PUBLICATION
A multi-omic approach to elucidate low-dose effects of xenobiotics in zebrafish (Danio rerio) larvae
- Authors
- Huang, S.S., Benskin, J.P., Veldhoen, N., Chandramouli, B., Butler, H., Helbing, C.C., Cosgrove, J.R.
- ID
- ZDB-PUB-161126-1
- Date
- 2017
- Source
- Aquatic toxicology (Amsterdam, Netherlands) 182: 102-112 (Journal)
- Registered Authors
- Keywords
- Alternative animal model, Metabolomics, Sublethal exposure, Systems biology, Transcriptomics, Zebrafish
- MeSH Terms
-
- Acetaminophen/toxicity
- Animals
- Carbamazepine/toxicity
- Diphenhydramine/toxicity
- Dose-Response Relationship, Drug
- Fluoxetine/toxicity
- Larva/drug effects
- Metabolome/drug effects*
- Models, Animal*
- Toxicity Tests
- Transcriptome/drug effects*
- Water Pollutants, Chemical/toxicity*
- Xenobiotics/toxicity*
- Zebrafish/metabolism*
- PubMed
- 27886581 Full text @ Aquat. Toxicol.
Citation
Huang, S.S., Benskin, J.P., Veldhoen, N., Chandramouli, B., Butler, H., Helbing, C.C., Cosgrove, J.R. (2017) A multi-omic approach to elucidate low-dose effects of xenobiotics in zebrafish (Danio rerio) larvae. Aquatic toxicology (Amsterdam, Netherlands). 182:102-112.
Abstract
Regulatory-approved toxicity assays such as the OECD Fish Embryo Toxicity Assay (TG236) allow correlation of chemical exposure to adverse morphological phenotypes. However, these assays are ineffective in assessing sub-lethal (i.e. low-dose) effects, or differentiating between similar phenotypes induced by different chemicals. Inclusion of multi-omic analyses in studies investigating xenobiotic action provides improved characterization of biological response, thereby enhancing prediction of toxicological outcomes in whole animals in the absence of morphological effects. In the current study, we assessed perturbations in both the metabolome and transcriptome of zebrafish (Danio rerio; ZF) larvae exposed from 96 to 120h post fertilization to environmental concentrations of acetaminophen (APAP), diphenhydramine (DH), carbamazepine (CBZ), and fluoxetine (FLX); common pharmaceuticals with known mechanisms of action. Multi-omic responses were evaluated independently and integrated to identify molecular interactions and biological relevance of the responses. Results indicated chemical- and dose-specific changes suggesting differences in the time scale of transcript abundance and metabolite production. Increased impact on the metabolome relative to the transcriptome in FLX-treated animals suggests a stronger post-translational effect of the treatment. In contrast, the transcriptome showed higher sensitivity to perturbation in DH-exposed animals. Integration of 'omic' responses using multivariate approaches provided additional insights not obtained by independent 'omic' analyses and demonstrated that the most distinct overall response profiles were induced following low-dose exposure for all 4 pharmaceuticals. Importantly, changes in transcript abundance corroborated with predictions from metabolomic enrichment analyses and the identified perturbed biological pathways aligned with known xenobiotic mechanisms of action. This work demonstrates that a multi-omic toxicological approach, coupled with a sensitive animal model such as ZF larvae, can help characterize the toxicological relevance of acute low-dose chemical exposures.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping