Humans are ubiquitously exposed to mixtures of per- and polyfluoroalkyl substances (PFAS). Exposure to well-studied PFAS including perfluorooctanoic acid (PFOA) is associated with multiple adverse health effects in humans including dysregulated lipid homeostasis. Evidence from epidemiological studies consistently shows a positive association between PFOA exposure and circulating total and low-density lipoprotein cholesterol levels with emerging evidence suggesting PFOA disrupts liver lipid homeostasis as well. Animal toxicity studies show that PFOA decreases, has no effect on, or increases circulating cholesterol levels in rodents and induces liver lipid accumulation. Mechanisms through which PFOA and other PFAS disrupt liver and whole body lipid homeostasis, and an explanation for the differences between species are poorly understood. The overarching hypothesis of this dissertation is that PFOA disrupts serum and liver lipid homeostasis through interactions with multiple hepatic nuclear receptors including peroxisome proliferator activated receptor α (PPARα). This hypothesis was tested with a focus on human-relevant experimental designs.
In the first research aim, an in vivo exposure was used to test the hypothesis that the effects of PFOA on liver and serum triacylglyceride and cholesterol concentrations differ by PPARα genotype. Female mice expressing mouse PPARα, human PPARα (hPPARα), or no PPARα were exposed to PFOA (1.2, 3.4, or 14.8 μM) for 14 weeks via drinking water to achieve steady state exposure with co-exposure to a diet containing fat and cholesterol based on “What we eat in America.” PFOA increased liver and serum cholesterol content through PPARα-dependent mechanisms. Analysis of hepatic mRNA expression showed that the PPARα-dependent increase in serum and liver cholesterol was accompanied by a PPARα-dependent decrease in the mRNA expression of the rate-limiting enzyme that converts cholesterol to bile acids and represents an important source of cholesterol turnover in humans.
In the second research aim, an in vivo exposure was used to test the hypothesis that PFOA disrupts liver lipid homeostasis by modulating multiple hepatic nuclear receptor pathways. Male and female hPPARα and PPARα null mice were exposed to PFOA (8 μM) for 6 weeks via drinking water in the context of a fat and cholesterol rich diet based on “What we eat in America.” PFOA exposure changed the abundance of multiple lipid classes in the liver with some changes depending on PPARα expression while others occurred via mechanisms independent of PPARα. Less than 60% of PFOA-induced transcriptomic changes depended on hPPARα. Signaling pathways for other nuclear receptors including CAR and PXR may account for the non- PPARα-dependent transcriptomic and lipidomic changes.
Because the effects of PFOA on liver and whole-body lipid homeostasis are partially mediated by PPARα, the third research aim tested the hypothesis that hPPARα activation by PFAS mixtures can be predicted with the mathematical model Generalized Concentration Addition (GCA). Data generated using a full-length hPPARα-driven reporter assay showed that, in addition to differences in potency, PFAS differ in the efficacy with which they activate hPPARα. Perfluorinated carboxylic acids (PFCAs) tended to act as full hPPARα agonists while perfluorinated sulfonic acids (PFSAs) tended to act as partial hPPARα agonists. Because of these differences in efficacy, GCA more accurately predicted hPPARα activation by human-relevant PFAS mixtures than traditional mixtures modeling approaches that do not take into account differences in efficacy.
Taken together, the research presented in this dissertation shows that hPPARα activation is one of several important molecular initiating events underlying PFOA-induced lipid dysregulation, including increased liver and serum cholesterol levels. Results from these studies support a causal association between PFOA exposure and increased serum cholesterol in humans. The data define important distinctions between PFCAs and PFSAs, which warrant consideration for regulatory agencies acting on the joint toxicity of PFAS mixtures. / 2026-01-03T00:00:00Z
| Identifer | oai:union.ndltd.org:bu.edu/oai:open.bu.edu:2144/47902 |
| Date | 04 January 2024 |
| Creators | Nielsen, Greylin Hillary Rinaldo |
| Contributors | Schlezinger, Jennifer J. |
| Source Sets | Boston University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis/Dissertation |
| Rights | Attribution 4.0 International, http://creativecommons.org/licenses/by/4.0/ |
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