%0 Journal Article %J Toxicol Appl Pharmacol %D 2013 %T Comparative developmental toxicity of environmentally relevant oxygenated PAHs. %A Knecht, Andrea L %A Goodale, Britton C %A Truong, Lisa %A Simonich, Michael T %A Swanson, Annika J %A Matzke, Melissa M %A Kim A Anderson %A Katrina M Waters %A Robyn L Tanguay %K Abnormalities, Drug-Induced %K Animals %K Biological Markers %K Embryo, Nonmammalian %K Environmental Pollutants %K Extracellular Space %K Gene Expression Regulation, Developmental %K Immunohistochemistry %K Mitochondria %K Oxidation-Reduction %K Oxidative Stress %K Oxygen Consumption %K Polycyclic Hydrocarbons, Aromatic %K Real-Time Polymerase Chain Reaction %K RNA %K Teratogens %K Zebrafish %X

Oxygenated polycyclic aromatic hydrocarbons (OPAHs) are byproducts of combustion and photo-oxidation of parent PAHs. OPAHs are widely present in the environment and pose an unknown hazard to human health. The developing zebrafish was used to evaluate a structurally diverse set of 38 OPAHs for malformation induction, gene expression changes and mitochondrial function. Zebrafish embryos were exposed from 6 to 120h post fertilization (hpf) to a dilution series of 38 different OPAHs and evaluated for 22 developmental endpoints. AHR activation was determined via CYP1A immunohistochemistry. Phenanthrenequinone (9,10-PHEQ), 1,9-benz-10-anthrone (BEZO), xanthone (XAN), benz(a)anthracene-7,12-dione (7,12-B[a]AQ), and 9,10-anthraquinone (9,10-ANTQ) were evaluated for transcriptional responses at 48hpf, prior to the onset of malformations. qRT-PCR was conducted for a number of oxidative stress genes, including the glutathione transferase(gst), glutathione peroxidase(gpx), and superoxide dismutase(sod) families. Bioenergetics was assayed to measure in vivo oxidative stress and mitochondrial function in 26hpf embryos exposed to OPAHs. Hierarchical clustering of the structure-activity outcomes indicated that the most toxic of the OPAHs contained adjacent diones on 6-carbon moieties or terminal, para-diones on multi-ring structures. 5-carbon moieties with adjacent diones were among the least toxic OPAHs while the toxicity of multi-ring structures with more centralized para-diones varied considerably. 9,10-PHEQ, BEZO, 7,12-B[a]AQ, and XAN exposures increased expression of several oxidative stress related genes and decreased oxygen consumption rate (OCR), a measurement of mitochondrial respiration. Comprehensive in vivo characterization of 38 structurally diverse OPAHs indicated differential AHR dependency and a prominent role for oxidative stress in the toxicity mechanisms.

%B Toxicol Appl Pharmacol %V 271 %P 266-75 %8 11/2013 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/23684558?dopt=Abstract %R 10.1016/j.taap.2013.05.006 %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