Multiple Stressors in the Environment: Interactions Between Aryl Hydrocarbon Receptor Agonists and Hypoxia

EPA Grant Number: F6D40996
Title: Multiple Stressors in the Environment: Interactions Between Aryl Hydrocarbon Receptor Agonists and Hypoxia
Investigators: Fleming, Carrie R
Institution: Duke University
EPA Project Officer: Zambrana, Jose
Project Period: September 1, 2006 through September 1, 2008
Project Amount: $105,528
RFA: STAR Graduate Fellowships (2006) RFA Text |  Recipients Lists
Research Category: Academic Fellowships , Biology/Life Sciences , Fellowship - Toxicology , Health Effects


Hypoxic events are common environmental stressors that are increasing in frequency and severity due to human activity. Hypoxia can cause developmental toxicity and cardiovascular alterations in fish. A number of pollutants that act through the aryl hydrocarbon receptor (AhR) pathway, such as polycyclic aromatic hydrocarbons (PAHs), can also impact cardiovascular development. Due to the use of a common nuclear element—the aryl hydrocarbon nuclear translocator (ARNT)—the hypoxia response pathway is hypothesized to compete with the AhR pathway, leading to increased toxicity. Therefore, it is expected that the hypoxia response will be inhibited by AhR agonists in a dose dependent fashion and that the AhR response will be inhibited by hypoxia as well.

To characterize molecular-level interactions between the hypoxia pathway and the AhR pathway and to examine the toxic effects of exposures to hypoxia, AhR agonists a combination of the two.


This effect will be assessed in Fundulus heteroclitus embryos by dosing embryos with hypoxia, AhR agonist, or both and measuring the expression of various genes whose expression are promoted by the hypoxia and AhR pathways. Toxic endpoints will also be assessed between treatments to determine if coexposure to an AhR agonist and hypoxia increases toxicity to the embryo. Our laboratory also studies a population of F. heteroclitus from a PAH-contaminated site (Elizabeth River, VA) and has found these fish to be particularly sensitive to hypoxia. Because many PAHs are AhR agonists, we hypothesize that the hypoxic hypersensitivity of these fish occurs through an AhR dependent mechanism. AhR knockdown in Elizabeth River embryos by morpholino will be used to determine the involvement of AhR in this vulnerability to hypoxia.

Expected Results:

It is predicted that reciprocal crosstalk occurs between these two pathways, such that activation of each pathway will cause decreased activity in the other pathway. Accordingly, it is predicted that hypoxia and AhR agonists will exacerbate one another’s toxicity. This work should help elucidate the interactions between AhR agonists and hypoxia, allowing for more informed regulation of levels of AhR agonists in the environment. More broadly, it should help draw attention to the need to assess the interactions between chemical pollutants and natural stressors to accurately portray toxic effects that may be caused by pollutants in the aquatic environment.

Supplemental Keywords:

hypoxia, aryl hydrocarbon receptor (AhR), ARNT, polycyclic aromatic hydrocarbons (PAHs), multiple stressors, Fundulus heteroclitus, Elizabeth River, hypoxia-inducible factor 1α (HIF1α),, RFA, Scientific Discipline, Ecosystem Protection/Environmental Exposure & Risk, Aquatic Ecosystems & Estuarine Research, Aquatic Ecosystem, Biochemistry, Environmental Monitoring, anthropogenic stress, fish developmental toxicity, hypoxia, fish communities, gene expression, aquatic ecosystems

Progress and Final Reports:

  • 2007
  • Final