Exposure to TBBPA and polystyrene nanoplastics induces cardiac fibrosis via the activation of the ESR/H19/Wnt pathway.

Cardiac fibrosis is a key pathological driver of heart failure and cardiovascular mortality, with environmental pollutants being increasingly implicated. Tetrabromobisphenol A (TBBPA), a dominant brominated flame retardant (BFR), is environmentally pervasive and poses potential cardiotoxic risks. However, direct evidence for TBBPA-induced cardiac fibrosis in mammals is lacking. Additionally, its ability to adsorb onto nanoplastics, such as polystyrene (PS-NPs), raises concerns about combined toxicity, especially cardiotoxicity. To addressed this, we systematically evaluated the cardiotoxicity of TBBPA and PS-NPs in vivo and in vitro. In mice, environmentally relevant TBBPA exposure impaired cardiac function and induced inflammation and fibrosis, leading to cardiac remodeling, whereas co-exposure with PS-NPs only induced fibrosis. In H9C2 cells, TBBPA and PS-NPs individually promoted the expression of inflammatory, fibrotic, and hypertrophic markers, with co-exposure resulting in a synergistic exacerbation and a remodeling phenotype. Furthermore, transcriptomic and mechanistic data showed that ESR inhibitors blocked the H19/Wnt pathway activation induced by TBBPA or PS-NPs. Through gain- and loss-of-function experiments, we further confirmed that H19 mediates pollutant-induced Wnt/β-catenin activation and fibrotic responses, positioning H19 as a critical downstream mediator of the ESR/H19/Wnt axis. Overall, for the first time, this study elucidates the cardiotoxic profiles of TBBPA and PS-NPs and identifies the ESR/H19/Wnt axis as a key pro-fibrotic mechanism, highlighting a cardiovascular risk and a potential therapeutic target.