Tuesday, December 30, 2025 12/30/2025

Understanding mechanisms of liver carcinogenesis following developmental BPA exposure

Award Number: R01ES034836
ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/20/2022
PERIOD OF PERFORMANCE END DATE: 10/31/2027

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Understanding mechanisms of liver carcinogenesis following developmental BPA exposure - PROJECT SUMMARY Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and ranks third in cancer mortality. HCC has limited treatment options and carries a poor prognosis (17% 5-year survival rate), highlighting the importance of disease prevention. Known HCC risk factors include hepatitis B or C infection, alcohol abuse, or environmental contaminants like aflatoxin B1. These risk factors are most common in East Asia, South America, and Africa, which have proportionally higher HCC rates. However, HCC incidence and mortality in Western countries are increasing; liver cancer is poised to become the third leading cause of cancer-related death in the U.S. by 2030. New risk factors, including non-alcoholic steatohepatitis, account for less than a fifth of U.S. cases, suggesting the existence of unidentified environmental risk factors. We have found that developmental exposure to environmentally relevant doses of the chemical pollutant bisphenol A (BPA) is associated with HCC in both male and female C57BL/6J mice. Exposed mice show dose-responsive rates of HCC in response to BPA alone, with no known co-exposures. This finding implicates BPA as a complete carcinogen in the liver, responsible for both stages of carcinogenesis: initiation and promotion. In addition, the dose-responsive increase in HCC with increasing BPA dose is characteristic of genotoxic cancer initiation. Prior data show that BPA increases cellular reactive oxygen species (ROS) and that BPA induces a mutation spectrum consistent with ROS-induced oxidative DNA damage. BPA also disrupts endocrine signaling through estrogen receptor α (ERα). ERα signaling protects females against HCC, which is why males are more prone to this form of cancer. However, we found that this sex difference in HCC incidence was lost in BPA-exposed mice, suggesting that the endocrine disruptive effects of BPA eliminated the protection normally afforded females by intact ERα function. In this proposal, we will test the central hypothesis that BPA acts as a complete carcinogen in the liver. Specifically, we hypothesize that developmental BPA initiates HCC via oxidatively induced DNA damage and promotes HCC via endocrine disruption. In Aim 1, we will test the causal role of oxidative mutagenesis in HCC initiation by experimentally increasing the rate of mutation accumulation (in DNA repair-deficient mice exposed to BPA) and rescuing damage (by co-exposing mice to an antioxidant). In Aim 2, we will test the causal role of ERα signaling in HCC promotion by experimentally increasing signaling (by co-exposing mice to BPA and an ERα agonist) and decreasing signaling (by co-exposing mice to BPA and an ERα antagonist). The results of these studies will settle a long-standing debate about the carcinogenic potential of BPA, as well delineate the role of this ubiquitous environmental pollutant as a potential new environmental risk factor for HCC.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $469,759 )
2026	2026	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Environmental Health	000	4	12/10/2025	NON-COMPETING CONTINUATION	$469,759
														Subtotal = $469,759

Issue Date FY: 2025 ( Subtotal = $632,254 )
2025	2025	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Environmental Health	001	3	10/30/2024	SUPPLEMENT FOR EXPANSION	$140,877
2025	2025	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Environmental Health	000	3	10/29/2024	NON-COMPETING CONTINUATION	$491,377
														Subtotal = $632,254

Issue Date FY: 2024 ( Subtotal = $490,521 )
2024	2024	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Environmental Health	000	2	10/23/2023	NON-COMPETING CONTINUATION	$490,521
														Subtotal = $490,521

Issue Date FY: 2023 ( Subtotal = $521,588 )
2023	2023	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Environmental Health	000	1	12/20/2022	NEW	$521,588
														Subtotal = $521,588

Grand Total All Awards = $2,114,122

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Understanding mechanisms of liver carcinogenesis following developmental BPA exposure

Award Number: R01ES034836

ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 12/20/2022

PERIOD OF PERFORMANCE END DATE: 10/31/2027

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