Polycyclic aromatic hydrocarbons (PAHs), are routinely found at Superfund sites, are widespread environmental contaminants and have been shown to cross the placenta. Consequently, developmental exposure to PAHs has the potential to cause adverse health outcomes. This supposition is supported by recent epidemiological data indicating strong associations between early life stage PAH exposures and the increased occurrence of birth defects and increases in significant neurobehavioral deficits and heart disease. Human exposure to Superfund PAHs is complex;exposures always occur as complex mixtures rather than as individual parent PAHs. The potency for individual parent PAHs to produce adverse developmental outcomes is not well-defined, and more importantly the additive, antagonistic or synergistic effects of PAHs in mixtures is unknown. An added level of uncertainty is that PAHs are environmentally transformed, and the toxicity of these transformed PAHs is largely unstudied. Risk assessors are desperately in need of relevant in vivo data to develop comprehensive models for predictive toxicity. An immediate goal is to identify the environmentally relevant mixtures that pose hazard, and to identify the gene responses that drive the toxic endpoints. This project will use systems approaches in zebrafish to begin to define the mechanism of PAH toxicity. Our underlying hypothesis is that exposure to complex mixtures containing PAHs produce toxicity by aryl hydrocarbon receptor (AHR)-dependent and AHR-independent mechanisms, dependent on the structure and composition of the mixtures. We will test this hypothesis in three Specific Aims: 1) Determine the phenotypic impact of embryonic exposure to individual environmentally relevant PAHs, complex mixtures, and environmentally transformed PAHs and define the role of AHRs in the response;2) To continue to use next generation sequencing to identify the early developmental biomarkers of PAH exposure to individual environmentally relevant PAHs, complex mixtures, and environmentally transformed PAHs;3) To define the long lasting impacts of these embryonic exposure on the adult cardiovascular and central nervous systems.

Public Health Relevance

The proposed research addresses three of the four mandated SRP research areas involving the development of advanced techniques for the detection, assessment, and evaluation of health effects, methods to assess the risks to human health, and methods and technologies to detect hazardous substances in the environment.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Hazardous Substances Basic Research Grants Program (NIEHS) (P42)
Project #
2P42ES016465-05
Application #
8552217
Study Section
Special Emphasis Panel (ZES1-LWJ-D (SF))
Project Start
Project End
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
5
Fiscal Year
2013
Total Cost
$308,707
Indirect Cost
$88,207
Name
Oregon State University
Department
Type
DUNS #
053599908
City
Corvallis
State
OR
Country
United States
Zip Code
97339
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Bugel, Sean M; Wehmas, Leah C; La Du, Jane K et al. (2016) Phenotype anchoring in zebrafish reveals a potential role for matrix metalloproteinases (MMPs) in tamoxifen's effects on skin epithelium. Toxicol Appl Pharmacol 296:31-41
Sadler, Natalie C; Nandhikonda, Premchendar; Webb-Robertson, Bobbie-Jo et al. (2016) Hepatic Cytochrome P450 Activity, Abundance, and Expression Throughout Human Development. Drug Metab Dispos 44:984-91
Haggard, Derik E; Noyes, Pamela D; Waters, Katrina M et al. (2016) Phenotypically anchored transcriptome profiling of developmental exposure to the antimicrobial agent, triclosan, reveals hepatotoxicity in embryonic zebrafish. Toxicol Appl Pharmacol 308:32-45
Bugel, Sean M; Bonventre, Josephine A; Tanguay, Robert L (2016) Comparative Developmental Toxicity of Flavonoids Using an Integrative Zebrafish System. Toxicol Sci 154:55-68
Paulik, L Blair; Smith, Brian W; Bergmann, Alan J et al. (2016) Passive samplers accurately predict PAH levels in resident crayfish. Sci Total Environ 544:782-91
Tidwell, Lane G; Allan, Sarah E; O'Connell, Steven G et al. (2016) PAH and OPAH Flux during the Deepwater Horizon Incident. Environ Sci Technol 50:7489-97
Garcia, Gloria R; Noyes, Pamela D; Tanguay, Robert L (2016) Advancements in zebrafish applications for 21st century toxicology. Pharmacol Ther 161:11-21
Zhang, Guozhu; Roell, Kyle R; Truong, Lisa et al. (2016) A data-driven weighting scheme for multivariate phenotypic endpoints recapitulates zebrafish developmental cascades. Toxicol Appl Pharmacol 314:109-117
Truong, Lisa; Bugel, Sean M; Chlebowski, Anna et al. (2016) Optimizing multi-dimensional high throughput screening using zebrafish. Reprod Toxicol 65:139-147

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