Triphenyl phosphate induces lipid metabolism disorder and promotes obesity through PI3K/AKT signaling pathway

Triphenyl phosphate (TPHP) is a widely used organic phosphate flame retardant that has been reported as a potential environmental obesogen. However, the potential impact and mechanism of action of TPHP on adipose tissue are still unclear. This study investigates the potential impact of TPHP on lipid metabolism disorders through in vivo and in vitro experiments. Male and female BALB/c mice were exposed to TPHP (0, 1, 10, and 150 mg/kg/day) for 60 days, and 3T3-L1 preadipocytes were treated with concentrations of TPHP (0, 0.1, 1, 10 μM) during differentiation. The results showed that exposure to TPHP could cause gender specific dyslipidemia, with male mice exhibiting dose-dependent increases in inguinal adipose tissue coefficient, adipocyte hypertrophy, and upregulation of adipose differentiation and adipogenesis-related genes. In contrast, female mice did not show significant changes in tissue morphology. This suggested that TPHP might promote the potential occurrence of adiposity by disrupting the lipid metabolism homeostasis of male adipose tissue. During the differentiation and maturation process of 3T3-L1 preadipocytes, exposure to TPHP led to increased lipid accumulation and disrupted lipid homeostasis by simultaneous activation adipogenesis and lipolysis. Multiple omics data showed that the activation of the peroxisome proliferator-activated receptor γ (PPARγ) signaling pathway and fatty acid metabolism was the core mechanism of TPHP induced metabolic dysfunction. Further research showed that TPHP activated the PI3K/AKT pathway, and PI3K inhibitor (LY294002) could rescue TPHP induced lipid droplet formation and normalize the expression of adipogenic markers. These findings confirm that TPHP is a potential environmental obesogen that can disrupt the metabolic homeostasis of white adipose tissue through the PPARγ and PI3K/AKT signaling pathways, with higher susceptibility in males. This study provides compelling evidence for the obesogenic effects of TPHP and information for risk assessment of organophosphorus flame retardants.