%0 Journal Article %J Toxicol Appl Pharmacol %D 2013 %T Structurally distinct polycyclic aromatic hydrocarbons induce differential transcriptional responses in developing zebrafish. %A Goodale, Britton C %A Susan C Tilton %A Corvi, Margaret M %A Glenn R Wilson %A Janszen, Derek B %A Kim A Anderson %A Katrina M Waters %A Robyn L Tanguay %K Animals %K Embryo, Nonmammalian %K Polycyclic Hydrocarbons, Aromatic %K Structure-Activity Relationship %K Transcription, Genetic %K Zebrafish %X

Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous in the environment as components of fossil fuels and by-products of combustion. These multi-ring chemicals differentially activate the aryl hydrocarbon receptor (AHR) in a structurally dependent manner, and induce toxicity via both AHR-dependent and -independent mechanisms. PAH exposure is known to induce developmental malformations in zebrafish embryos, and recent studies have shown cardiac toxicity induced by compounds with low AHR affinity. Unraveling the potentially diverse molecular mechanisms of PAH toxicity is essential for understanding the hazard posed by complex PAH mixtures present in the environment. We analyzed transcriptional responses to PAH exposure in zebrafish embryos exposed to benz(a)anthracene (BAA), dibenzothiophene (DBT) and pyrene (PYR) at concentrations that induced developmental malformations by 120 h post-fertilization (hpf). Whole genome microarray analysis of mRNA expression at 24 and 48 hpf identified genes that were differentially regulated over time and in response to the three PAH structures. PAH body burdens were analyzed at both time points using GC-MS, and demonstrated differences in PAH uptake into the embryos. This was important for discerning dose-related differences from those that represented unique molecular mechanisms. While BAA misregulated the least number of transcripts, it caused strong induction of cyp1a and other genes known to be downstream of the AHR, which were not induced by the other two PAHs. Analysis of functional roles of misregulated genes and their predicted regulatory transcription factors also distinguished the BAA response from regulatory networks disrupted by DBT and PYR exposure. These results indicate that systems approaches can be used to classify the toxicity of PAHs based on the networks perturbed following exposure, and may provide a path for unraveling the toxicity of complex PAH mixtures.

%B Toxicol Appl Pharmacol %V 272 %P 656-70 %8 11/2013 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/23656968?dopt=Abstract %R 10.1016/j.taap.2013.04.024 %0 Journal Article %J Toxicology %D 2012 %T Neurodevelopmental low-dose bisphenol A exposure leads to early life-stage hyperactivity and learning deficits in adult zebrafish. %A Saili, Katerine S %A Corvi, Margaret M %A Weber, Daniel N %A Patel, Ami U %A Das, Siba R %A Przybyla, Jennifer %A Kim A Anderson %A Robyn L Tanguay %K Animals %K Behavior, Animal %K Benzhydryl Compounds %K Chromatography, High Pressure Liquid %K Dose-Response Relationship, Drug %K Embryo, Nonmammalian %K Endocrine Disruptors %K Environmental Pollutants %K Estradiol %K Hydrazines %K Hyperkinesis %K Larva %K Learning Disorders %K Maze Learning %K Phenols %K Receptors, Estrogen %K Receptors, G-Protein-Coupled %K Reversal Learning %K Teratogens %K Zebrafish %X

Developmental bisphenol A (BPA) exposure has been implicated in adverse behavior and learning deficits. The mode of action underlying these effects is unclear. The objectives of this study were to identify whether low-dose, developmental BPA exposure affects larval zebrafish locomotor behavior and whether learning deficits occur in adults exposed during development. Two control compounds, 17β-estradiol (an estrogen receptor ligand) and GSK4716 (a synthetic estrogen-related receptor gamma ligand), were included. Larval toxicity assays were used to determine appropriate BPA, 17β-estradiol, and GSK4716 concentrations for behavior testing. BPA tissue uptake was analyzed using HPLC and lower doses were extrapolated using a linear regression analysis. Larval behavior tests were conducted using a ViewPoint Zebrabox. Adult learning tests were conducted using a custom-built T-maze. BPA exposure to <30μM was non-teratogenic. Neurodevelopmental BPA exposure to 0.01, 0.1, or 1μM led to larval hyperactivity or learning deficits in adult zebrafish. Exposure to 0.1μM 17β-estradiol or GSK4716 also led to larval hyperactivity. This study demonstrates the efficacy of using the zebrafish model for studying the neurobehavioral effects of low-dose developmental BPA exposure.

%B Toxicology %V 291 %P 83-92 %8 01/2012 %G eng %N 1-3 %1 http://www.ncbi.nlm.nih.gov/pubmed/22108044?dopt=Abstract %R 10.1016/j.tox.2011.11.001