Background:

Per- and polyfluoroalkyl Substances (PFAS) are synthetic chemicals widely detected in humans and the environment. Exposure to perfluorooctanesulfonic acid (PFOS) or perfluorohexanesulfonic acid (PFHxS) was previously shown to cause dark-phase hyperactivity in larval zebrafish.

Objectives:

The objective of this study was to elucidate the mechanism by which PFOS or PFHxS exposure caused hyperactivity in larval zebrafish.

Methods:

Swimming behavior was assessed in 5-d postfertilization (dpf) larvae following developmental (1–4 dpf) or acute (5 dpf) exposure to 0.43–7.86μM PFOS, 7.87–120μM PFHxS, or 0.4% dimethyl sulfoxide (DMSO). After developmental exposure and chemical washout at 4 dpf, behavior was also assessed at 5–8 dpf. RNA sequencing was used to identify differences in global gene expression to perform transcriptomic benchmark concentration–response (BMC_T) modeling, and predict upstream regulators in PFOS- or PFHxS-exposed larvae. CRISPR/Cas9-based gene editing was used to knockdown peroxisome proliferator-activated receptors (ppars) pparaa/ab, pparda/db, or pparg at day 0. Knockdown crispants were exposed to 7.86μM PFOS or 0.4% DMSO from 1–4 dpf and behavior was assessed at 5 dpf. Coexposure with the ppard antagonist GSK3787 and PFOS was also performed.