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RNA-Seq of Human Neural Progenitor Cells Exposed to Lead (Pb) Reveals Transcriptome Dynamics, Splicing Alterations and Disease Risk Associations.

ABSTRACT: Lead (Pb) is a well-known toxicant, especially for the developing nervous system, albeit the mechanism is largely unknown. In this study, we use time series RNA-seq to conduct a genome-wide survey of the transcriptome response of human embryonic stem cell-derived neural progenitor cells to lead treatment. Using a dynamic time warping algorithm coupled with statistical tests, we find that lead can either accelerate or decelerate the expression of specific genes during the time series. We further show that lead disrupts a neuron- and brain-specific splicing factor NOVA1 regulated splicing network. Using lead induced transcriptome change signatures, we predict several known and novel disease risks under lead exposure. The findings in this study will allow a better understanding of the mechanism of lead toxicity, facilitate the development of diagnostic biomarkers and treatment for lead exposure, and comprise a highly valuable resource for environmental toxicology. Our study also demonstrates that a human (embryonic stem) cell-derived system can be used for studying the mechanism of toxicants, which can be useful for drug or compound toxicity screens and safety assessment.

SUBMITTER: Jiang P

PROVIDER: S-EPMC6372217 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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RNA-Seq of Human Neural Progenitor Cells Exposed to Lead (Pb) Reveals Transcriptome Dynamics, Splicing Alterations and Disease Risk Associations.

Jiang Peng P Hou Zhonggang Z Bolin Jennifer M JM Thomson James A JA Stewart Ron R

Toxicological sciences : an official journal of the Society of Toxicology 20170901 1

Lead (Pb) is a well-known toxicant, especially for the developing nervous system, albeit the mechanism is largely unknown. In this study, we use time series RNA-seq to conduct a genome-wide survey of the transcriptome response of human embryonic stem cell-derived neural progenitor cells to lead treatment. Using a dynamic time warping algorithm coupled with statistical tests, we find that lead can either accelerate or decelerate the expression of specific genes during the time series. We further ...[more]

PMID: 28903495

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Project description:Soil lead (Pb) contamination is one of the environmental problems facing the modern world. Sources of Pb in soil include industrial activities such as mining and smelting processes, agricultural activities such as application of insecticide and municipal sewage sludges, and urban activities such as use of lead in gasoline, paints, and other materials. Phytoremediation is the direct use of living green plants and is an effective, cheap, non-invasive, and environmentally friendly technique used to transfer or stabilize all the toxic metals and environmental pollutants in polluted soil or groundwater. Current work in this area is invested in elucidating mechanisms that underpin toxic-metal tolerance and detoxification mechanisms. The present study aims to gain insight into the mechanisms of Pb tolerance in T. qataranse by comparative proteomics. MALDI-TOF/MS and in silico proteome analysis showed differential protein expression between treated (50 mg kg⎯1 Pb) and untreated (0 mg kg⎯1 Pb) T. qataranse. A total of eighty-six (86) differentially expressed proteins, most of which function in ion and protein binding, antioxidant activity, transport, and abiotic response stress, were identified. In addition, essential stress-regulating metabolic pathways, including glutathione metabolism, cellular response to stress, and regulation of HSF1-mediated heat shock response, were also enriched. Also, at 52- and 49-kDa MW band areas, up to six hypothetical proteins with unknown functions were identified. Of these, protein AXX17_AT2G26660 is highly rich in glycine amino acid residues (up to 76%), suggesting that it is a probable glycine-rich protein (GRP) member. Although GRPs are known to be involved in plant defense against abiotic stress, including salinity and drought, there is no report on their role on Pb tolerance and or detoxification in plants. Further enrichment analysis in the current study reveals that the hypothetical proteins do not interact with known proteins and are not part of any enriched pathway. However, additional research is needed to functionally validate the role of the identified proteins in Pb detoxification mechanism.

Project description:Determination of Pb-210 (210Pb) in aqueous solution is a common radioanalytical challenge in environmental science. Widely used methods for undertaking these analyses (e.g., ASTM D7535) rely on the use of stable lead (Pb) as a yield tracer that takes into account losses of 210Pb that inevitably occur during elemental/radiochemical separations of the procedures. Although effective, these methods introduce technical challenges that can be difficult to track and potentially introduce uncertainty that can be difficult to quantify. Examples of these challenges include interference from endogenous stable Pb in complex sample matrices; contamination of stable Pb carrier with 210Pb; and high detection limits due to counting efficiency limitations. We hypothesized that many of these challenges could be avoided by the use of the electron-capture, gamma-emitting isotope, 203Pb as a chemical yield tracer in the analysis of 210Pb. A series of experiments were performed to evaluate the efficacy of 203Pb as a tracer. Four different matrices were analyzed, including a complex matrix (hydraulic-fracturing produced fluids); and samples comprising less complicated matrices (i.e., river water, deionized water, and tap water). Separation techniques and counting methodologies were also compared and optimized. Due to a relatively short-half life (52 h), 203Pb tracer is effectively massless for the purposes of chemical separations, allowing for reduced chromatography column resin bed volumes. Because 203Pb is a gamma emitter (279 keV; 81% intensity), recovery can be determined non-destructively in a variety of matrices, including liquid scintillation cocktail. The use of liquid scintillation as a counting methodology allowed for determination of 210Pb activities via 210Pb or 210Po; and recoveries of greater than 90% are routinely achievable using this approach. The improved method for the analysis of 210Pb in aqueous matrices allows for the analysis of complex matrices, at reduced cost, while providing greater counting flexibility in achieving acceptable detections limits.

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Dataset Information

RNA-Seq of Human Neural Progenitor Cells Exposed to Lead (Pb) Reveals Transcriptome Dynamics, Splicing Alterations and Disease Risk Associations.

Publications

RNA-Seq of Human Neural Progenitor Cells Exposed to Lead (Pb) Reveals Transcriptome Dynamics, Splicing Alterations and Disease Risk Associations.

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