RESUMEN
Delta-aminolevulinic acid dehydratase single nucleotide polymorphism 2 (ALAD2) and peptide transporter haplotype 2*2 (hPEPT2*2) through different pathways can increase brain levels of delta-aminolevulinic acid and are associated with higher blood lead burden in young children. Past child and adult findings regarding ALAD2 and neurobehavior have been inconsistent, and the possible association of hPEPT2*2 and neurobehavior has not yet been examined. Mean blood lead level (BLL), genotype, and neurobehavioral function (fine motor dexterity, working memory, visual attention and short-term memory) were assessed in 206 males and 215 females ages 5.1-11.8years. Ninety-six percent of children had BLLs<5.0µg/dl. After adjusting for covariates (sex, age and mother's level of education) and sibling exclusion (N=252), generalized linear mixed model analyses showed opposite effects for the ALAD2 and hPEPT2*2 genetic variants. Significant effects for ALAD2 were observed only as interactions with BLL and the results suggested that ALAD2 was neuroprotective. As BLL increased, ALAD2 was associated with enhanced visual attention and enhanced working memory (fewer commission errors). Independent of BLL, hPEPT2*2 predicted poorer motor dexterity and poorer working memory (more commission errors). BLL alone predicted poorer working memory from increased omission errors. The findings provided further substantiation that (independent of the genetic variants examined) lowest-level lead exposure disrupted early neurobehavioral function, and suggested that common genetic variants alter the neurotoxic potential of low-level lead. ALAD2 and hPEPT2*2 may be valuable markers of risk, and indicate novel mechanisms of lead-induced neurotoxicity. Longitudinal studies are needed to examine long-term influences of these genetic variants on neurobehavior.
Asunto(s)
Discapacidades del Desarrollo/inducido químicamente , Discapacidades del Desarrollo/genética , Plomo/toxicidad , Polimorfismo de Nucleótido Simple/genética , Porfobilinógeno Sintasa/genética , Simportadores/genética , Atención/efectos de los fármacos , Atención/fisiología , Niño , Preescolar , Conducta de Elección/efectos de los fármacos , Conducta de Elección/fisiología , Femenino , Predisposición Genética a la Enfermedad/genética , Haplotipos , Humanos , Plomo/sangre , Masculino , Memoria a Corto Plazo/efectos de los fármacos , Actividad Motora/efectos de los fármacos , Actividad Motora/genética , Pruebas NeuropsicológicasRESUMEN
The mechanisms by which early chronic lead (Pb) exposure alter brain development have not been identified. We examined neuroimmune system effects in C57BL/6J mice with Pb exposure, including levels that may be common among children in lower socioeconomic income environments. Pups were exposed via dams' drinking water from birth to post-natal day 28 to low, high or no Pb conditions. We compared gene expression of neuroinflammatory markers (study 1); and microglial mean cell body volume and mean cell body number in dentate gyrus, and dentate gyrus volume (study 2). Blood Pb levels in exposed animals at sacrifice (post-natal day 28) ranged from 2.66 to 20.31µg/dL. Only interleukin-6 (IL6) differed between groups and reductions were dose-dependent. Microglia cell body number also differed between groups and reductions were dose-dependent. As compared with controls, microglia cell body volume was greater but highly variable in only low-dose animals; dentate gyri volumes in low- and high-dose animals were reduced. The results did not support a model of increased neuroinflammation. Instead, early chronic exposure to Pb disrupted microglia via damage to, loss of, or lack of proliferation of microglia in the developing brains of Pb-exposed animals.
Asunto(s)
Intoxicación por Plomo/patología , Microglía/patología , Compuestos Organometálicos/toxicidad , Animales , Animales Recién Nacidos , Animales Lactantes , Biomarcadores/metabolismo , Proliferación Celular/efectos de los fármacos , Tamaño de la Célula/efectos de los fármacos , Enfermedad Crónica , Citocinas/genética , Citocinas/metabolismo , Giro Dentado/efectos de los fármacos , Giro Dentado/metabolismo , Giro Dentado/patología , Relación Dosis-Respuesta a Droga , Femenino , Regulación del Desarrollo de la Expresión Génica/efectos de los fármacos , Marcadores Genéticos , Lactancia/efectos de los fármacos , Masculino , Espectrometría de Masas , Ratones , Ratones Endogámicos C57BL , Microglía/efectos de los fármacos , Microglía/metabolismo , Compuestos Organometálicos/farmacocinética , ARN Mensajero/metabolismoRESUMEN
Child low-level lead (Pb) exposure is an unresolved public health problem and an unaddressed child health disparity. Particularly in cases of low-level exposure, source removal can be impossible to accomplish, and the only practical strategy for reducing risk may be primary prevention. Genetic biomarkers of increased neurotoxic risk could help to identify small subgroups of children for early intervention. Previous studies have suggested that, by way of a distinct mechanism, δ-aminolevulinic acid dehydratase single nucleotide polymorphism 2 (ALAD(2)) and/or peptide transporter 2*2 haplotype (hPEPT2*2) increase Pb blood burden in children. Studies have not yet examined whether sex mediates the effects of genotype on blood Pb burden. Also, previous studies have not included blood iron (Fe) level in their analyses. Blood and cheek cell samples were obtained from 306 minority children, ages 5.1 to 12.9 years. (208)Pb and (56)Fe levels were determined with inductively coupled plasma-mass spectrometry. General linear model analyses were used to examine differences in Pb blood burden by genotype and sex while controlling for blood Fe level. The sample geometric mean Pb level was 2.75 µg/dl. Pb blood burden was differentially higher in ALAD(2) heterozygous boys and hPEPT2*2 homozygous boys. These results suggest that the effect of ALAD(2) and hPEPT2*2 on Pb blood burden may be sexually dimorphic. ALAD(2) and hPEPT2*2 may be novel biomarkers of health and mental health risks in male children exposed to low levels of Pb.
Asunto(s)
Haplotipos , Plomo/toxicidad , Polimorfismo de Nucleótido Simple , Porfobilinógeno Sintasa/genética , Simportadores/genética , Carga Corporal (Radioterapia) , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Niño , Preescolar , Monitoreo del Ambiente/métodos , Femenino , Marcadores Genéticos , Predisposición Genética a la Enfermedad , Humanos , Hierro/sangre , Plomo/sangre , Modelos Lineales , Masculino , Porfobilinógeno Sintasa/metabolismo , Simportadores/metabolismoRESUMEN
Chronic childhood lead exposure, yielding blood lead levels consistently below 10 µg/dL, remains a major public health concern. Low neurotoxic effect thresholds have not yet been established. Progress requires accurate, efficient, and cost-effective methods for testing large numbers of children. The LeadCare® System (LCS) may provide one ready option. The comparability of this system to the "gold standard" method of inductively coupled plasma mass spectrometry (ICP-MS) for the purpose of detecting blood lead levels below 10 µg/dL has not yet been examined. Paired blood samples from 177 children ages 5.2-12.8 years were tested with LCS and ICP-MS. Triplicate repeat tests confirmed that LCS and ICP-MS had comparable repeatability. As compared with ICP-MS, LCS had a negative bias of 0.457 µg/dL with an average variability of 1.0 µg/dL. The reproducibility and precision of the LCS is appropriate for the evaluation and monitoring of blood lead levels of individual children in a clinical setting. Recent research however has suggested that increments as small as 0.5 µg/dL may distinguish those at risk of low-level lead-induced neurotoxicity. Thus, we also conclude that the LCS is not useful for research applications attempting to identify neurotoxic effect thresholds for chronic lowest level lead exposure in children. For these types of research applications, a convenient and low-cost device is needed for the precise detection of child blood lead levels below 10 µg/dL.