Text

theses

Perfluoroalkylated substances (PFASs) are a class of compounds with widespread occurrence in the environment, and long chain PFASs (C-8/C-9) are reported to cause developmental toxicities and alterations in lipid homeostasis. This has led companies that once relied on long chain PFASs to switch to alternatives, such as the (C-6) low molecular weight alternatives, PFHxA, PFHxS, and 6:2 FTOH. However, fewer toxicity assessments have been completed on these compounds. This dissertation addresses this data gap through developmental toxicity assessment in early (5 days post fertilization, dpf) and later (14 dpf) life stage larval zebrafish. Endpoints examined include effects at the cellular and whole organism level to assess different levels of biological organization, and develop specific adverse outcome pathways (AOPs) for each compound. Previous research from our lab examined these endpoints following exposures to long chain PFASs. This allowed for comparison of AOPs of long chain PFASs and the low molecular weight alternatives. In 5 dpf larvae, exposures to 0.2-20 µM resulted in few morphometric effects; however, gene expression endpoints were the most sensitive to exposures. In 14 dpf larvae, behavioral effects were observed with exposure to 6:2 FTOH and PFHxS, but not PFHxA, suggesting that nervous tissue development AOPs may not apply to this PFAS. Similarly, lipid distribution in 14 dpf larvae was altered only with PFHxS and 6:2 FTOH exposures. The involvement of PFASs in the manifestation of dysregulation of lipid homeostasis was examined in larval zebrafish using the long chain PFASs as a proof of concept. These studies were completed using BODIPY-FL fatty acids which allowed for visualization of the packaging and uptake of yolk sac lipids, and expression analysis of genes related to lipid distribution. Alterations in the packaging and uptake of yolk sac lipids were observed with the long chain PFASs, and these compounds were each associated with a different gene expression profile. These same genes were examined with the low molecular weight PFAS alternatives, and while again, each PFAS resulted in a unique gene expression profile, some of the same pathways impacted by long chain PFAS exposures appeared to be affected by the low molecular weight alternatives. Overall, the low molecular weight alternatives, PFHxA, PFHxS, and 6:2 FTOH were found to be less toxic than long chain PFASs in zebrafish, and while different toxicity profiles exist, there is some overlap in growth, neural development, and lipid homeostasis AOPs impacted with PFAS exposures.

ETD_9084

doi:10.7282/T3DF6VV4

Ph.D.

Includes bibliographical references

by Kate M. Annunziato

ETD doctoral

The author owns the copyright to this work.