Project Leader, Mark E. Hahn (Woods Hole Oceanographic Institution)
Understanding mechanisms underlying differential sensitivity to the developmental toxicity of halogenated aromatic hydrocarbons (HAHs) 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 polychlorinated biphenyls (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 induced nor inducible in NBH fish. More recently, we found that killifish AHR1 is highly polymorphic, with numerous single-nucleotide polymorphisms (SNPs), at least nine of which result in amino acid changes. AHR1 SNP profiles differ between the SC and NBH populations. 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 cross-talk between the AHR pathway and other environmental signaling pathways. The proposed research addresses both ecological and biomedical/mechanistic questions regarding the impact of chemicals at Superfund sites.
The major objectives of the basic research proposed here are 1) to understand mechanisms underlying differential sensitivity to the developmental toxicity of HAHs and PAHs that act through AHR-dependent signaling, and 2) to determine the impact of evolved HAH/PAH resistance on the sensitivity to other environmental stressors. The first objective will be achieved by focusing on population genetic and functional aspects of polymorphisms in AHR-pathway genes. The second objective will be approached by focusing on responses to environmental hypoxia as well as through collaborations exploring the response of NBH and SC fish to environmental estrogens (Project 7) and oxidative stress (Project 6).
Principal Investigator: Mark E. Hahn, Woods Hole Oceanographic Institute
SBRP e-Posted Notes: June 21, 2004: EPA Risk Assessors Meeting
External Advisory Committee Presentation: A PDF of the presentation Dr. Hahn gave to the BU SBRP External Advisory Committee on March 20, 2007.
