposure during human development: lead.


Asunto(s)
Encéfalo/efectos de los fármacos , Exposición a Riesgos Ambientales , Epigénesis Genética , Intoxicación del Sistema Nervioso por Plomo en la Infancia/genética , Encéfalo/crecimiento & desarrollo , Niño , Humanos
7.
Postgrad Med ; 123(1): 160-8, 2011 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-21293095

RESUMEN

Children in the United States are exhibiting extremely high levels of attentional and learning disabilities. Although lead has been eliminated from many industrial products, children continue to come into contact with it, such as in toys and cosmetics. Lead exposure occurs most commonly in poor, urban populations, and can exacerbate psychiatric disorders associated with stress. We present 1) an overview of lead exposure; 2) a detailed summary of current research on the molecular synergy of toxicity caused by lead and stress; 3) a review of human studies that appear to correlate with these molecular findings, including understanding nutrition, environmental enrichment, and caregiving as risk modifiers; and 4) a systematic approach for mental health practitioners in managing children presenting with multiple symptoms and risk factors for mental health conditions. In this article, we review some of the clinical and scientific challenges that relate to the assessment and treatment of children presenting for mental health care who may have potential lead exposure.


Asunto(s)
Exposición a Riesgos Ambientales/efectos adversos , Exposición a Riesgos Ambientales/análisis , Intoxicación del Sistema Nervioso por Plomo en la Infancia/diagnóstico , Guías de Práctica Clínica como Asunto , Metilación de ADN , Humanos , Intoxicación del Sistema Nervioso por Plomo en la Infancia/complicaciones , Intoxicación del Sistema Nervioso por Plomo en la Infancia/genética , Estrés Oxidativo , Factores de Riesgo , Estrés Psicológico/complicaciones , Estados Unidos
9.
Neurotoxicology ; 30(6): 881-7, 2009 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-19723536

RESUMEN

Low-level lead exposure during early childhood has long been associated with altered neurocognitive development and diminished cognitive functions. Over nine thousand U.S. industrial facilities annually emit significant amounts of lead, creating exposure risk particularly for minority children. The mechanisms by which low-level lead exerts neurotoxic effects are poorly understood. Once absorbed, the only intervention is source removal, thus primary prevention is key. Genetic biomarkers could provide an efficient means of identifying children at greatest risk. Common functional variants of genes that alter lead's neurotoxic potential have been identified and include delta-aminolevulinic acid dehydratase (ALAD(2)) and peptide transporter 2 (PEPT2*2). These polymorphisms have not been examined previously in Hispanic minority samples, or with regard to lowest level lead exposure. In 116 children of Mexican-American/Hispanic descent residing in zip codes previously designated as "high risk" for lead exposure (mean age=8.1, S.D.=1.9), blood lead level was measured at three time points over a 3-month period and averaged. DNA extraction was completed using buccal swab samples. The frequencies of the ALAD(2) and PEPT2*2 polymorphisms observed in this sample closely approximated those previously reported for Anglo, European and Asian samples. As compared to children heterozygous for the PEPT2*2 polymorphism, and without the PEPT2*2 polymorphism, the geometric mean blood lead level of children homozygous for the PEPT2*2 polymorphism was significantly higher. In contrast to past studies, mean blood lead level of children heterozygous and homozygous for the ALAD2 polymorphism in this sample did not differ from that of children without the ALAD2 polymorphism. Higher blood lead burden in children with the PEPT2*2 mutation may suggest that this common genetic variant is a biomarker of increased vulnerability to the neurotoxic effects of lowest level lead exposure.


Asunto(s)
Transportadoras de Casetes de Unión a ATP/genética , Predisposición Genética a la Enfermedad , Intoxicación del Sistema Nervioso por Plomo en la Infancia/genética , Polimorfismo Genético/genética , Porfobilinógeno Sintasa/genética , Miembro 3 de la Subfamilia B de Transportadores de Casetes de Unión a ATP , Análisis de Varianza , Niño , Preescolar , Análisis Mutacional de ADN , Femenino , Hispánicos o Latinos , Humanos , Plomo/sangre , Intoxicación del Sistema Nervioso por Plomo en la Infancia/sangre , Masculino
10.
Biol Psychiatry ; 62(3): 243-9, 2007 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-17239353

RESUMEN

BACKGROUND: Prior studies have examined independent effects of a dopamine receptor D4 polymorphism (DRD4-7) and lead exposure on executive functions but not their interaction or the role of sex as a modifier of their effects. METHODS: Multivariable analyses were used to examine effects of DRD4-7 genotype, 60-month blood lead level, and sex on spatial working memory, rule learning and reversal, spatial span, and planning for 174 children. RESULTS: DRD4-7 was associated with poorer spatial working memory, and increasing blood lead levels were associated with impaired rule learning and reversal, spatial span, and planning. Adverse effects of lead on planning and rule learning and reversal were seen primarily for boys. In addition, the effect of lead on rule learning and reversal was evident predominately for those lacking DRD4-7. CONCLUSIONS: We observed independent effects of DRD4-7 and lead on various executive functions and modifications of lead effects by DRD4 genotype and sex.


Asunto(s)
Trastornos del Conocimiento/genética , Intoxicación del Sistema Nervioso por Plomo en la Infancia/complicaciones , Memoria a Corto Plazo/fisiología , Polimorfismo Genético , Receptores de Dopamina D4/genética , Percepción Espacial/fisiología , Análisis de Varianza , Niño , Preescolar , Cognición/fisiología , Trastornos del Conocimiento/sangre , Trastornos del Conocimiento/etiología , Estudios de Cohortes , Femenino , Humanos , Lactante , Plomo/sangre , Intoxicación del Sistema Nervioso por Plomo en la Infancia/sangre , Intoxicación del Sistema Nervioso por Plomo en la Infancia/genética , Masculino , Memoria a Corto Plazo/efectos de los fármacos , Pruebas Neuropsicológicas , Estudios Prospectivos , Factores Sexuales , Percepción Espacial/efectos de los fármacos , Estadísticas no Paramétricas
11.
Growth Dev Aging ; 66(1): 43-50, 2002.
Artículo en Inglés | MEDLINE | ID: mdl-12212631
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