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. 2025 Sep 1;111(9):6036-6049.
doi: 10.1097/JS9.0000000000002680. Epub 2025 Jun 24.

Integrated network toxicology and population-based analysis uncovers organophosphate flame retardant exposure as a risk factor for hepatic steatosis and fibrosis: mechanistic and clinical insights

Lin Che  1   2 , Rongjuan Jiang  1 , Chengqiang Wang  1 , Junling He  1 , Zhiyong Zhang  1 , Bo Qian  1
Affiliations

Integrated network toxicology and population-based analysis uncovers organophosphate flame retardant exposure as a risk factor for hepatic steatosis and fibrosis: mechanistic and clinical insights

Lin Che et al. Int J Surg. .

Abstract

Background: Laboratory evidence has recently shown that exposure to organophosphate flame retardants (OPFRs) can cause adverse liver outcomes, which lacks further validation.

Objective: This investigated the correlation and toxicological mechanism between OPFRs exposure and hepatic steatosis or fibrosis.

Method: To explore the association of OPFRs exposure and hepatic steatosis or liver fibrosis, we conducted the population analysis using the data of urinary OPFRs monitoring and liver vibration-controlled transient elastography examinations from the National Health and Nutrition Examination Survey during 2017-2018. Network toxicology and transcriptomics analyses were used to explore the potential toxicological mechanisms of OPFRs-associated hepatic steatosis.

Results: Univariate analysis suggested that urinary bis(1,3-dichloro-2-propyl) phosphate level was negatively correlated with the risk of hepatic steatosis. Nonlinear relationships were observed between urinary diphenyl phosphate levels and the risk of hepatic steatosis in restricted cubic splines analysis. Network toxicology and transcriptomics analysis suggested that OPFRs might directly interact with several metabolism-related proteins, including monoglyceride lipase, fatty acid amide hydrolase, cannabinoid receptor 1 (CNR1), CNR2, and phosphatidylinositol-5-phosphate 4-kinase type 2 gamma (PIP4K2C). These interactions could disrupt lipid metabolic processes by altering lipid metabolism (e.g. PPAR signaling pathway and insulin signaling pathway), energy metabolism (e.g. adipocytokine signaling pathway and HIF-1 signaling pathway), and apoptosis pathway (e.g. p53 signaling pathway), thereby contributing to hepatic steatosis.

Conclusion: Our results indicate that OPFRs exposure was associated with adverse pathological changes in the liver.

Keywords: Bayesian kernel machine regression; hepatic steatosis; network toxicology; organophosphate flame retardant metabolites; restricted cubic spline.

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References

    1. Du J, Li H, Xu S, Zhou Q, Jin M, Tang J. A review of organophosphorus flame retardants (OPFRs): occurrence, bioaccumulation, toxicity, and organism exposure. Environ Sci Pollut Res Int 2019;26:22126–36.
    1. Marklund A, Andersson B, Haglund P. Screening of organophosphorus compounds and their distribution in various indoor environments. Chemosphere 2003;53:1137–46.
    1. Wensing M, Uhde E, Salthammer T. Plastics additives in the indoor environment–flame retardants and plasticizers. Sci Total Environ 2005;339:19–40.
    1. Kademoglou K, Xu F, Padilla-Sanchez JA, Haug LS, Covaci A, Collins CD. Legacy and alternative flame retardants in Norwegian and UK indoor environment: implications of human exposure via dust ingestion. Environ Int 2017;102:48–56.
    1. Wong F, de Wit Ca, Newton SR. Concentrations and variability of organophosphate esters, halogenated flame retardants, and polybrominated diphenyl ethers in indoor and outdoor air in Stockholm, Sweden. Environ Pollut 2018;240:514–22.