Developmental effects are among the most important and least well-understood concerns in toxicology. Our long-term goal is to identify and understand developmental effects of chemicals that are abundant at Superfund sites, and molecular participants in effects. Polychlorinated biphenyls (F'CBs) are persistent and prevalent contaminants in the global environment, of continuing concern at many Superfund sites, including New Bedford Harbor (NBH). Non-ortho (dioxin-like) PCBs bind to the aryl hydrocarbon receptor (AHR), induce cytochrome P4501 (CYPI) genes, and cause developmental abnormalities. Ortho-substituted PCBs are far more abundant but effects, especially on development, are poorly known. There is no knowledge of which congeners interact with receptors (other than AHR), induce CYPs or exert toxicity in premier nonmammalian models for developmental and environmental toxicology (zebrafish, Danio rerio and killifish, Fundulus heterociitus).
Aim 1. This Aim will address the hypothesis that ortho-PCBs elicit distinct molecular and phenotypic responses in zebrafish. Ortho-PCB congeners abundant at the Superfund site at NBH will be studied. We will identify transcriptomic effects with a unique microarray (with probes for all 94 zebrafish CYP genes) and by microfluidic qPCR. Ortho-PCB action as agonists or antagonists of PXR will be detennined. Transcriptomic changes and potential mechanisms will be anchored to phenotypic changes (morphological and behavioral).
Aim 2. Ortho-PCBs will be examined as substrates/ligands for CYPs and receptors (likely PXR) implicated in Aim 1. Involvement in toxicity will be assessed by knockdown of CYP or receptor expression.
Aim 3. We will determine effects of defined mixtures of ortho-PCBs with non-ortho-PCB and polycyclic aromatic hydrocarbon (PAH) AHR agonists, using a Generalized Concentration Addition model.
Aim 4. Studies in killifish will address the environmental and general relevance of findings in zebrafish, and will test the hypothesis that a population that has developed resistance to dioxin-like PCBs is resistant also to effects of ortho-PCBs, expanding our understanding of resistance adaptation. This will be a uniquely comprehensive study of ortho-PCB congener effects on development, and the possible mechanisms.

Public Health Relevance

The project will generate important resources and knowledge for the basic research and risk assessment communities. Information generated will help us understand how ortho-PCBs and chemical mixtures affect development in animals generally, which may inform studies for such effects in other animals including humans. Information and tools will be important for researchers studying mechanisms of chemical effects.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Hazardous Substances Basic Research Grants Program (NIEHS) (P42)
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Special Emphasis Panel (ZES1-JAB-J)
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Henry, Heather F
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Boston University
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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

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