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Environmental fluoxetine promotes skin cell proliferation and wound healing

ABSTRACT: 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 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 keratinocyte cell lines, we show that exposure to environmental FLX enhances wound closure. We show dose-dependent increases in wound closure with FLX concentrations from 125 ng/l. 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 related to the MAPK pathway. Consistent with this, phosphoproteomics analyses identified 235 differentially phosphorylated proteins after exposure, with enriched GO terms related to cell cycle, division, and protein biosynthesis. These findings collectively show that exposure to environmental FLX promotes wound healing through modulation of serotonin signalling, gene expression and protein phosphorylation, leading to enhanced cell proliferation. Our results open the door for further research to investigate the effects of environmental FLX on cell metabolism and proliferation, and clinical applications of FLX in the setting of wound healing. We argue that there is an urgent need to develop models that can inform on the risks, and potential benefits, of environmental pollution with selective serotonin reuptake inhibitors.

ORGANISM(S): Homo sapiens

PROVIDER: GSE268987 | GEO | 2024/09/13

REPOSITORIES: GEO

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Project description:Fluoxetine (FLX) is the most common selective serotonin reuptake inhibitor pharmaceutical used for the treatment of psychological disorders such as depression and anxiety. Increased prescription use of FLX by human populations has led to its pseudo-persistence in effluent-receiving waterways. Despite emerging concerns of FLX becoming a potential threat to the aquatic environment, there is currently limited information on effects of FLX on aquatic wildlife, including its specific mechanism of action and associated toxicity pathways in fish. The main goal of this study was to identify and validate key molecular toxicity pathways that are predictive of apical endpoints induced by exposure to FLX using the fathead minnow (Pimephales promelas), a model species common to North American freshwater systems. Adult fathead minnows were exposed to three concentrations of FLX (2.42, 10.7, and 56.7 µg/L) and a control for 21 days. After 96 hours, a subset of fish was sampled, and liver and brain tissue were collected to characterize molecular toxicity pathways using whole transcriptome and proteome analyses. In addition, at the end of the 21-day exposure, individuals were assessed for apical outcomes of regulatory relevance including histopathology and fecundity. Differential gene expression observed in the liver of fish exposed to the highest FLX treatment and revealed dysregulation of pathways associated with biosynthesis and metabolism of fatty acids, which may be an upstream molecular response that led to lipid-type vacuolation of hepatocytes, as observed in the histology analysis. Whole proteome analysis of the same fish revealed dysregulation of PPAR signalling, which may be associated with the enrichment of lipid-related pathways observed in the transcriptome. In addition, there was an indication of pathway enrichment of transcription- and translation-related pathways in the proteome. Common dysregulated genes in the brain of the treated fish were related to cellular signalling processes that are influenced by serotonin levels and shown to be involved in reproductive behaviour and, in turn, reproductive success. This was confirmed through a significant decrease in fecundity following the 21-day exposure. Pathways to measurable adverse outcomes are complex, however, this research does provide some important clues to the mechanistic toxicity that FLX inflicts.

Project description:Current methods to support chemical hazard assessment face significant challenges given the rapidly growing number of compounds of emerging concern (CEC) requiring assessment. Standard testing strategies rely upon live animal testing, which are time-consuming, expensive, and ethically questionable. These concerns serve as an impetus to develop new approach methodologies (NAMs) that do not rely on live animal tests. This study explored the application of the molecular benchmark dose (BMD) approach in a 7-day embryo-larval fathead minnow (FHM) assay to derive determine transcriptomic points-of-departure (tPODs) which can be useds to predict apical BMDs of fluoxetine (FLX), a highly prescribed and potent selective serotonin reuptake inhibitor frequently detected in surface waters. Fertilized FHM embryos were exposed to graded concentrations of FLX (confirmed at <LOD, 0.19, 0.74, 3.38, 10.2, 47.5 µg/L) for 32 days. Subsets of fish were subjected to omics and locomotor analyses at 7 days post-fertilization (dpf) and to histological and biometric measurements at 32 dpf. Enrichment analyses of transcriptomics and proteomics data revealed significant perturbations in gene sets associated with serotonergic and axonal functions. BMD analysis resulted in tPOD values of 0.56 µg/L (median of the 20 most sensitive gene-level BMDs), 5.0 µg/L (tenth percentile of all gene-level BMDs), 7.51 µg/L (mode of the first peak of all gene-level BMDs) , and 5.66 µg/L (pathway-level BMD). These tPODs are protective of apical locomotor and reduced weight effects (LOEC of 10.2 µg/L) observed in this study and are well within the range of chronic apical BMDs of FLX reported in the literature. Furthermore, the distribution of gene-level BMDs followed a bimodal pattern, revealing disruption of sensitive neurotoxic pathways at low concentrations and metabolic pathway perturbations at higher concentrations. This is one of the first studies to derive tPODs for FLX using a short-term embryo assay at a life stage not considered to be a live animal under current legislations.

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Environmental fluoxetine promotes skin cell proliferation and wound healing

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