Adipogenic Effects\nof Cresyl Diphenyl Phosphate (Triphenyl\nPhosphate Alternative) through Peroxisome Proliferator-Activated Receptor\nGamma Pathway: A Comprehensive Study Integrating <i>In Vitro</i>, <i>In Vivo</i>, and <

Cresyl diphenyl phosphate (CDP), a novel organophosphate\nester\n(OPE), has been detected in various environmental and human samples.\nHowever, there is very limited knowledge regarding its toxicity, mechanisms\nof action, and potential health risks. Using new alternative methods\n(NAMs), across the molecular interactions, signaling pathways, cell\nfunctions, animal effects, and population risks, we investigated the\npotential adipogenic effects and associated risks of CDP and legacy\nOPE triphenyl phosphate (TPHP) by acting on peroxisome proliferator-activated\nreceptor gamma (PPARγ). Among the 19 screened OPEs, CDP bound\nto PPARγ with the highest binding potency, followed by TPHP.\nCDP activated PPARγ through fitting into the binding pocket\nwith strong hydrophobicity and hydrogen bond interactions; CDP exhibited\nhigher potency compared to TPHP. In 3T3-L1 cells, CDP enhanced the\nPPARγ-mediated adipogenesis activity, exhibiting greater potency\nthan TPHP. The intracellular concentration and receptor-bound concentrations\n(RBC) of CDP were also higher than those of TPHP in both HEK293 cells\nand 3T3-L1 cells. In mice, exposure to CDP activated the PPARγ-mediated\nadipogenic pathway, leading to an increased white adipose tissue weight\ngain. Overall, CDP could bind to and activate PPARγ, thereby\npromoting preadipocyte differentiation and the development of white\nadipose tissue. Its potential obesogenic risks should be of high concern.