The NIEHS Superfund Research Program & NCEH/ATSDR Office of Science present
How Small Fish Help Predict Human Risk from Non-Dioxin like PCBs
John Stegeman, PhD
Boston University Superfund Research Center & Director, Center for Oceans and Human Health Woods Hole Oceanographic Institution Animal models have long been used to identify and understand how chemicals contribute to disease processes. Over the past 15 years, efforts involving small fish models have focused most on the zebrafish (eol.org/pages/204011/overview), but there is renewed interest in other species including the estuarine killifish Fundulus heteroclitis (eol.org/pages/1157172/overview). Fish models are helping to decipher the molecular mechanisms by which dioxins and dioxin-like chemicals including non-ortho polychlorinated biphenyls (PCBs)
cause toxicity, especially during development, and to uncover mechanisms of resistance to that toxicity. But what about the non-dioxin-like (NDL) ortho-PCBs? Our understanding of the toxicity and the mechanisms by which these chemicals are toxic is still fragmentary. Do ortho-PCBs have similar effects in mammals and fish? Can small fish provide insights into such mechanisms, as they have for the dioxin-like compounds? Our gene
expression studies with ortho-PCBs in zebrafish are highlighting pathways of response to the NDL PCBs, including induction of P450s via the pregnane X receptor (PXR), as yet a poorly understood participant in NDL-chemical effects in fish. Our studies also point to novel molecular targets that may participate in causing the neurobehavioral effects of NDL PCBs. In the killifish, our results suggest that multigenerational exposure to very
high levels of NDL PCBs causes adaptation by altering the function of calcium channels. This raises questions about whether structurally similar persistent environmental chemicals may cause similar effects. We should soon better understand the similarities and differences involved in different species’ responses to NDL compounds.

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