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.



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