The goal of the basic research proposed here is to understand the effects of long-term, multi-generational exposure to high levels of contaminants on natural populations of animals inhabiting Superfund sites. The research addresses a key question concerning the extent to which adaptive changes in the sensitivity to one class of chemicals may have far-reaching effects on the ability of animals to respond to other types of chemicals or environmental stressors. The research applies innovative molecular approaches in an ecological context to investigate mechanisms of cross-talk among signaling pathways involved in the response to many Superfund chemicals. The studies will be performed in the Atlantic killifish Fundulus heterociitus, a unique model system for integrated investigation of ecological and mechanistic questions concerning the impact of chemicals at Superfund sites. At several locations along the Atlantic coast, populations of killifish have evolved resistance to planar (dioxin-like, non-ortho-subsituted) polychlorinated biphenyls (PCBs) and other chemicals that act through the aryl hydrocarbon receptor (AHR). The central hypothesis is that diminished AHR-dependent signaling in dioxin/PCB-resistant fish impairs the ability of these fish to respond to environmental chemicals and stressors acting through other signaling pathways. To test this hypothesis, in Aim 1 we will measure the sensitivity of PCB-sensitive and PCB-resistant killifish to a suite of environmental stressors including hypoxia, a pro-oxidant chemical (NRF2 activator), an orthosubstituted, non-planar PCB (PXR agonist), and an estrogenic compound (ER agonist).
In Aim 2, we will characterize two new AHRs and use morpholino anti-sense and zinc finger nuclease (ZFN) technologies to generate AHR-null and compound AHR-null killifish and use them to investigate the role of each AHR in regulating the response to these stressors. The proposed experiments represent a unique opportunity to obtain new insight on AHR function and the effects of long-term exposure to AHR agonists by utilizing naturally occurring populations exhibiting differences in chemical sensitivity, together with engineered null mutants and duplicated AHR genes that will allow pleiotropic functions of the AHR to be studied in isolation.

Public Health Relevance

The proposed research addresses two of the mandates of the Superfund Research Program, investigating mechanisms underlying health effects of Superfund chemicals and providing results that will contribute to risk assessment at Superfund sites. The results of this research will have relevance both for understanding long-term ecological effects of superfund chemicals and for elucidating AHR functions in vivo.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Hazardous Substances Basic Research Grants Program (NIEHS) (P42)
Project #
5P42ES007381-17
Application #
8548349
Study Section
Special Emphasis Panel (ZES1-JAB-J)
Project Start
Project End
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
17
Fiscal Year
2013
Total Cost
$199,031
Indirect Cost
Name
Boston University
Department
Type
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118
Lille-Langøy, Roger; Karlsen, Odd André; Myklebust, Line Merethe et al. (2018) Sequence variations in pxr (nr1i2) from zebrafish (Danio rerio) strains affect nuclear receptor function. Toxicol Sci :
Lemaire, Benjamin; Karchner, Sibel I; Goldstone, Jared V et al. (2018) Molecular adaptation to high pressure in cytochrome P450 1A and aryl hydrocarbon receptor systems of the deep-sea fish Coryphaenoides armatus. Biochim Biophys Acta Proteins Proteom 1866:155-165
Eide, Marta; Rydbeck, Halfdan; Tørresen, Ole K et al. (2018) Independent losses of a xenobiotic receptor across teleost evolution. Sci Rep 8:10404
Watt, James; Baker, Amelia H; Meeks, Brett et al. (2018) Tributyltin induces distinct effects on cortical and trabecular bone in female C57Bl/6J mice. J Cell Physiol 233:7007-7021
Aschengrau, Ann; Gallagher, Lisa G; Winter, Michael et al. (2018) Modeled exposure to tetrachloroethylene-contaminated drinking water and the risk of placenta-related stillbirths: a case-control study from Massachusetts and Rhode Island. Environ Health 17:58
Kim, Stephanie; Li, Amy; Monti, Stefano et al. (2018) Tributyltin induces a transcriptional response without a brite adipocyte signature in adipocyte models. Arch Toxicol 92:2859-2874
Herkert, Nicholas J; Spak, Scott N; Smith, Austen et al. (2018) Calibration and evaluation of PUF-PAS sampling rates across the Global Atmospheric Passive Sampling (GAPS) network. Environ Sci Process Impacts 20:210-219
Timme-Laragy, Alicia R; Hahn, Mark E; Hansen, Jason M et al. (2018) Redox stress and signaling during vertebrate embryonic development: Regulation and responses. Semin Cell Dev Biol 80:17-28
Glazer, Lilah; Kido Soule, Melissa C; Longnecker, Krista et al. (2018) Hepatic metabolite profiling of polychlorinated biphenyl (PCB)-resistant and sensitive populations of Atlantic killifish (Fundulus heteroclitus). Aquat Toxicol 205:114-122
Basra, Komal; Scammell, Madeleine K; Benson, Eugene B et al. (2018) Ambient Air Exposure to PCBs: Regulation and Monitoring at Five Contaminated Sites in EPA Regions 1, 2, 4, and 5. New Solut 28:262-282

Showing the most recent 10 out of 398 publications