Environmental fluoxetine promotes skin cell proliferation and wound healing

• Published in: Environmental pollution (1987) 2024-12, Vol.362, p.124952, Article 124952
• Main Authors: Rodriguez-Barucg, Quentin, Garcia, Angel A., Garcia-Merino, Belen, Akinmola, Tomilayo, Okotie-Eboh, Temisanren, Francis, Thomas, Bringas, Eugenio, Ortiz, Inmaculada, Wade, Mark A., Dowle, Adam, Joyce, Domino A., Hardman, Matthew J., Wilkinson, Holly N., Beltran-Alvarez, Pedro
• Format: Article
• Language: English
• Subjects: Cell Line; Cell Proliferation - drug effects; Fluoxetine; Fluoxetine - pharmacology; Humans; Keratinocyte; Keratinocytes - drug effects; Selective Serotonin Reuptake Inhibitors - pharmacology; Serotonin; Serotonin - metabolism; Skin; Skin - drug effects; Water Pollutants, Chemical - toxicity; Wound healing; Wound Healing - drug effects
• ISSN: 0269-7491; 1873-6424; 1873-6424
• DOI: 10.1016/j.envpol.2024.124952

This study investigates the effects of environmentally-relevant concentrations of fluoxetine (FLX, commercial name: Prozac) on wound healing. Pollution of water systems with pharmaceutical and personal care products, including antidepressants such as FLX and other selective serotonin reuptake inhibitors, is a growing environmental concern. Environmentally-relevant FLX concentrations are known to impact physiological functions and behaviour of aquatic animals, however, the effects of exposure on humans are currently unknown. Using a combination of human skin biopsies and a human keratinocyte cell line, we show that exposure to environmental FLX promotes wound closure. We show dose-dependent increases in wound closure with FLX concentrations from 125 ng/l. Using several –omics and pharmaceutical approaches, we demonstrate that the mechanisms underlying enhanced wound closure are increased cell proliferation and serotonin signalling. Transcriptomic analysis revealed 350 differentially expressed genes after exposure. Downregulated genes were enriched in pathways related to mitochondrial function and metabolism, while upregulated genes were associated with cell proliferation and tissue morphogenesis. Kinase profiling showed altered phosphorylation of kinases linked to the MAPK pathway. Consistent with this, phosphoproteomic analyses identified 235 differentially phosphorylated proteins after exposure, with enriched GO terms related to cell cycle, division, and protein biosynthesis. Treatment of skin biopsies and keratinocytes with ketanserin, a serotonin receptor antagonist, reversed the increase in wound closure observed upon exposure. These findings collectively show that exposure to environmental FLX promotes wound healing through modulating serotonin signalling, gene expression and protein phosphorylation, leading to enhanced cell proliferation. Our results justify a transition from the study of behavioural effects of environmental FLX in aquatic animals to the investigation of effects of exposure on wound healing in aquatic and terrestrial animals, including direct impacts on human health. [Display omitted] •Exposure to environmental concentrations of antidepressants promote wound healing.•Wounds inflicted on human skin biopsies heal faster when exposed to fluoxetine.•Human keratinocytes exposed to fluoxetine proliferate and close wounds.•Exposure leads to hundreds of differentially expressed genes and phosphosites.•We open avenues for research on the effe