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.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Hazardous Substances Basic Research Grants Program (NIEHS) (P42)
Project #
Application #
Study Section
Special Emphasis Panel (ZES1-JAB-J (SF))
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Boston University
United States
Zip Code
Aschengrau, Ann; Janulewicz, Patricia A; White, Roberta F et al. (2016) Long-term Neurotoxic Effects of Early-life Exposure to Tetrachloroethylene-contaminated Drinking Water. Ann Glob Health 82:169-79
Mahalingaiah, S; Hart, J E; Laden, F et al. (2016) Adult air pollution exposure and risk of infertility in the Nurses' Health Study II. Hum Reprod 31:638-47
Hewlett, Meghan; Chow, Erika; Aschengrau, Ann et al. (2016) Prenatal Exposure to Endocrine Disruptors: A Developmental Etiology for Polycystic Ovary Syndrome. Reprod Sci :
Girguis, Mariam S; Strickland, Matthew J; Hu, Xuefei et al. (2016) Maternal exposure to traffic-related air pollution and birth defects in Massachusetts. Environ Res 146:1-9
Reid, Noah M; Proestou, Dina A; Clark, Bryan W et al. (2016) The genomic landscape of rapid repeated evolutionary adaptation to toxic pollution in wild fish. Science 354:1305-1308
Mahalingaiah, Shruthi; Winter, Michael R; Aschengrau, Ann (2016) Association of prenatal and early life exposure to tetrachloroethylene (PCE) with polycystic ovary syndrome and other reproductive disorders in the cape cod health study: A retrospective cohort study. Reprod Toxicol 65:87-94
Padilla, Cindy M; Kihal-Talantikit, Wahida; Vieira, Verónica M et al. (2016) City-Specific Spatiotemporal Infant and Neonatal Mortality Clusters: Links with Socioeconomic and Air Pollution Spatial Patterns in France. Int J Environ Res Public Health 13:
Townley, Ian K; Karchner, Sibel I; Skripnikova, Elena et al. (2016) Sequence and functional characterization of hypoxia inducible factors, HIF1α, HIF2αa, and HIF3α, from the estuarine fish, Fundulus heteroclitus. Am J Physiol Regul Integr Comp Physiol :ajpregu.00402.2016
Bolt, Alicia M; Grant, Michael P; Wu, Ting Hua et al. (2016) Tungsten Promotes Sex-Specific Adipogenesis in the Bone by Altering Differentiation of Bone Marrow-Resident Mesenchymal Stromal Cells. Toxicol Sci 150:333-46
Pennell, Kelly G; Scammell, Madeleine K; McClean, Michael D et al. (2016) Field data and numerical modeling: A multiple lines of evidence approach for assessing vapor intrusion exposure risks. Sci Total Environ 556:291-301

Showing the most recent 10 out of 355 publications