# Understanding mechanisms of liver carcinogenesis following developmental BPA exposure

> **NIH NIH R01** · OREGON HEALTH & SCIENCE UNIVERSITY · 2024 · $490,521

## Abstract

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.

## Key facts

- **NIH application ID:** 10756162
- **Project number:** 5R01ES034836-02
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Caren Weinhouse
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $490,521
- **Award type:** 5
- **Project period:** 2022-12-20 → 2027-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10756162

## Citation

> US National Institutes of Health, RePORTER application 10756162, Understanding mechanisms of liver carcinogenesis following developmental BPA exposure (5R01ES034836-02). Retrieved via AI Analytics 2026-06-02 from https://api.ai-analytics.org/grant/nih/10756162. Licensed CC0.

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