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(http://www.niehs.nih.gov//portfolio/index.cfm?do=portfolio.grantdetail&&grant_number=R15ES034885&format=word)
| Principal Investigator: Lavado, Ramon | |
|---|---|
| Institute Receiving Award | Baylor University |
| Location | Waco, TX |
| Grant Number | R15ES034885 |
| Funding Organization | National Institute of Environmental Health Sciences |
| Award Funding Period | 05 Sep 2023 to 31 Aug 2026 |
| DESCRIPTION (provided by applicant): | 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. |
| Science Code(s)/Area of Science(s) |
Primary: 05 - Signal Transduction Secondary: 03 - Carcinogenesis/Cell Transformation |
| Publications | No publications associated with this grant |
| Program Officer | Carol Shreffler |