Triphenyl　phosphate　(TPHP)　is　an　emerging　endocrine-disrupting　chemical　that　has　been　widely　used　as　a　flame　retardant.　Although　the　neurotoxicity　of　TPHP　to　aquatic　animals　had　been　highlighted　in　previous　studies,　its　effects　on　mammals,　particularly　at　environmentally　relevant　doses　(ERDs),　have　remained　largely　unknown.　In　this　study,　a　28-week　mouse　model　was　established　to　investigate　the　potential　neurotoxicity　induced　by　ERDs　of　TPHP　(0.89　and　9.19　μg/kg/day).　The　mechanisms　underlying　gut-brain　axis　communication　were　explored　using　behavioral　tests,　16S　rRNA　sequencing,　and　multiomics　analysis.　The　results　demonstrated　that　chronic　exposure　to　an　ERD　of　TPHP　(9.19　μg/kg/day)　significantly　reduced　the　abundance　of　Lactobacillus　in　the　gut　microbiota　of　mice　and　led　to　an　increase　in　pro-inflammatory　bacterium.　These　alterations　activated　the　NF-κB　signaling　pathway　in　the　prefrontal　cortex,　resulting　in　the　accumulation　of　quinolinic　acid　and　glutamate.　Ultimately,　these　changes　induced　anxiety-　and　depression-like　behaviors　in　mice.　This　study　provides　novel　insights　into　the　indirect　neurotoxic　effects　of　TPHP　exposure　at　ERDs　in　mammals　and　emphasizes　the　need　for　more　stringent　regulatory　policies　regarding　the　use　of　TPHP.　©　2025　American　Chemical　Society.