Journal article
Evaluating the Role of the Steroid and Xenobiotic Receptor (SXR/PXR) in PCB-153 Metabolism and Protection against Associated Adverse Effects during Perinatal and Chronic Exposure in Mice
Environmental health perspectives, Vol.128(4), pp.47011-47011
04/2020
DOI: 10.1289/EHP6262
PMID: 32352317
Abstract
Polychlorinated biphenyls (PCBs) are environmental toxicants; PCB exposure has been associated with adverse effects on wildlife and humans. However, the mechanisms underlying these adverse effects are not fully understood. The steroid and xenobiotic receptor [SXR; also known as the pregnane X receptor (PXR) and formally known as NR1I2] is a nuclear hormone receptor that regulates inducible metabolism of drugs and xenobiotics and is activated or inhibited by various PCB congeners.
The aim of this study was to investigate the effects of exposure to PCB-153, the most prevalent PCB congener in human tissues, on SXR knockout mice (SXRKO) and to elucidate the role of SXR in PCB-153 metabolism and promotion of its harmful effects.
Wild-type (WT) and SXRKO mice were chronically or perinatally exposed to a low dose (
) of PCB-153. Blood, livers, and spleens were analyzed using transcriptome sequencing (RNA-seq) and molecular techniques to investigate the impacts of exposure on metabolism, oxidative stress, and hematological parameters.
SXRKO mice perinatally exposed to PCB-153 displayed elevated oxidative stress, symptoms of hemolytic anemia, and premature death. Transcriptomal analysis revealed that expression of genes involved in metabolic processes was altered in SXRKO mice. Elevated levels of the PCB-153 metabolite, 3-OH-PCB-153, were found in exposed SXRKO mice compared to exposed WT mice. Blood hemoglobin (HGB) levels were lower throughout the lifespan, and the occurrence of intestinal tumors was larger in SXRKO mice chronically exposed to PCB-153 compared to vehicle and WT controls.
Our results suggest that altered metabolism induced by SXR loss of function resulted in the accumulation of hydroxylated metabolites upon exposure to PCB-153, leading to oxidative stress, hemolytic anemia, and tumor development in a mouse model. These results support a major role for SXR/PXR in protection against xenobiotic-induced oxidative stress by maintaining proper metabolism in response to PCB-153 exposure. This role of SXR could be generally applicable to other environmental toxicants as well as pharmaceutical drugs. https://doi.org/10.1289/EHP6262.
Details
- Title: Subtitle
- Evaluating the Role of the Steroid and Xenobiotic Receptor (SXR/PXR) in PCB-153 Metabolism and Protection against Associated Adverse Effects during Perinatal and Chronic Exposure in Mice
- Creators
- Riann Jenay Egusquiza - Department of Pharmaceutical Sciences, University of California, Irvine, California, USAMaria Elena Ambrosio - Department of Developmental and Cell Biology, University of California, Irvine, California, USAShuyi Gin Wang - Department of Developmental and Cell Biology, University of California, Irvine, California, USAKaelen Marie Kay - Department of Developmental and Cell Biology, University of California, Irvine, California, USAChunyun Zhang - Department of Occupational and Environmental Health, University of Iowa, Iowa City, Iowa, USAHans-Joachim Lehmler - Department of Occupational and Environmental Health, University of Iowa, Iowa City, Iowa, USABruce Blumberg - Department of Developmental and Cell Biology, University of California, Irvine, California, USA
- Resource Type
- Journal article
- Publication Details
- Environmental health perspectives, Vol.128(4), pp.47011-47011
- DOI
- 10.1289/EHP6262
- PMID
- 32352317
- NLM abbreviation
- Environ Health Perspect
- ISSN
- 0091-6765
- eISSN
- 1552-9924
- Publisher
- United States
- Language
- English
- Date published
- 04/2020
- Academic Unit
- Occupational and Environmental Health; Iowa Neuroscience Institute; Iowa Superfund Research Program
- Record Identifier
- 9984001079402771
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