What We Do

Our team is interested in understanding how exposure to PAHs is associated with birth defects, neurobehavioral deficits and heart disease in humans. There are hundreds of different PAHs with similar but different chemical structures. The structure of a chemical can often predict how toxic it might be. We test PAHs using zebrafish because they are small, rapidly developing fish that share over 70% of their genes with humans. Changes in zebrafish development identifies chemicals that may be hazardous to humans, and because they develop so rapidly, we can test 1000s of potentially toxic chemicals. We can measure toxicity in many different ways. We can look at the way a zebrafish develops, its behavior and even if exposure to PAHs changes gene expression.

Our project asks the following questions

How can we determine which of the hundreds of PAHs in our environment pose the greatest risk?

The proven advantages of the zebrafish model can provide the relative toxicity of real-world mixtures from superfund sites in just a few days. Additionally, the zebrafish data are used to guide cleanup efforts at contaminated sites to better protect human health and the environment.

Can we identify genes associated with development that might be changed by PAH exposure?

We are building a PAH library and categorizing PAHs based on their toxicity in the zebrafish.

How do mixtures of PAHs impact development?

We know PAHs exist in combination with many other chemicals in the environment. We are testing different PAH mixtures to determine if the toxicity of different PAHs changes based on other chemicals in the environment.

Does exposure to PAHs during early developmental stages cause long-lasting health effects?

We know that early developmental stages can be more vulnerable to chemical exposure. Our goal is to understand the potential for long-lasting toxic effects following exposure during development.

Does exposure to PAHs and PAH mixtures produce toxic effects that may be seen over multiple generations?

We do not know if a person that is exposed to a chemical during development may then pass on toxic effects to their children or even grandchildren. These effects may not always be visible in the original person. To answer this question, we are exposing developing zebrafish to low amounts of PAHs and PAH mixtures. We then look at toxicity in these fish and their offspring.

Our Current Research

  • Determine the phenotypic and neurobehavioral impacts of embryonic exposure to individual environmentally relevant PAHs, complex mixtures, and environmentally transformed PAHs and define the role of aryl hydrocarbon receptors (AHRs) in the response.
  • Apply next-generation sequencing to identify the early developmental biomarkers of PAH exposure to individual environmentally relevant PAHs, complex mixtures, and environmentally transformed PAHs.
  • Define the long-lasting impacts of embryonic exposure to individual environmentally relevant PAHs, complex mixtures, and environmentally transformed PAHs on the adult cardiovascular and central nervous system.
  • Share gene expression data. The project uses the NCBI Gene Expression Omnibus(GEO) to disseminate raw data files. After we expand the AHR2 KO line in our facility, we will submit it to The Zebrafish Model Organism Database (ZFIN) for their propagation. We will also make the specific pathogen-free (SPF) lines freely available as sufficient brood stocks are available at the SARL.

Collaborations

Our Previous Research

  • We reported using embryonic zebrafish that benzo[k]fluoranthene (BkF) exposures caused growth of a lateral, duplicate caudal fin fold. This previously undocumented effect is completely aryl hydrocarbon receptor-2 dependent. By measuring gene expression in the fin over time, BkF increased the expression of genes associated with AHR activation, appendage development, and tissue patterning. Our results demonstrate a novel aspect of AHR activity with implications for developmental processes conserved across vertebrate species. 
  • To begin to better understand how PAHs produce toxicity, we conducted RNA sequencing following exposure to 16 different PAHs. The 16 PAHs formed two broad clusters of gene expression changes: The PAHs in cluster A were more similar to the unexposed controls, while Cluster B consisted of PAHs that were generally more developmentally toxic. Importantly, we found that cyp1a transcript levels were associated with transcriptomic response, but not with PAH developmental toxicity. While all cluster B PAHs predominantly activated Ahr2, they also each enriched unique pathways like ion transport signaling, which likely points to differing molecular events between the PAHs downstream of Ahr2. Thus, using a systems biology approach, we have begun to evaluate, classify, and define mechanisms of PAH toxicity.
  • While the zebrafish model promises to be useful to make safety and risk assessment decisions, a lack of exposure protocol harmonized across laboratories has limited full model adoption. To help fill this knowledge gap, we screened a set of eight chemicals and one 2D nanomaterial using four different protocols to determine if experimental protocols impact toxicity conclusions.  The results of this study indicate that with the exception for the 2D nanomaterial, the screening design did not change the conclusion regarding chemical toxicity, but did change the concentrations needed to produce toxicity. Importantly, these results suggest that it is reasonably feasible to reach agreement on a standardized exposure regimen, which will promote data sharing without sacrificing data content.

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