Project 5

Developmental Toxicity of non-Dioxin-like PCBs and Chemical Mixtures

A comprehensive study of ortho-PCB effects on development, and possible mechanisms using fish models.

ahr pathway

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) are persistent and common contaminants in the global environment and are of continuing concern at many Superfund sites, including New Bedford Harbor (NBH). It is well known that non-ortho(dioxin-like) PCB congeners bind to the aryl hydrocarbon receptor (AHR) in cells, turn on cytochrome P450 1 (CYP1) gene expression, and cause developmental abnormalities.  (Cytochrome P450 (CYPs) are a family of enzymes in the body involved in hormone synthesis and breakdown of hormones and toxic substances.)  Ortho-substituted PCBs, structurally different than dioxin-like PCBs, are far more abundant but their effects, especially on development, are poorly known. The lack of information on ortho-PCBs constitutes a critical barrier to risk assessment. There is little knowledge of which types of PCBs (non-ortho, mono-ortho or poly-ortho) interact with receptors other than AHR and no data on CYPs induced or other mechanisms in premier non-mammalian models for toxicology (zebrafish, Danio rerioand killifish, Fundulus heteroclitus). We are identifying ortho-PCB effects on gene expression and function in zebrafish, relating transcriptomic changes and potential mechanisms to phenotypic (observable) changes. We will determine effects of defined mixtures of ortho-PCB congeners with PCB and  polycyclic aromatic hydrocarbon (PAH) AHR agonists. The studies will be extended to populations of Fundulus to address the possibility of resistance to ortho-PCBs.

This project is the first study of CYPs induced by or involved in metabolism of ortho-PCB congeners in zebrafish. Furthermore, the study is addressing the effect of mixtures of chemicals prevalent at Superfund sites – developmental effects of mixtures that co-occur have rarely been systematically addressed in a way that could reveal interactive mechanisms. Studies in killifish will test whether a population that has developed resistance to dioxin-like PCBs (Project 4) is resistant also to effects of ortho-PCBs, expanding our understanding of resistance adaptation in ecosystems affected by contamination.  Ortho-PCBs have been linked to a variety of neurological problems, in humans and in animal models. A connection to human health consequences in the vicinity of New Bedford Harbor is suggested by neurological developmental deficits in children from this region, which may be linked to PCBs.  Knowledge of developmental outcomes from our studies may be relevant to understanding the broader question of developmental consequences of the mixture of chemicals in the New Bedford area.

Project 5 participates in our interdisciplinary work with the New Bedford Harbor and surrounding communities. Learn more about the history of the harbor and our work there.

Summer 2016 State of the Science Update

Project 5 continues to explore the molecular and phenotypic responses to non-dioxin-like ortho-PCBs in the biomedical model zebrafish, and the environmental model killifish. Neuronal function appears to be susceptible to ortho-PCBs, and neuro-developmental processes may be particularly vulnerable to PCB toxicity, including in humans. Prior results suggested that ortho-PCBs affect higher-level integrated neural function, evident as altered visual response and overall activity in zebrafish. A particular gene (a cytochrome P450) was identified as a possible participant in the hyperactivity effects of ortho-PCBs, potentially linking PCB exposures to various effects in different exposed populations, including humans. Analysis of brain transcriptomes and intracellular calcium channels of killifish supports the idea that fish in the highly PCB-exposed population in New Bedford Harbor have a molecular adaption to ortho-PCBs.  The possible role of particular nuclear receptors is being explored. The extent to which the molecular pathways are shared among vertebrates makes the studies with these fish models relevant to both ecological and human health risk assessment.



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