RESUMO
Triphenyl phosphate (TPhP), a widely used organophosphate-flame retardant, is ubiquitously found in household environments and may adversely affect human health. Evidence indicates that TPhP exposure causes metabolic dysfunctions in vivo; however, the underlying mechanism of such adverse effects has not been comprehensively investigated. Herein, we utilized two in vitro models including mouse and human preadipocytes to delineate adipogenic mechanisms of TPhP. The results revealed that both mouse and human preadipocytes exposed to TPhP concentration-dependently accumulated more fat through a significant upregulation of epidermal growth factor receptor (EGFR). We demonstrated that TPhP significantly promoted adipogenesis through the activation of EGFR/ERK/AKT signaling pathway as evident by a drastic reduction in adipogenesis of preadipocytes cotreated with inhibitors of EGFR and its major effectors. Furthermore, we confirmed the mechanism of TPhP-induced metabolic dysfunctions in vivo. We observed that male mice perinatally exposed to TPhP had a significant increase in adiposity, hepatic triglycerides, insulin resistance, plasma insulin levels, hypotension, and phosphorylated EGFR in gonadal fat. Interestingly, an administration of a potent and selective EGFR inhibitor significantly ameliorated the adverse metabolic effects caused by TPhP. Our findings uncovered a potential mechanism of TPhP-induced metabolic dysfunctions and provided implications on toxic metabolic effects posed by environmental chemicals.
