Association of flame retardants exposure with overweight and obesity risk: mechanistic insights from cross-sectional findings, network toxicology, and experimental evidence

Overweight and obesity (OV/OB) have currently become a significant global public health crisis with a sustained upward trend, and recent studies have already demonstrated the potential association between several flame retardants (FRs) and the occurrence of OV/OB. However, the predominant FR components causing OV/OB and their underlying molecular mechanisms remain unclear. In this study, a multidisciplinary approach integrating epidemiology, network toxicology, and in vitro cell experiments was employed to elucidate novel mechanistic insights into the FRs-induced OV/OB. Based on cross-sectional data from National Health and Nutrition Examination Survey (NHANES) 2011-2018, which included 2,404 eligible participants, four distinct epidemiological models (multivariable logistic regression, restricted cubic spline (RCS), quantile g-computation (qgcomp), and Bayesian kernel machine regression (BKMR)) were established in the epidemiological analysis. These models identified that tris (2-chloroethyl) phosphate (TCEP) appeared to be a potentially important contributor to OV/OB among the examined FRs. A comprehensive assay integrating network toxicology and molecular docking was performed to identify two potential target genes ( PPARG and TNF ) involved in OV/OB induced by TCEP and its metabolite bis (2-chloroethyl) phosphate (BCEtP), and further proposed the underlying molecular mechanism: BCEtP and TCEP may modulate the TSC2-RHEB-MTOR axis and the TAK1-IKK-NF-κB axis via activation of PPARG and inactivation of TNF, thus promoting lipid deposition. In vitro experiments further confirmed that TCEP exposure induces excessive lipid accumulation in HepG2 cells. These findings emphasize the urgency of regulating FR exposures and provide a critical scientific basis for both assessment of environmental health risks and establishment of environmental standards.