%0 Journal Article %J Int J Environ Res Public Health %D 2022 %T A Comparative Multi-System Approach to Characterizing Bioactivity of Commonly Occurring Chemicals. %A Rivera, Brianna N %A Lindsay B Wilson %A Kim, Doo Nam %A Pande, Paritosh %A Kim A Anderson %A Robyn L Tanguay %K Animals %K Flame Retardants %K Organic Chemicals %K Pesticides %K Retrospective Studies %K Zebrafish %X

A 2019 retrospective study analyzed wristband personal samplers from fourteen different communities across three different continents for over 1530 organic chemicals. Investigators identified fourteen chemicals (G14) detected in over 50% of personal samplers. The G14 represent a group of chemicals that individuals are commonly exposed to, and are mainly associated with consumer products including plasticizers, fragrances, flame retardants, and pesticides. The high frequency of exposure to these chemicals raises questions of their potential adverse human health effects. Additionally, the possibility of exposure to mixtures of these chemicals is likely due to their co-occurrence; thus, the potential for mixtures to induce differential bioactivity warrants further investigation. This study describes a novel approach to broadly evaluate the hazards of personal chemical exposures by coupling data from personal sampling devices with high-throughput bioactivity screenings using in vitro and non-mammalian in vivo models. To account for species and sensitivity differences, screening was conducted using primary normal human bronchial epithelial (NHBE) cells and early life-stage zebrafish. Mixtures of the G14 and most potent G14 chemicals were created to assess potential mixture effects. Chemical bioactivity was dependent on the model system, with five and eleven chemicals deemed bioactive in NHBE and zebrafish, respectively, supporting the use of a multi-system approach for bioactivity testing and highlighting sensitivity differences between the models. In both NHBE and zebrafish, mixture effects were observed when screening mixtures of the most potent chemicals. Observations of BMC-based mixtures in NHBE (NHBE BMC Mix) and zebrafish (ZF BMC Mix) suggested antagonistic effects. In this study, consumer product-related chemicals were prioritized for bioactivity screening using personal exposure data. High-throughput high-content screening was utilized to assess the chemical bioactivity and mixture effects of the most potent chemicals.

%B Int J Environ Res Public Health %V 19 %8 2022 03 23 %G eng %N 7 %R 10.3390/ijerph19073829 %0 Journal Article %J Arch Toxicol %D 2018 %T Comparative developmental toxicity of a comprehensive suite of polycyclic aromatic hydrocarbons. %A Mitra Geier %A Chlebowski, Anna C %A Truong, Lisa %A Staci M Simonich %A Kim A Anderson %A Robyn L Tanguay %K Animals %K Cytochrome P-450 CYP1A1 %K Embryo, Nonmammalian %K Larva %K Polycyclic Aromatic Hydrocarbons %K Toxicity Tests %K Zebrafish %X

Polycyclic aromatic hydrocarbons (PAHs) are widespread environmental contaminants that occur in complex mixtures. Several PAHs are known or suspected mutagens and/or carcinogens, but developmental toxicity data is lacking for PAHs, particularly their oxygenated and nitrated derivatives. Such data are necessary to understand and predict the toxicity of environmental mixtures. 123 PAHs were assessed for morphological and neurobehavioral effects for a range of concentrations between 0.1 and 50 µM, using a high throughput early-life stage zebrafish assay, including 33 parent, 22 nitrated, 17 oxygenated, 19 hydroxylated, 14 methylated, 16 heterocyclic, and 2 aminated PAHs. Additionally, each PAH was evaluated for AHR activation, by assessing CYP1A protein expression using whole animal immunohistochemistry (IHC). Responses to PAHs varied in a structurally dependent manner. High-molecular weight PAHs were significantly more developmentally toxic than the low-molecular weight PAHs, and CYP1A expression was detected in five distinct tissues, including vasculature, liver, skin, neuromasts and yolk.

%B Arch Toxicol %V 92 %P 571-586 %8 2018 Feb %G eng %N 2 %R 10.1007/s00204-017-2068-9 %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 %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 %0 Journal Article %J Chemosphere %D 2010 %T Exploiting lipid-free tubing passive samplers and embryonic zebrafish to link site specific contaminant mixtures to biological responses. %A Hillwalker, Wendy E %A Sarah E Allan %A Robyn L Tanguay %A Kim A Anderson %K Animals %K Embryo, Nonmammalian %K Embryonic Development %K Environmental Monitoring %K Lipids %K Rivers %K Water Pollutants, Chemical %K Zebrafish %X

The Biological Response Indicator Devices Gauging Environmental Stressors (BRIDGES) bio-analytical tool was developed in response to the need for a quantitative technology for assessing the toxicity of environmentally relevant contaminant mixtures. This tool combines passive samplers with the embryonic zebrafish model. When applied in an urban river it effectively linked site specific, bioavailable contaminant mixtures to multiple biological responses. Embryonic zebrafish exposed to extracts from lipid-free passive samplers that were deployed at five locations, within and outside of the Portland Harbor Superfund Megasite, displayed different responses. Six of the eighteen biological responses observed in 941 exposed zebrafish were significantly different between sites. This demonstrates the sensitivity of the bio-analytical tool for detecting spatially distinct toxicity in aquatic systems; bridging environmental exposure to biological response.

%B Chemosphere %V 79 %P 1-7 %8 03/2010 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/20172587?dopt=Abstract %R 10.1016/j.chemosphere.2010.02.001