Project description:A definition of RNA expression changes that correlate with liver response programs and an understanding of the similarities and differences in responses to different classes of chemicals would aid in new chemical or drug characterization and add to our understanding of liver biology. We have used a supervised classification approach to systematically mine a large microarray database derived from livers of compound-treated rats. Thirty-four distinct signatures (classifiers) for pharmacological and toxicological endpoints resolvable by gene expression can be identified. The contribution of genes to signatures is not correlated to average expression or amplitude of regulation, and pre-selection of genes can significantly reduce signature performance. Just 200 genes are sufficient to classify all endpoints and can form the basis of a small diagnostic array useful in toxicogenomics. Signature genes were enriched in xenobiotic and acute phase response genes as well as un-annotated genes, suggesting that not all key genes in liver xenobiotic responses have been identified. Individual signatures can be re-derived up to 25 times from a gene set cyclically .stripped. of the signature genes. The union of these non-overlapping sets was used to describe the biological mechanisms of liver fibrosis. Guidelines for commercial use: http://www.iconixbiosciences.com/guidelineCommUse.pdf Keywords: dose response, time course, compound treatment
Project description:A definition of RNA expression changes that correlate with liver response programs and an understanding of the similarities and differences in responses to different classes of chemicals would aid in new chemical or drug characterization and add to our understanding of liver biology. We have used a supervised classification approach to systematically mine a large microarray database derived from livers of compound-treated rats. Thirty-four distinct signatures (classifiers) for pharmacological and toxicological endpoints resolvable by gene expression can be identified. The contribution of genes to signatures is not correlated to average expression or amplitude of regulation, and pre-selection of genes can significantly reduce signature performance. Just 200 genes are sufficient to classify all endpoints and can form the basis of a small diagnostic array useful in toxicogenomics. Signature genes were enriched in xenobiotic and acute phase response genes as well as un-annotated genes, suggesting that not all key genes in liver xenobiotic responses have been identified. Individual signatures can be re-derived up to 25 times from a gene set cyclically .stripped. of the signature genes. The union of these non-overlapping sets was used to describe the biological mechanisms of liver fibrosis. Guidelines for commercial use: http://www.iconixbiosciences.com/guidelineCommUse.pdf Keywords: dose response, time course, compound treatment Treatment of male Sprague-Dawley rats with 344 compounds at various doses and durations, in biological triplicate, along with vehicle-matched control animals. Liver samples were assayed for gene expression. A total of 1695 samples were hybridized to single-channel CodeLink RU1 arrays. Biological triplicates were combined with matched control samples to calculate log ratios. Classifiers were generated and evaluated for 2112 biological questions, resulting in 34 distinct, high-performance "signatures."
Project description:Anaerobic ammonium oxidation (anammox) emerges as a sustainable solution for nitrogen removal in sewage, but it is susceptible to stress induced by xenobiotics that are ubiquitous in sewage. Despite wide recognition of this critical issue, a comprehensive understanding of the molecular and ecological mechanisms underlying the response of anammox consortia to xenobiotic stress remain elusive. Here, we integrated multi-omics approaches with biofilm reactor operation to unravel how bisphenol A (BPA, a representative xenobiotic) perturbs anammox consortia across environmentally relevant concentrations. We show that anammox consortia tolerated low BPA levels (0.2–2 mg/L), where nitrogen removal efficiency transiently declined and subsequently recovered, aided by a 30.9% increase in quorum-sensing (QS) signal C6-HSL. By contrast, exposure to ≥10 mg/L BPA caused severe and irreversible inhibition, with total inorganic nitrogen removal dropping to 17.8%. High BPA concentrations suppressed QS signaling, intensified oxidative stress, and compromised membrane integrity, leading to enzymatic inhibition and transcriptional repression of anammox functional genes. Multi-omics evidence revealed that BPA stress also promoted horizontal transfer of the BPA-degrading gene bisdA via extracellular DNA, suggesting a new community-level adaptive mechanism. Metagenomic and metabolomic analyses further indicated BPA-driven restructuring of microbial networks, namely high BPA levels favored denitrifiers and BPA degraders while suppressing anammox bacteria, and triggered metabolic reprogramming toward xenobiotic degradation at the expense of nucleotide and amino acid biosynthesis. Together, these findings reveal a multifaceted collapse mechanism of anammox under BPA stress, providing a mechanistic basis for designing strategies to safeguard microbial nitrogen removal in xenobiotic-laden wastewaters.
Project description:Phenobarbital is a well studied xenobiotic compound. In this study, we describe the genomic responses in fruit flies and examine whether animals mutant for DHR96, an ortholog of xenobiotic nuclear receptors PXR and CAR, plays a role in mediating xenobiotic responses in Drosophila. Experiment Overall Design: Canton S is a commonly used wild type control strain for xenobiotic studies. Wild type or DHR96 mutant flies were starved overnight and then exposed to either sucrose alone or sucrose supplemented with 0.3% Phenobarbital.
Project description:We report the transcriptional changes associated with toxic effects of methanolic coal dust extract on normal zebrafish development. Early exposure of wild type embryos at 4 hpf to coal dust extract led to 3 groups of malformed phenotypes - tail deformity (P1), deformed yolk (P2) and smaller embryos with extruded yolks (P3). RNAseq of each phenotypic group revealed changes in genes involved in xenobiotic metabolism, intermediate filament composition, oxidation-reduction processes, calcium ion binding, focal adhesion and the ECM-receptor interaction pathway.