PROJECT SUMMARY / ABSTRACT
Dioxin-like compounds (DLCs), such as polychlorinated biphenyls (PCBs), and polycyclic aromatic
hydrocarbons (PAHs), are often present in contaminated habitats and have been observed to drive
evolutionary adaptation in organisms inhabiting polluted environments. This project utilizes previously
described adapted populations of Gulf killifish (Fundulus grandis) as a model system to better understand the
linkages between chemical sensitivity and biotransformation. Gulf killifish have adapted to resist PCB- and
PAH-associated cardiovascular teratogenicity in response to chronic chemical exposures in Galveston Bay.
Similar to other adapted fish populations, this adapted population phenotype is associated with a deletion in
the aryl hydrocarbon receptor (AHR) and a recalcitrant AHR pathway. This is counter-intuitive, given the critical
role of the AHR pathway in the biotransformation and subsequent excretion of xenobiotic chemicals. While not
fully elucidated, previous work has shown that adapted fish more slowly biotransform some PAHs, including
benzo[a]pyrene (BaP). Additionally, there is evidence that different metabolic pathways are being favored.
What is not currently known is whether the observed alterations in the biotransformation process produce safer
or more toxic metabolites. In other words, are the alterations to biotransformation indicative of a fitness cost, or
do they represent a compensatory adaptation or acclimation, providing an alternative solution for the
successful biotransformation and excretion of PAHs? It is clear from existing literature that a recalcitrant AHR
pathway provides strong protection against DLC-induced cardiovascular teratogenicity and that a deletion in
the AHR can provide this protection. Genomic studies of adapted populations suggest that multiple genes are
likely involved in observed resistant phenotypes. We aim to determine the role of the AHR deletion on the
biotransformation of BaP, a model PAH, and its influence on the immune system as an example of a non-
biotransformation AHR-associated pathway. We hypothesize that the AHR deletion has a significant impact on
the rate of biotransformation as well as on the decrease of proinflammatory cytokines in different tissues. We
propose that other naturally evolved compensatory changes are a critical second stage of adaptation to DLCs,
that they explain previously documented cross-resistance to other contaminant classes with different modes of
action, and can provide important insights into the vulnerability of different populations to a variety of chemical
stressors. The proposed research is significant because it will be the first step in a continuum of research that
will systematically identify significant alterations of biotransformation pathways associated with chemical
resistance resulting from selection pressure. Furthermore, the work outlined in this proposal will provide
substantial research opportunities for both graduate and undergraduate students to engage in hands-on
research that will provide insights into the relationships between evolution, toxicology, biotransformation,
metabolomics and transcriptomics, and environmental health.
