Superfund Research Program
Mechanisms and Impacts of PCB Resistant Fish
Project Leader: Mark E. Hahn (Woods Hole Oceanographic Institution)
Co-Investigators: Sibel I. Karchner (Woods Hole Oceanographic Institution), Neelakanteswar Aluru (Woods Hole Oceanographic Institution)
Grant Number: P42ES007381
Funding Period: 1995-2020
The overall objective of this project is to determine the effect of long-term exposure to high levels of chlorinated dioxins and dioxin-like chemicals, including certain polychlorinated biphenyls (PCBs). In addition, this research seeks to determine the mechanisms underlying differential sensitivity to the developmental toxicity of dioxins. To address this problem, Dr. Hahn is studying a population of estuarine fish, Atlantic killifish (Fundulus heteroclitus), inhabiting New Bedford Harbor, MA (NBH), a Superfund site that is highly contaminated with PCBs and other chemicals. Previously, the investigators showed that NBH killifish are approximately 14-fold less sensitive to dioxins than killifish from a reference site, Scorton Creek, in Sandwich, MA (SC), and that this difference in sensitivity is heritable.
In fish, as in mammals, the toxic and biochemical effects of dioxin-like chemicals occur through the interaction of these chemicals with the aryl hydrocarbon receptor (AHR), leading to altered gene expression. Project investigators have identified two distinct aryl hydrocarbon receptors (AHR1 and AHR2) in killifish and other species of fish. The specific objective of the research in this project is to determine the role of these two receptors--as well as other proteins in the AHR signaling pathway--in the dioxin/PCB resistance that has evolved in NBH fish.
One possible mechanism for the dioxin resistance of NBH fish is the enhanced expression of an inhibitor or repressor of AHR function. To investigate the presence of such repressors in killifish, a killifish homolog of the mouse AHR repressor (AHRR) was cloned and sequenced. The killifish AHRR protein was found to inhibit the ability of dioxins to cause AHR1- or AHR2-dependent changes in gene expression. In addition, the synthesis of AHRR is increased by treatment of fish with dioxins or PCBs, in an AHR-dependent manner. Preliminary studies show that the amount of AHRR is not increased in adult fish from NBH. However, this protein could be active in NBH fish embryos and contribute to their resistance to dioxins and PCBs; this possibility is currently under investigation.
Another possible resistance mechanism involves polymorphisms (multiple forms) in AHR genes. The AHR1 gene was found to be highly polymorphic in killifish. NBH fish (dioxin resistant) and SC fish (dioxin sensitive) differ in the types of AHR1 variants they possess, suggesting that certain variants confer resistance to fish possessing them. The researchers have begun to investigate the function of AHR1 proteins encoded by different AHR1 variants and are now beginning a more detailed survey of the structure and function of these alleles at NBH and several other sites, to better understand the distribution and functional significance of these polymorphisms.
Understanding how dioxin/PCB resistance occurs in these highly-exposed fish will improve the ability to predict the sensitivity of humans and wildlife to these compounds. In addition, this research will help us understand the long-term impact of chemicals at this and other Superfund sites.