Dataset Information

Assessing windows of susceptibility to lead-induced cognitive deficits in Mexican children.

ABSTRACT:

Background

The identification of susceptible periods to Pb-induced decrements in childhood cognitive abilities remains elusive.

Objective

To draw inferences about windows of susceptibility using the pattern of associations between serial childhood blood lead (BPb) concentrations and children's cognitive abilities at 4 years of age among 1035 mother-child pairs enrolled in 4 prospective birth cohorts from Mexico City.

Methods

Multiple longitudinally collected BPb measurements were obtained from children (1, 2, 3, and 4 years) between 1994 and 2007. Child cognitive abilities were assessed at 4 years using the general cognitive index (GCI) of the McCarthy Scales of Children's Abilities. We used multivariable linear regression to estimate the change in cognitive abilities at 4 years of age with a 10 ?g/dL increase in childhood BPb concentrations adjusting for maternal IQ, education, marital status, child sex, breastfeeding duration, and cohort.

Results

In separate models for each BPb measurement, 2 year BPb concentrations were most strongly associated with reduced GCI scores at 4 years after adjusting for confounders (?: -3.8; 95% confidence interval CI: -6.3, -1.4). Mutual adjustment for other BPb concentrations in a single model resulted in larger, but less precise estimate between 2 year BPb concentrations and GCI scores at 4 years of age (?: -7.1; 95% CI: -12, -2.0). The association between 2 year BPb and GCI was not heterogeneous (p=0.89), but some BPb and GCI associations varied in magnitude and direction across the cohorts. Additional adjustment for child hemoglobin, birth weight, gestational age, gestational BPb concentrations, or test examiner did not change the pattern of associations.

Conclusions

Higher BPb concentrations at 2 years of age were most predictive of decreased cognitive abilities among these Mexico City children; however, the observed pattern may be due to exposure, outcome, or cohort related factors. These results may help developing countries more efficiently implement childhood Pb prevention strategies.

SUBMITTER: Braun JM

PROVIDER: S-EPMC3576696 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

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Publications

Assessing windows of susceptibility to lead-induced cognitive deficits in Mexican children.

Braun Joe M JM Hoffman Elaine E Schwartz Joel J Sanchez Brisa B Schnaas Lourdes L Mercado-Garcia Adriana A Solano-Gonzalez Maritsa M Bellinger David C DC Lanphear Bruce P BP Hu Howard H Tellez-Rojo Martha M MM Wright Robert O RO Hernandez-Avila Mauricio M

Neurotoxicology 20120510 5

<h4>Background</h4>The identification of susceptible periods to Pb-induced decrements in childhood cognitive abilities remains elusive.<h4>Objective</h4>To draw inferences about windows of susceptibility using the pattern of associations between serial childhood blood lead (BPb) concentrations and children's cognitive abilities at 4 years of age among 1035 mother-child pairs enrolled in 4 prospective birth cohorts from Mexico City.<h4>Methods</h4>Multiple longitudinally collected BPb measurement ...[more]

PMID: 22579785

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Project description:Up to seventy-five percent of patients treated for cancer suffer from cognitive deficits which can persist for months to decades, severely impairing quality of life. Although the number of cancer survivors is increasing tremendously, no efficacious interventions exist. Cisplatin, most commonly employed for solid tumors, leads to cognitive impairment including deficits in memory and executive functioning. We recently proposed deficient neuronal mitochondrial function as its underlying mechanism. We hypothesized nasal administration of mitochondria isolated from human mesenchymal stem cells to mice, can reverse cisplatin-induced cognitive deficits. Methods: Puzzle box, novel object place recognition and Y-maze tests were used to assess the cognitive function of mice. Immunofluorescence and high-resolution confocal microscopy were employed to trace the nasally delivered mitochondria and evaluate their effect on synaptic loss. Black Gold II immunostaining was used to determine myelin integrity. Transmission electron microscopy helped determine mitochondrial and membrane integrity of brain synaptosomes. RNA-sequencing was performed to analyse the hippocampal transcriptome. Results: Two nasal administrations of mitochondria isolated from human mesenchymal stem cells to mice, restored executive functioning, working and spatial memory. Confocal imaging revealed nasally delivered mitochondria rapidly arrived in the meninges where they were readily internalized by macrophages. The administered mitochondria also accessed the rostral migratory stream and various other brain regions including the hippocampus where they colocalized with GFAP+ cells. The restoration of cognitive function was associated with structural repair of myelin in the cingulate cortex and synaptic loss in the hippocampus. Nasal mitochondrial donation also reversed the underlying synaptosomal mitochondrial defects. Moreover, transcriptome analysis by RNA-sequencing showed reversal of cisplatin-induced changes in the expression of about seven hundred genes in the hippocampus. Pathway analysis identified Nrf2-mediated response as the top canonical pathway. Conclusion: Our results provide key evidence on the therapeutic potential of isolated mitochondria - restoring both brain structure and function, their capability to enter brain meninges and parenchyma upon nasal delivery and undergo rapid cellular internalization and alter the hippocampal transcriptome. Our data identify nasal administration of mitochondria as an effective strategy for reversing chemotherapy-induced cognitive deficits and restoring brain health, providing promise for the growing population of both adult and pediatric cancer survivors.

Dataset Information

Assessing windows of susceptibility to lead-induced cognitive deficits in Mexican children.

Background

Objective

Methods

Results

Conclusions

Publications

Assessing windows of susceptibility to lead-induced cognitive deficits in Mexican children.

Similar Datasets

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