# Endocrine disruptor mediated activation of PXR causes dyslipidemia and atherosclerosis

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA RIVERSIDE · 2020 · $349,875

## Abstract

PROJECT SUMMARY
Despite major advances in developing diagnostic techniques and effective treatments, atherosclerotic
cardiovascular disease (CVD) is still the leading cause of mortality and morbidity worldwide. Recent large-
scale human studies have implicated a novel link between exposure to endocrine disrupting chemicals (EDCs)
and CVD. However, how exposure to EDCs influences CVD risk is still poorly understood, and continues to
hamper rational assessment of the health risks of EDC exposure. We have previously identified many plastic-
associated EDCs as potent agonists of the xenobiotic sensor pregnane X receptor (PXR), which has provided
an important tool for the study of new mechanisms through which EDC exposure impacts diseases. Our
laboratory was the first to reveal the novel function of PXR in the regulation of atherosclerosis development,
and has also demonstrated that several widely-used EDCs increase atherosclerosis and dyslipidemia through
PXR signaling in mouse models. To understand the detailed mechanisms underlying EDC-induced
dyslipidemia and atherosclerosis, novel tissue-specific PXR knockout mice have been generated, and
preliminary studies demonstrated that exposure to a newly identified PXR agonistic EDC increased intestinal
lipid absorption, hyperlipidemia, and hepatic steatosis in a PXR-dependent manner. Further, EDC-mediated
PXR activation led to elevated circulating levels of ceramides, a class of bioactive sphingolipids that has been
independently associated with increased CVD risk in humans. Our exciting preliminary findings support a
central hypothesis that plastic-associated EDCs that activate PXR stimulate intestinal lipid absorption and
ceramide production, leading to increased dyslipidemia, hepatic steatosis, and atherosclerosis. We propose
three specific aims to test this hypothesis: 1) Determine the tissue-specific contribution of PXR signaling
towards EDC-induced dyslipidemia and ceramide production using novel conditional knockout mice; 2) Define
the enterohepatic signaling through which PXR agonistic EDCs regulate lipid and ceramide homeostasis; and
3) Determine the impact of EDC-mediated PXR activation on atherosclerosis development. Influences of the
chemical environment on human health have become the subject of intense interest but very few studies in the
EDC research field have focused on the impact of EDCs on atherosclerosis development. This renewal
application will expand our initial research scope, pursue new research directions, utilize newly developed
animal models, and combine in vitro, ex vivo, and in vivo approaches to investigate EDCs’ atherogenic effects.
The proposed studies will contribute to our understanding of “gene-EDC interactions” in predisposing
individuals to atherosclerosis and other chronic diseases.

## Key facts

- **NIH application ID:** 10071896
- **Project number:** 2R01ES023470-06A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA RIVERSIDE
- **Principal Investigator:** Changcheng Zhou
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $349,875
- **Award type:** 2
- **Project period:** 2013-09-26 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10071896

## Citation

> US National Institutes of Health, RePORTER application 10071896, Endocrine disruptor mediated activation of PXR causes dyslipidemia and atherosclerosis (2R01ES023470-06A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10071896. Licensed CC0.

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