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Access Type
WSU Access
Date of Award
January 2024
Degree Type
Dissertation
Degree Name
Ph.D.
Department
Pharmacology
First Advisor
Michael Petriello
Abstract
Polychlorinated biphenyl 126 (PCB 126), a dioxin-like pollutant, is known to cause oxidative stress, hepatotoxicity, and gut microbiota alterations. This study aimed to evaluate the effects of PCB 126 exposure on wild-type (WT) and flavin-containing monooxygenase 3 knockout (FMO3 KO) mice, focusing on liver pathology, oxidative stress, and gut microbiota changes. Additionally, we investigated how maternal PCB 126 exposure affects the gut microbiota of aged offspring. In the adult exposure model, male C57BL/6 WT and FMO3 KO mice were administered PCB 126 over 12 weeks. Hepatic histology, oxidative stress markers (F2-isoprostanes), and gut microbiota composition were analyzed. WT mice exhibited significant hepatotoxicity, characterized by macro- and microvesicular fat deposition in the liver, which was absent in FMO3 KO mice. WT mice also showed increased oxidative stress with elevated levels of 8-iso-15-keto PGE2, while FMO3 KO mice were not changed in response to PCB 126 exposure. PCB 126-induced changes in gut microbiota varied significantly between genotypes. In WT mice, Proteobacteria levels decreased following exposure, while they increased in FMO3 KO mice, indicating a genotype-specific microbiome response to environmental toxins. In the maternal exposure model, dams were exposed to PCB 126 during preconception, gestation, and lactation, with half of the groups also receiving exercise interventions. Offspring gut microbiota composition was assessed at 49 weeks of age using 16S rRNA sequencing. Maternal PCB 126 exposure significantly reduced microbial richness and diversity in offspring, regardless of diet or exercise. Specific taxa alterations were observed, including a depletion of Verrucomicrobiaceae and Akkermansia muciniphila, and an increase in Anaeroplasma. These microbial shifts suggest that maternal PCB 126 exposure may predispose offspring to chronic diseases later in life. Overall, the study highlights the differential response of FMO3 deletion in mitigating PCB 126-induced oxidative stress and liver damage, as well as the complex interactions between genetic factors and environmental toxins in shaping gut microbiota compared to WT mice. These findings underscore the importance of considering both genetic predispositions and early-life environmental exposures in assessing long-term health risks associated with PCB 126.
Recommended Citation
Agarwal, Manisha, "Polychlorinated Biphenyl 126 Triggers Oxidative Stress And Reshapes The Gut Microbiome Across The Life-Span" (2024). Wayne State University Dissertations. 4110.
https://digitalcommons.wayne.edu/oa_dissertations/4110