Dataset Information

Developmental exposure to lead (Pb) alters the expression of the human tau gene and its products in a transgenic animal model.

ABSTRACT: Tauopathies are a class of neurodegenerative diseases associated with the pathological aggregation of the tau protein in the human brain. The best known of these illnesses is Alzheimer's disease (AD); a disease where the microtubule associated protein tau (MAPT) becomes hyperphosphorylated (lowering its binding affinity to microtubules) and aggregates within neurons in the form of neurofibrillary tangles (NFTs). In this paper we examine whether environmental factors play a significant role in tau pathogenesis. Our studies were conducted in a double mutant mouse model that expressed the human tau gene and lacked the gene for murine tau. The human tau mouse model was tested for the transgene's ability to respond to an environmental toxicant. Pups were developmentally exposed to lead (Pb) from postnatal day (PND) 1-20 with 0.2% Pb acetate. Mice were then sacrificed at PND 20, 30, 40 and 60. Protein and mRNA levels for tau and CDK5 as well as tau phosphorylation at Ser396 were determined. In addition, the potential role of miRNA in tau expression was investigated by measuring levels of miR-34c, a miRNA that targets the mRNA for human tau, at PND20 and 50. The expression of the human tau transgene was altered by developmental exposure to Pb. This exposure also altered the expression of miR-34c. Our findings are the first of their kind to test the responsiveness of the human tau gene to an environmental toxicant and to examine an epigenetic mechanism that may be involved in the regulation of this gene's expression.

SUBMITTER: Dash M

PROVIDER: S-EPMC5738909 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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Developmental exposure to lead (Pb) alters the expression of the human tau gene and its products in a transgenic animal model.

Dash M M Eid A A Subaiea G G Chang J J Deeb R R Masoud A A Renehan W E WE Adem A A Zawia N H NH

Neurotoxicology 20160609

Tauopathies are a class of neurodegenerative diseases associated with the pathological aggregation of the tau protein in the human brain. The best known of these illnesses is Alzheimer's disease (AD); a disease where the microtubule associated protein tau (MAPT) becomes hyperphosphorylated (lowering its binding affinity to microtubules) and aggregates within neurons in the form of neurofibrillary tangles (NFTs). In this paper we examine whether environmental factors play a significant role in ta ...[more]

PMID: 27293183

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Project description:Chronic lead (Pb) exposure causes long term health effects. While recent exposure can be assessed by measuring blood lead (half-life 30 days), chronic exposures can be assessed by measuring lead in bone (half-life of many years to decades). Bone lead measurements, in turn, have been measured non-invasively in large population-based studies using x-ray fluorescence techniques, but the method remains limited due to technical availability, expense, and the need for licensing radioactive materials used by the instruments. Thus, we developed prediction models for bone lead concentrations using a flexible machine learning approach--Super Learner, which combines the predictions from a set of machine learning algorithms for better prediction performance. The study population included 695 men in the Normative Aging Study, aged 48 years and older, whose bone (patella and tibia) lead concentrations were directly measured using K-shell-X-ray fluorescence. Ten predictors (blood lead, age, education, job type, weight, height, body mass index, waist circumference, cumulative cigarette smoking (pack-year), and smoking status) were selected for patella lead and 11 (the same 10 predictors plus serum phosphorus) for tibia lead using the Boruta algorithm. We implemented Super Learner to predict bone lead concentrations by calculating a weighted combination of predictions from 8 algorithms. In the nested cross-validation, the correlation coefficients between measured and predicted bone lead concentrations were 0.58 for patella lead and 0.52 for tibia lead, which has improved the correlations obtained in previously-published linear regression-based prediction models. We evaluated the applicability of these prediction models to the National Health and Nutrition Examination Survey for the associations between predicted bone lead concentrations and blood pressure, and positive associations were observed. These bone lead prediction models provide reasonable accuracy and can be used to evaluate health effects of cumulative lead exposure in studies where bone lead is not measured.

Project description:Lead (Pb) poisoning has been a major public health issue globally and the recent Flint water crisis has drawn nation-wide attention to its effects. To better understand how lead plays a role as a neurotoxin, we utilized the Drosophila melanogaster model to study the genetic effects of lead exposure during development and identified lead-responsive genes. In our previous studies, we have successfully identified hundreds of lead-responsive expression QTLs (eQTLs) by using RNA-seq analysis on heads collected from the Drosophila Synthetic Population Resource. Cis-eQTLs, also known as allele-specific expression (ASE) polymorphisms, are generally single-nucleotide polymorphisms in the promoter regions of genes that affect expression of the gene, such as by inhibiting the binding of transcription factors. Trans-eQTLs are genes that regulate mRNA levels for many genes, and are generally thought to be SNPs in trans-acting transcription or translation factors. In this study, we focused our attention on alternative splicing events that are affected by lead exposure. Splicing QTLs (sQTLs), which can be caused by SNPs that alter splicing or alternative splicing (AS), such as by changing the sequence-specific binding affinity of splicing factors to the pre-mRNA. We applied two methods in search for sQTLs by using RNA-seq data from control and lead-exposed w1118Drosophila heads. First, we used the fraction of reads in a gene that falls in each exon as the phenotype. Second, we directly compared the transcript counts among the various splicing isoforms as the phenotype. Among the 1,236 potential Pb-responsive sQTLs (p < 0.0001, FDR < 0.39), mostly cis-sQTLs, one of the most distinct genes is Dscam1 (Down Syndrome Cell Adhesion Molecule), which has over 30,000 potential alternative splicing isoforms. We have also identified a candidate Pb-responsive trans-sQTL hotspot that appears to regulate 129 genes that are enriched in the "cation channel" gene ontology category, suggesting a model in which alternative splicing of these channels might lead to an increase in the elimination of Pb2+ from the neurons encoding these channels. To our knowledge, this is the first paper that uses sQTL analyses to understand the neurotoxicology of an environmental toxin in any organism, and the first reported discovery of a candidate trans-sQTL hotspot.

Dataset Information

Developmental exposure to lead (Pb) alters the expression of the human tau gene and its products in a transgenic animal model.

Publications

Developmental exposure to lead (Pb) alters the expression of the human tau gene and its products in a transgenic animal model.

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