Project 5
A Novel Mechanism of Ortho-PCB-induced Toxicity: Targeting Nuclear Receptors in Brain of Fish
A comprehensive study of ortho-PCB effects on development, and possible mechanisms using fish models.
Figure 1: Complexity of molecular participants and outcomes in PCB toxicity. The red connectors indicate aspects we will address, where there are substantial knowledge gaps.
Project Leaders
John J. Stegeman, Project Leader
Woods Hole Oceanographic Institution
Jared V. Goldstone, Co-Leader
Woods Hole Oceanographic Institution
Project Description
Polychlorinated biphenyls (PCBs) remain a serious environmental problem. Non-dioxin-like ortho-PCBs (o-PCBs) have a broad range of adverse effects, including neurotoxicity, which are more insidious than the well-recognized effects of dioxin-like (DL) non-ortho-PCBs. (o-PCBs have non-coplanar substituted biphenyl rings, rather than the planar DL-like PCBs). Behavioral and cognitive effects are linked to developmental o-PCB exposure by epidemiological studies in humans, and experimentally in rodents. We find that o-PCBs affect fish as well. O-PCBs are orders of magnitude more abundant than DL-PCBs in the environment, in humans, and in wildlife, increasing the concerns for unrecognized human and ecological effects.
PCB levels in killifish (Fundulus heteroclitus) from the New Bedford Harbor, MA (NBH) Superfund site are extremely high, more than a thousand times greater than levels in uncontaminated populations. Over generations of exposure, NBH killifish have become tolerant to DL-PCBs, and our studies now suggest, to o-PCBs as well. The mechanisms of o-PCB behavioral effects, and of tolerance to o-PCBs, are unknown. Transcriptional studies with killifish and zebrafish (Danio rerio) in our current Superfund research show that o-PCB153 misregulates large numbers of genes in various physiological pathways in developing zebrafish and killifish and in adult killifish brain. The receptors mediating the brain transcriptional changes and consequent effects of o-PCBs in fish are unknown. We suggest that important mechanisms by which o-PCBs act in vivo are yet to be uncovered.
Our overall hypothesis is that o-PCBs act via multiple nuclear receptors in a congener-dependent manner to alter brain and developmental gene expression and behavior. In this study, we will explore o-PCB responses in the ecological model killifish and the biological model zebrafish. Our goals are to (1) identify heretofore unrecognized pathways and genes responding to o-PCBs, particularly in forebrain, (2) establish the contribution of NRs and target genes to phenotypic outcomes, emphasizing behavioral outcomes, and (3) determine whether these genes also are involved in the proposed resistance to o-PCBs in the highly-exposed NBH fish population. We will use gene expression methods to establish pathways affected by o-PCBs, particularly in brain. Engineered mutant zebrafish strains, reference killifish (Scorton Creek MA), and PCB-adapted NBH killifish will be used to define novel o-PCB effect linkages, and involvement in resistance adaption.
Recent results include discovery in the zebrafish model that the non-dioxin-like ortho-PCBs affect sensory pathways in ways that are completely different from the dioxin-like PCB congeners.
Resources
- BUSRP Laboratory Reagents and Tools
- Research Brief No. 124: DNA Damage Index: A New Tool For Assessing Toxic Effects of Contaminants
News
- MAY 2019 Project 5 members present at PRIMO 20 (Pollutant Responses in Marine Organisms)
- MAR 2019 Project 5 members present at Society of Toxicology 58th Annual Meeting and ToxExpo
- SUMMER 2018 John Stegeman organizes 10 annual Woods Hole Toxicology Roundtable, featuring among others, Dave Eaton (U Wash) and Trever Penning (Penn)
- MAR 2018 Project 5 members present at Society of Toxicology 57th Annual Meeting and ToxExpo
- OCT 2017 John Stegeman featured on life and research
- AUG 2017 Project 4 and Project 5 participate in Woods Hole Science Stroll
- AUG 2017 Jennifer Schlezinger at WHOI to work with zebrafish
- JUL 2017 Jed Goldstone discusses research with STEM students
- JUL 2017 Project 5 presents at PRIMO19
- JUN 2017 BUSRP program-wide meeting strengthens collaborations
- MAY 2017 John Stegeman receives honorary Doctorate of Science
- MAR 2017 BUSRP presents at Society of Toxicology 56th Annual Meeting and ToxExpo
- JAN 2017 John Stegeman participates in Oxford Emerging Markets Symposium, Oxford UK
- DEC 2016 New publication from Project 4 and Project 5 in partnership with FIOCRUZ
- DEC 2016 BUSRP presents at NIEHS FEST
- DEC 2016 Project 5 presents at meeting on fish and amphibian embryos
- OCT 2016 9th International PCB Workshop in Japan includes plenary by Madeleine Scammell
- SEP 2016 John Stegeman participates in Submerge Festival
- AUG 2016 Project 4 presents at Ocean Outlook 2016 meeting
- AUG 2016 Trainees present research at EPA visit
- AUG 2016 Trainee presents poster in showcase
- AUG 2016 NOAA Hollings scholar works with Project 5
- JUL 2016 Project 5 Leaders present at two conferences
- JUN 2016 Project 4 and Project 5 PEER collaborators receive WHOI Visitor Award
- APR 2016 Project 4 presents at Ocean Outlook 2016 meeting
- DEC 2015 Meet and Greet at US EPA Atlantic Ecology Division
- NOV 2015 Project 5 attends brown-bag lunch events at MassDEP
- SEP 2015 BUSRP receives supplement to develop genomic analysis platform
- MAY 2015 Project 5 Leader Stegeman presents SRA-NE Seminar on Fish Models and PCBs
- MAR 2015 Upcoming Society for Risk Analysis seminar on fish models and PCBs
- MAR 2015 BUSRP at SOT 2015
- DEC 2014 Upcoming Event: The State of the Water: Linking Ocean Health to Human Health
- OCT 2014 Engaging Community at the Eighth International PCB Workshop
- AUG 2014 Upcoming Event: How Small Fish Help Predict Human Risk from Non-Dioxin like PCBs
- AUG 2014 Upcoming Event: CHE Partnership Call on PCBs in Schools
- JUL 2014 NIEHS Environmental Factor Features Project 5 Leader John Stegeman
- MAY 2014 The Eighth International PCB Workshop: PCBs in Schools
- APR 2014 Marine Pollution Inspiration for Falmouth High School Ceramics Class
- MAR 2014 BUSRP at SOT 2014
- AUG 2013 Collaborative work receives SRP supplement award
- MAY 2013 SRP Trainee Erika Fritsch presents work at PRIMO conference and upcoming webinar
- MAR 2013 BUSRP goes to San Antonio for SOT Annual Meeting
- OCT 2008 New book chapter from Projects 5 and 6
- APR 2008 New Publication in Aquatic Toxicology
BUSRP Publications
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