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(http://www.niehs.nih.gov//portfolio/index.cfm?do=portfolio.grantdetail&&grant_number=K08ES034821&format=word)
| Principal Investigator: Hale, Vanessa L | |
|---|---|
| Institute Receiving Award | Ohio State University |
| Location | Columbus, OH |
| Grant Number | K08ES034821 |
| Funding Organization | National Institute of Environmental Health Sciences |
| Award Funding Period | 08 Sep 2023 to 31 Aug 2028 |
| DESCRIPTION (provided by applicant): | PROJECT SUMMARY / ABSTRACT Bladder cancer (BC) is the tenth most diagnosed cancer in the world, and is strongly linked to environmental chemical exposures including benzo[a]pyrene (BaP). BaP is a polycyclic aromatic hydrocarbon (PAH) and widespread pollutant found in automobile exhaust, tobacco smoke, and charred food, but the mechanisms underlying the links between BaP and BC remain unclear. Additionally, not all individuals exposed to BaP develop BC, indicating that there are additional undefined or individualized risk factors associated with BC. While human cells can metabolize BaP, host-associated microbes can too. Moreover, host-associated microbiomes, like host genomes, are individualized, which could drive differences in host responses to BaP exposure. However, the role of microbes in BC, and specifically, how the gut and urine microbiome modulate exposure to BaP, is largely unexplored. There is a critical need to evaluate chemical-microbe-host interactions in relation to high-risk chemicals – like BaP – on bladder health. The objective of this application is to define microbial metabolism of BaP in vitro and in vivo and asses the effects of this metabolism on the urothelium. BaP along with its metabolites are excreted in urine, have been linked to BC, and can be metabolized by microbes. However, it is unknown if microbial metabolism of BaP is occurring in vivo and how the microbiome may influence this metabolism. Our overarching hypothesis is that microbial metabolism of BaP is playing a role in bladder carcinogenesis. Specifically, we predict that urine and stool microbes can either “toxify” or “detoxify” BaP, with “toxifying” metabolism defined here as that which yields secondary metabolites more damaging or carcinogenic to host cells. In our first aim, we will characterize metabolism of BaP in vitro by urothelial cells and by gut or urinary tract-associated microbes. Host cells and bacteria will be grown in the presence or absence of BaP, separately and together, and we will apply targeted metabolomics (GC-MS) to quantify BaP metabolism. In the second aim, we will characterize metabolism of BaP in vivo through the gut and urine microbiome and metabolome of mouse models with differing microbial community profiles. In aim three, we will evaluate urothelial response (toxicity and inflammation) to BaP exposure in vitro and in vivo using samples from the first two aims. The proposed research is innovative because it represents a substantive departure from the status quo by defining chemical-microbe interactions and their direct impact on the bladder epithelium. This approach will create novel opportunities for bladder health and BC management through microbial community manipulation and engineering. Upon completion of the proposed aims, we will have identified which microbes can metabolize BaP, how they do so, if this metabolism is occurring in vivo, how differing microbial communities influence this metabolism, and how this affects urothelial response. This research is significant because it will establish a novel chemical-microbe-host framework for evaluating chemical safety, bladder health, and BC development. |
| Science Code(s)/Area of Science(s) |
Primary: 68 - Microbiome Secondary: 03 - Carcinogenesis/Cell Transformation |
| Publications | No publications associated with this grant |
| Program Officer | Anika Dzierlenga |