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A Novel Cardiotoxic Mechanism for a Pervasive Global Pollutant.

ABSTRACT: The Deepwater Horizon disaster drew global attention to the toxicity of crude oil and the potential for adverse health effects amongst marine life and spill responders in the northern Gulf of Mexico. The blowout released complex mixtures of polycyclic aromatic hydrocarbons (PAHs) into critical pelagic spawning habitats for tunas, billfishes, and other ecologically important top predators. Crude oil disrupts cardiac function and has been associated with heart malformations in developing fish. However, the precise identity of cardiotoxic PAHs, and the mechanisms underlying contractile dysfunction are not known. Here we show that phenanthrene, a PAH with a benzene 3-ring structure, is the key moiety disrupting the physiology of heart muscle cells. Phenanthrene is a ubiquitous pollutant in water and air, and the cellular targets for this compound are highly conserved across vertebrates. Our findings therefore suggest that phenanthrene may be a major worldwide cause of vertebrate cardiac dysfunction.

SUBMITTER: Brette F

PROVIDER: S-EPMC5282528 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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A Novel Cardiotoxic Mechanism for a Pervasive Global Pollutant.

Brette Fabien F Shiels Holly A HA Galli Gina L J GL Cros Caroline C Incardona John P JP Scholz Nathaniel L NL Block Barbara A BA

Scientific reports 20170131

The Deepwater Horizon disaster drew global attention to the toxicity of crude oil and the potential for adverse health effects amongst marine life and spill responders in the northern Gulf of Mexico. The blowout released complex mixtures of polycyclic aromatic hydrocarbons (PAHs) into critical pelagic spawning habitats for tunas, billfishes, and other ecologically important top predators. Crude oil disrupts cardiac function and has been associated with heart malformations in developing fish. How ...[more]

PMID: 28139666

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Project description:Tyrosine kinase inhibitors (TKIs) are characterized as multi-targeted anticancer agents that lack specificity, leading to cardiovascular adverse effects. To date, there are no reliable means to predict the cardiotoxicity of TKIs under development. The present study assessed the usual variants of genes to determine the molecular targets of TKIs associated with heart failure (HF). Gene or gene products affected by TKIs were assessed using the Drug Gene Interaction Database. These genes were investigated in genome-wide association studies (GWAS) datasets associated with HF at a genome-wide significant level (P<1×10-5). Subsequently, single-nucleotide polymorphisms (SNPs) that reached the established GWAS threshold (P<5×10-8) were investigated for genome-wide significance. Based on a threshold score of 3, nine gene loci yielded associations according to their biological function using RegulomeDB. Finally, comprehensive functional analysis of SNPs was performed using bioinformatics databases to identify potential drug targets. Using rSNPBase, rs7115242, rs143160639 and rs870064 were found to interfere with proximal transcription regulation, while rs7115242, rs143160639 and rs117153772 were involved in distal regulation, and most SNPs participated in post-transcriptional RNA binding protein-mediated regulation. rs191188930 on platelet-derived growth factor receptor (PDGFR) α was associated with numerous TKI drugs, including sunitinib, pazopanib, sorafenib, dasatinib and nilotinib. Using RegulomeDB and HaploReg v4.1, rs191188930 was predicted to be located in enhancer histone markers. PhenoScanner GWAS analysis revealed that rs191188930 was associated with other diseases or phenotypes, in addition to HF. Genotype-Tissue Expression analysis indicated that the PDGFRα gene had the highest median expression in 'Cells-Transformed fibroblasts', and the Search Tool for the Retrieval of Interacting Genes/Proteins revealed the protein-protein interaction network of PDGFRα. The present findings demonstrated the overlap of TKI-induced genes and those mediating HF risk, suggesting molecular mechanisms potentially responsible for TKI-induced HF risk. Additionally, the present genetic study may be helpful to further investigate off-target drug effects.

Dataset Information

A Novel Cardiotoxic Mechanism for a Pervasive Global Pollutant.

Publications

A Novel Cardiotoxic Mechanism for a Pervasive Global Pollutant.

Similar Datasets

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