DAF-16/FOXO Insulin Signaling Modulates F-53B Toxicity by Regulating Intestinal Redox Homeostasis and Permeability in Caenorhabditis elegans.

Abstract

Although 6:2 Chlorinated polyfluorinated ether sulfonate (6:2 Cl-PFES, F-53B) is gaining popularity in China as an alternative to perfluorooctane sulfonate (PFOS), its environmental effects on organisms are still not fully understood. This research employed C. elegans to assess the chronic toxicological effects of F-53B at environmentally relevant concentrations (ERCs), while also elucidating the molecular regulatory mechanisms of the insulin signaling cascade in response to F-53B-induced perturbations. Locomotion behaviors were significantly attenuated upon exposure to F-53B at concentrations ≥ 0.15 μg/L, as evidenced by diminished head thrashes and body bends frequencies, concomitant with a marked exacerbation of reactive oxygen species (ROS) generation in wild-type nematodes. F-53B exposure engendered a downregulation of insulin signaling constituents, including daf-2, age-1, akt-1, and akt-2, alongside the downstream transcription factor daf-16 was concurrently upregulated. The intestinal insulin signaling pathway DAF-2/IGFR-AGE-1/PI3K-AKT-1/2-DAF-16/FOXO plays a key role in controlling Caenorhabditis elegans (C. elegans)' response to F-53B toxicity, according to tissue-specific activity and genetic relationship analysis. Furthermore, exposure to F-53B also elevated expression of genes associated to intestinal development like pkc-3 and erm-1, as well as oxidative stress-related genes including sod-3, ctl-3, and gst-4. Further analysis showed SOD-3, CTL-3, GST-4, PKC-3, and ERM-1 played a role in regulating C. elegans to F-53B toxicity and were situated downstream of the identified intestinal insulin signaling cascade. Consequently, a protective signaling cascade involving DAF-2/IGFR→ AGE-1/PI3K→AKT-1/2→DAF-16/FOXO→SOD-3/CTL-3/GST-4/PKC-3/ERM-1. was identified for environmental organisms against the adverse effects from F-53B. Our study provides a basis for elucidating the toxicity of F-53B exposure to environmental organisms under field-relevant conditions.