Skip Navigation
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Internet Explorer is no longer a supported browser.

This website may not display properly with Internet Explorer. For the best experience, please use a more recent browser such as the latest versions of Google Chrome, Microsoft Edge, and/or Mozilla Firefox. Thank you.

Your Environment. Your Health.

PROMOTION OF PANCREATIC CANCER BY PERFLUOROOCTANOIC ACID

Export to Word (http://www.niehs.nih.gov//portfolio/index.cfm/portfolio/grantdetail/grant_number/R15ES026370/format/word)
Principal Investigator: Hocevar, Barbara A
Institute Receiving Award Indiana University Bloomington
Location Bloomington, IN
Grant Number R15ES026370
Funding Organization National Institute of Environmental Health Sciences
Award Funding Period 30 Sep 2016 to 31 Mar 2021
DESCRIPTION (provided by applicant): SUMMARY/ABSTRACT As the fourth leading cause of cancer deaths in the United States, pancreatic cancer is one of the most lethal forms of cancer diagnosed. While the exact cause of pancreatic cancer is unknown, several risk factors have been identified as potential contributors to pancreatic cancer, including environmental factors such as smoking, drinking, diet, and exposure to environmental chemicals. Chronic exposure to perfluorooctanoic acid (PFOA) results in the induction of pancreatic cancer in rodents through an undefined mechanism. Due to the widespread human exposure to PFOA and its biological persistence, it is critical to understand how PFOA promotes pancreatic cancer in rodents. The objective in this application is to determine the biological mechanism through which PFOA promotes pancreatic cancer. The central hypothesis, based on strong preliminary data, is that PFOA exposure leads to ER and oxidative stress, which leads to acinar cell damage and inflammation, resulting in acinar to ductal metaplasia (ADM) and the promotion of pancreatic cancer. Three specific aims have been developed to test this hypothesis. Aim 1 will determine the time- and dose- dependent effects of PFOA on the promotion of pancreatic cancer using the well-established LSL-KRasG12D; Pdx-1 Cre mouse model. At two months of age, mice will be untreated or treated with PFOA followed by histological assessment of tumor progression at selected time-points, which will be correlated with PFOA levels and measures of oxidative stress. Aim 2 will determine whether PFOA exposure results in the generation of ER stress, leading to oxidative stress and inflammation. PFOA-mediated ER stress will be assessed using a combination of cell culture-based treatments, short term PFOA treatment in C57Bl/6 mice and PFOA treatment of KRasG12D mice which will be correlated with oxidative stress measurements. It will also be determined whether prevention of ER stress mitigates PFOA-stimulated oxidative stress. Aim 3 will determine whether PFOA exposure accelerates the process of ADM and/or increases the occurrence of ADM events. ADM, an early precursor lesion observed in pancreatic cancer progression will be evaluated in wild-type acinar cells and acinar cells which express KRasG12D in 2D and 3D cell cultures to assess whether PFOA treatment accelerates ADM and/or increases ADM events. The proposed research is innovative, as it will be the first to mechanistically identify the biological pathways and the doses at which PFOA exposure elicits ER and oxidative stress in the pancreas, and the first to evaluate the ability of an environmental chemical to promote pancreatic cancer progression in the KRasG12D genetic model. This contribution is significant, because identifying the mechanism for the induction of oxidative stress by PFOA will enable the development of strategies to prevent adverse health outcomes related to oxidative stress elicited by chemicals such as PFOA. Furthermore, these studies will enhance the research environment at the applicant’s institution and provide opportunities for engagement of undergraduate and graduate students in pancreatic cancer research.
Science Code(s)/Area of Science(s) Primary: 03 - Carcinogenesis/Cell Transformation
Publications See publications associated with this Grant.
Program Officer Leslie Reinlib
Back
to Top