Superfund Research Program
A Novel Mechanism of Ortho-PCB-induced Toxicity: Targeting Nuclear Receptors in Brain of Fish
Project Leader: John J. Stegeman (Woods Hole Oceanographic Institution)
Co-Investigators: Jared V. Goldstone (Woods Hole Oceanographic Institution), Neelakanteswar Aluru (Woods Hole Oceanographic Institution), Makoto Saito (Woods Hole Oceanographic Institution)
Grant Number: P42ES007381
Funding Period: 2017-2021
- Project Summary
Project Summary (2017-2021)
Ortho-polychlorinated biphenyls (o-PCBs, non-dioxin-like PCBs) are abundant Superfund chemicals that have a broad range of adverse effects linked to developmental exposure in vertebrates, including altered cognitive and behavioral outcomes. This Boston University Superfund Research Program (BU SRP) Center project explores mechanisms of o-PCB effects in the biological model zebrafish (Danio rerio) and the ecological model Atlantic killifish (Fundulus heteroclitus) to provide a mechanistic foundation for predicting and developing reliable markers of adverse outcomes linked to o-PCBs. O-PCBs are orders of magnitude more abundant than dioxin-like non-ortho substituted PCBs in the environment, in humans, and in wildlife, increasing the concerns for significant health and ecological effects. PCB levels in killifish from the Superfund site in New Bedford Harbor, MA (NBH) are an extreme example, being as much as a thousand times greater than levels in other populations. Over generations of exposure, NBH killifish have become tolerant to dioxin-like PCBs and, studies now suggest, to o-PCBs, as well. Data from this BU SRP project show that the ortho-congener PCB153 causes large changes in gene expression in zebrafish and killifish larvae exposed as embryos, and in adult killifish brains, suggesting that there are heretofore unrecognized pathways and genes involved in genetic and behavioral responses to o-PCBs.
The researchers are examining response mechanisms in the brain and establishing the contribution of nuclear receptor transcription factors and target genes to phenotypic and behavioral outcomes in exposed fish. Recent data indicate that effects of different ortho-PCB congeners may involve a number of nuclear receptors. The o-PCB congener PCB153 misregulates large numbers of genes in various physiological pathways in developing zebrafish and killifish, and in adult killifish forebrain. The research team is exposing adult and larval zebrafish and killifish from NBH and a reference site (Scorton Creek, MA) to o-PCB congeners, and using transcriptomics and proteomics to determine receptor-driven networks in the brain. Behavioral effects are being examined in adults raised from exposed embryos, to determine whether early exposure produces lasting effects.
Interaction of o-PCB congeners with candidate zebrafish and killifish nuclear receptors, PXR (a major "xenobiotic receptor"), PPARs, FXR, and LXR is being determined in vitro using reporter gene assays; in silico by modeling receptor proteins and docking o-PCBs; and in vivo using receptor knockout zebrafish generated by CRISPR-cas9 technology.
Ecologically relevant effects may be enhanced or muted in response to chemical exposure in the New Bedford Harbor PCB-adapted fish population, or in other fish exposed in the wild. The studies are providing new, fundamental information and tools important for risk assessment of established toxicants and related emerging chemicals of concern, which facilitates ecologically-relevant assessment of aquatic Superfund sites, including the success of remediation.