Dissertation
The effects of inhaled polychlorinated biphenyls on the liver
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Spring 2025
DOI: 10.25820/etd.007928
Abstract
Polychlorinated biphenyls (PCBs) are persistent environmental toxicants that were used extensively in building materials such as caulking, adhesives, and electrical equipment. Despite intentional PCB production being banned, elevated levels of volatilized PCBs have been observed in the air of older school buildings. This is of particular concern as PCB exposure has been linked to cancer, liver steatosis, cardiovascular disease, and diabetes. Previous research has been primarily focused on exposure to PCBs through ingestion and dermal absorption. There is a lack in knowledge surrounding the effects of exposure to PCBs via inhalation, despite this being a major route of exposure to humans, specifically children and adolescents in contaminated schools.
Using rodent models and cell culture methods, this thesis focuses on understanding the effects of inhaled PCB exposure in the liver and on the development of metabolic syndrome. The liver is the organ responsible for the metabolism and detoxification of xenobiotics, such as PCBs, but there is limited research on how volatilized congeners and mixtures induce gene expression changes and chronic disease in the liver. A key finding from a 4-week inhalation exposure to the lower chlorinated congener, 2,2’,5,5’-tetrachlorobiphneyl (PCB52), in young female rats, but not male rats, was that genes involved in fatty acid biosynthesis are upregulated in the liver after PCB52 exposure. A follow-up in vitro study utilizing the HepG2 hepatic cell line revealed that the major metabolite of PCB52, 4-OH-PCB52, is likely responsible for these transcriptional changes in human cells.
Humans are not exposed to single PCB congeners, but rather mixtures, and there are other environmental, genetic, and dietary factors that may influence the effects of PCB exposure. A 5- week inhalation exposure to the PCB mixture, Aroclor 1254, in young male mice fed viii Western diet revealed that PCB exposure can exacerbate the severity of parameters involved in metabolic syndrome including insulin resistance and changes in serum biomarkers associated with liver disease. Gene expression data from livers demonstrated significant changes in transcript levels of genes associated with type 2 diabetes in mice exposed to Aroclor 1254 and Western diet, further supporting the additive effects of diet and PCB exposure. Findings from an additional study in which young male and female mice were fed regular chow or Western diet and exposed to sham air or Aroclor 1254 focused on the fatty acid biosynthesis genes in the liver that were upregulated in the previous PCB52 inhalation study. Sex-specific increases in liver steatosis in Western diet and exposed groups was observed. While fatty acid synthesis genes were differentially expressed, the changes in these genes seemed more dependent on Western diet feeding than exposure to Aroclor 1254.
The studies presented in this thesis provide clear evidence that exposure to PCBs through inhalation plays a role in altering liver gene expression and promoting metabolic syndrome progression. The findings encourage further investigation into how early life exposure to inhaled PCBs affect liver disease.
Details
- Title: Subtitle
- The effects of inhaled polychlorinated biphenyls on the liver
- Creators
- Brynn Kyleakin Helm-Kwasny
- Contributors
- Aloysius Klingelhutz (Advisor)James Ankrum (Committee Member)Hanna Stevens (Committee Member)Yumi Imai (Committee Member)Renata Pereira Alambert (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Biomedical Science (Molecular Medicine)
- Date degree season
- Spring 2025
- DOI
- 10.25820/etd.007928
- Publisher
- University of Iowa
- Number of pages
- xxi, 221 pages
- Copyright
- Copyright 2025 Brynn Kyleakin Helm-Kwasny
- Grant note
- This research was supported by the Iowa Superfund Research Program (NIH P42 ES013661) and carried out in laboratory facilities supported by the Environmental Health Sciences Research Center (NIH P30 ES005605).
- Language
- English
- Date submitted
- 04/23/2025
- Description illustrations
- Illustrations, tables, graphs, charts
- Description bibliographic
- Includes bibliographical references (pages 135-159).
- Public Abstract (ETD)
PCBs are persistent pollutants that were used in the production of many industrial and commercial products. They are associated with diabetes, cancer, and heart disease, and are contaminants in food products as well as the air of older buildings such as schools. There have been limited studies on how breathing in PCBs at an early age causes disease. We found that exposure of young female rats to a PCB found at high levels in the air of contaminated buildings caused an increase in liver genes responsible for making fat, indicating a potential role in causing fatty liver disease.
To study if diet increases the dangers associated with PCB exposure, young mice were given a fatty and sugary diet similar to what children consume in the U.S. (U.S. diet) and exposed to a PCB mixture which resembles that found in older school buildings. PCB-exposed mice had worsened insulin resistance and exhibited changes in the expression of genes that may make them more susceptible to diabetes. An additional study exposed both male and female mice to the PCB mixture and fed them either normal food or a U.S. diet. Genes involved in making fat in the liver were changed, but these changes seemed more linked to eating the U.S. diet rather than PCB exposure, and the observed changes were different between males and females. Overall, my research demonstrates that breathing in PCBs at an early age can influence liver disease and, along with diet, may promote metabolic disease later in life.
- Academic Unit
- Biomedical Science Program
- Record Identifier
- 9984831124402771
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