Project description:Dieldrin is a legacy pesticide that has multiple modes of action (MOA) that include being an estrogen receptor agonist, GABA receptor antagonist, and a chemical that disrupts mitochondrial function. There is also evidence that dieldrin exposure is significantly associated with an increased risk for neurodegeneration in humans. The objective of this thesis was to clarify the effects of dieldrin in the hypothalamus, the major neuroendocrine region of the brain, in the zebrafish (Danio rerio). Zebrafish were fed pellets containing 0.03, 0.15, or 1.8 µg/g dieldrin for 21 days and a global gene expression analysis was performed to characterize cellular processes and pathways affected by dieldrin.
Project description:Rationale: Dieldrin is a legacy organochlorine pesticide that is persistent in the environment, despite being discontinued from use in North America since the 1970s. Some epidemiological studies suggest that exposure to dieldrin is associated with increased risks of neurodegenerative disease and breast cancer by inducing inflammatory responses in tissues as well as oxidative stress. However, the direct effects of organochlorine pesticides on the heart have not been addressed adequately to date. This is a significant knowledge gap because these chemicals are detectable in human serum and are environmentally persistent, thus individuals may show latent adverse effects due to chronic, low dose exposure over time. Objective: To determine whether low level exposure to dieldrin at an environmentally relevant dose results in aberrant molecular signaling in the vertebrate heart. Methods and Results: Using transcriptomic profiling and immunoblotting, we determined the global gene and targeted protein expression response to dieldrin treatment, and show that dieldrin effects gene regulator networks in the heart that are associated with protein degradation. Our results show that genes related to the development of cardiovascular disease, specifically cardiac arrest and ventricular fibrillation, are affected by environmentally relevant levels of dieldrin. We find that genes regulating inflammatory responses, a significant risk factor for cardiovascular disease, are upregulated by dieldrin treatments. Transcripts related to lysosomal function, also important to heart function, are significantly downregulated. To verify these findings, proteins in these pathways were examined with immunoblotting, and our data suggest that dieldrin constitutively activates Akt/mTOR signalling and downregulates lysosomal genes, which is hypothesized to be mediated through Transcription Factor EB (TFEB), the master regulator of lysosome function. Conclusions: This study is one of few to report that dieldrin alters molecular signaling cascades in the cardiovascular system and proposes a novel mechanism for pesticide-induced cardiotoxicity.
Project description:All vertebrates have multiple genes encoding for different CASQ isoforms. Increasing interest has been focused on mammalian and human CASQ genes since mutations of both cardiac (CASQ2) and skeletal (CASQ1) isoforms cause different, and sometime severe, human pathologies Danio rerio (zebrafish) is a powerful model for studying function and mutations of human proteins. In this work expression, biochemical properties and cellular and sub-cellular localization of Danio rerio native CASQ isoforms are investigated. By quantitative PCR three mRNAs were detected in skeletal muscle and one mRNA in heart. Three zebrafish CASQs were identified by mass spectrometry and they share properties with mammalian skeletal and cardiac CASQs. Skeletal calsequestrins were found primarily, but not exclusively, at the sarcomere Z-line level where Terminal Cisternae of Sarcoplasmic reticulum are located.
Project description:This SuperSeries is composed of the following subset Series: GSE37163: Gene expression data from time course of fin regeneration in Danio rerio (part 1) GSE37164: Gene expression data from time course of fin regeneration in Danio rerio (part 2) Refer to individual Series
Project description:Comparison of Danio rerio liver for 2 age groups treated with Rotenone. The RNA-seq data comprisess two age groups treated with Rotenone. Jena Centre for Systems Biology of Ageing - JenAge (www.jenage.de)
Project description:Comparison of temporal gene expression profiles from Danio rerio skin. The RNA-seq data comprise 3 age groups at 5, 24 and 30 months. Jena Centre for Systems Biology of Ageing - JenAge (www.jenage.de)
Project description:Comparison of Danio rerio skin for 2 age groups treated with Rotenone. The RNA-seq data comprises two age groups treated with different Rotenone dose levels. Jena Centre for Systems Biology of Ageing - JenAge (www.jenage.de)