Importance of post-translational protein modifications in PFAS toxicity

Abstract

Per- and polyfluoroalkyl substances (PFAS) are a group of synthetic compounds known for their high chemical stability, resistance to degradation. This class includes thousands of different compounds widely used in various products like non-stick cookware, water-repellent fabrics, food packaging, firefighting foam, and many personal care products. While these properties contribute to their industrial utility, they also pose significant environmental and health concerns due in part to long environmental and biological half-lives. PFAS contamination has been widely reported in water sources and soil, along with reports of bioaccumulation in the blood and tissues of living organisms. These chemicals have been linked to a range of health effects, including potential risks to cancer, neurotoxicity, and developmental disorders. Given their broad involvement in disease pathology, it is critical to investigate the underlying molecular mechanisms of PFAS toxicity. This review evaluates current research on the impact of various PFAS on different proteins, their post-translational modifications (PTMs), and the effects on cellular signalling pathways. It also reviews proteomic studies conducted over the years that aim to elucidate these protein-level changes, while highlighting existing gaps in the field. Despite growing attention to PFAS toxicity, significant advances are required in elucidating the primary mechanisms of toxic action. Studying PFAS effects from a proteome perspective could be very promising. In particular, the lack of organ-specific proteomic data, including studies on distinct brain regions and PTM-specific profiling, represents a critical area for future research.

Keywords: PFAS; Post-translational modifications; Proteomics; Signalling pathways.

Figure 1.. PFAS-induced neurotoxicity and tumorigenesis:

PFAS also triggers calcium (Ca²⁺) influx, which alters phosphorylation levels in the discs large homolog 1 (DLG1) phosphorylation and dissociation from glutamate transporter 1 (GLT-1) pathway and SMAD signalling, contributing to neurotoxicity and pyroptosis, respectively. Increased ubiquitination and degradation of SMAD7 and subsequent increase in downstream phosphorylation events also promote tumorigenesis via the SMAD pathway. Additionally, altered acetylation and tau hyperphosphorylation have been linked to Alzheimer’s disease pathology. Regulation of β-catenin results in ferroptosis and inhibited cell proliferation. P-Phosphorylation, Ub-Ubiquitination, Ac-Acetylation

Figure 2.. PFAS-induced post-translational modifications:

PFAS regulates various signaling pathways by altering the phosphorylation states of key proteins involved. These changes subsequently affect downstream signaling pathways, such as JNK, ERK, and NF-κB, and cause apoptosis, neurotoxicity, and blood-brain barrier (BBB) disruption. Increased phosphorylation of ERK triggers autophagic pathways, ultimately leading to apoptosis. Phosphorylated PKD and p38 contribute to the disruption of tight junctions and the blood-brain barrier. Additionally, the activation of JAK/STAT and NF-κB pathways promotes cytokine release and neuroinflammation. P-Phosphorylation; Ub-Ubiquitylation.