Project Leader, Mark E. Hahn (Woods Hole Oceanographic Institution)
Co-investigator, Sibel I. Karchner (Woods Hole Oceanographic Institution)
Understanding mechanisms underlying differential sensitivity to the developmental toxicity of polychlorinated biphenyls (PCBs) that act through the aryl hydrocarbon receptor (AHR).
In the previous grant periods, we characterized a HAH- and PAH-resistant population of killifish from New Bedford Harbor (NBH), Massachusetts, a Superfund site that is highly contaminated with PCBs. We showed that NBH fish are approximately 14-fold less sensitive to effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) than fish from a clean site (Scorton Creek; SC) and that this diminished sensitivity occurs at the level of gene transcription and is heritable. We identified two distinct AHRs in killifish, including a novel AHR form (AHR2) that has since been identified in several other species of fish, but not in mammals. We identified an AHR repressor (AHRR) in killifish and showed that it is inducible via an AHR-dependent mechanism but its expression is neither elevated nor inducible in resistant NBH fish. The studies proposed here will build on these previous findings to define the genetic mechanisms involved in dioxin resistance and explore the broader implications of the dioxin-resistant phenotype involving interaction between the AHR pathway and other environmental signaling pathways. A growing literature provides compelling evidence of cross-talk between the AHR and several other transcription factors involved in mediating the response to other chemicals. This suggests that PCB-resistant fish may have indirect disruptions in other signaling pathways that interact with the AHR-signaling pathway. The proposed research will address the cost of this evolved resistance to PCBs on the animal’s sensitivity to other contaminants—including oxidants, xenoestrogens, and ortho-substituted PCBs—and environmental stressors such as hypoxia, and the implications for ecological risk assessments at Superfund sites. This study will help elucidate the role of AHR in living systems and the long-term ecological effects of Superfund chemicals.