Sex-dependent effect of triphenyl phosphate on hepatic energy metabolism at the intersection of diet pattern in pubertal mice

Triphenyl phosphate (TPhP) is mostly residual in fat-rich foodstuff and ingestion is the main route for adolescents’ exposure. As a typical metabolic disruptor, however, sex-specific effect of TPhP-high fat diet (HFD) co-exposure in adolescent remains unknown. This study revealed that HFD exacerbated systematic inflammation and insulin insensitivity in female mice at pubertal stage after exposure to 25 mg/kg TPhP or above. Notably, the pattern of sexual selective metabolic disruption caused by TPhP was irrespective of diet after examined mice both in HFD and normal diet feeding. Female mice favored the energy storage in forms of D-glucose 6-phosphate, D-fructose 6-phosphate and triglyceride. That was further supported by mRNA levels of key enzymes in glycolysis, gluconeogenesis, and lipid metabolism. Contrastingly, the elevation of the corresponding genes ensuing by the depleted metabolites were observed in males. In mechanistic investigation, we observed a declination of serum estrogen, a master of energy homeostasis, in both sexes, irrespective of diet. However, only male mice displayed estrogen-hypothalamus negative feedback, supporting by the upregulation of gonadotropin-releasing hormone. Rather than the well-recognized estrogen receptor α, hepatic G protein-coupled estrogen receptor manifested sexual dichotomy, which desensitized to estrogenic response only in females. Collectively, this study posited that females were more susceptible to store energy under TPhP-HFD than males during pubertal partially through estrogenic pathway.