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

Abstract

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

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

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

Results: Single relationship analysis suggested that urinary bis(1,3-dichloro-2-propyl) phosphate (BDCIPP) level was negatively correlated with the risk of hepatic steatosis. Nonlinear relationships were observed between urinary diphenyl phosphate (DPHP) levels and the risk of hepatic steatosis in restricted cubic splines (RCS) analysis. Network toxicology and transcriptomics analysis suggested that OPFRs might directly interact with several metabolism-related proteins, including monoglyceride lipase (MGLL), fatty acid amide hydrolase (FAAH), cannabinoid receptor 1 (CNR1), CNR2, and phosphatidylinositol-5-phosphate 4-kinase type 2 gamma (PIP4K2C). This might affect the lipid metabolic processes by altering the 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 inducing hepatic steatosis.

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

Graphical abstract: A population, network toxicology, and bioinformatics study for the association of organophosphate flame retardant exposure with hepatic steatosis and liver fibrosis.

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