EVALUATING EFFECTS OF PERFLUORINATED ALKYL SUBSTANCES (PFAS) ON ANURAN LIPID HOMEOSTASIS THROUGH XENOPUS LAEVIS BODY & HEPATIC CONDITION

 Per- and polyfluoroalkyl substances (PFAS) are a class of persistent environmental contaminants that have become ubiquitous, resulting in widespread exposure among humans and wildlife. Amphibians are regularly exposed in the field, making them susceptible to sublethal effects of PFAS exposure. In amphibians exposed to PFAS, deleterious effects have been observed, including reduction in body condition measured using the scaled mass index (SMI) and degraded hepatic condition, among others. PFAS may dysregulate lipid metabolism by altering signaling cascades regulated by peroxisome proliferator activated receptors (PPAR), but whether changes in energy stores can explain changes in amphibian SMI and/or hepatic condition remain underexplored. Since lipids are a critical energy reserve for anurans, understanding whether lipid metabolism is being perturbed is critical. The central objective of this thesis was to investigate the effect of PFAS on lipid homeostasis in Xenopus laevis tadpoles within the context of a PPAR mechanism of action (MOA), considering apical, molecular, and lipidomic endpoints. I conducted three studies: (a) a study to characterize SMI and the relative expression of the hepatic xPPARα/β/γ during metamorphosis, (b) a pharmaceutical exposure to assess the in vivo effects of xPPARα/β/γ agonism on hepatic gene expression for select downstream targets (apoa5, fabp1, acox1,​ pck1), and (c) a chronic PFAS exposure to investigate the effects of environmentally relevant concentrations (PFOS, PFHxS, PFOA, PFHxA at 0.5 ppb; binary mixture of PFOS:PFHxS at 1 ppb) on lipid homeostasis through apical endpoints (mass, snout vent length, SMI, hepatic condition), relative hepatic gene expression, and Multiple Reaction Monitoring (MRM) profiling of the hepatic lipidome for changes in relative class abundance. In study (a), I identified SMI and hepatic expression of xPPARα/β/γ is dynamic during late metamorphosis, indicating the potential for heightened susceptibility. However, in study (b), pharmaceutical agonists had no effect on X. laevis at high doses. For study (c), I did not observe effects on a majority of apical endpoints, including SMI, but detected a significant sex-specific reduction in hepatic condition for male X. laevis tadpoles exposed to single-chemical perfluorosulfonic acid (PFSA) treatments. For gene expression, I observed a transient downregulation for apolipoprotein-V (apoa5) at Nieuwkoop and Faber (NF) stage 62 for X. laevis tadpoles exposed to single-chemical perfluorocarboxylic acid (PFCA) treatments. Lipid profiling detected transient dysregulation of predominantly membrane lipids in-response to short-chain PFAS treatments at NF 58. Overall, our findings indicate PFAS may exert toxicity during anuran metamorphosis through multiple mechanisms of action (MOA) with sex-specific and developmental-stage specific outcomes.