Di(2‐ethylhexyl) Phthalate Induces Placental Cellular Apoptosis via the PI3K/Akt‐p53 Pathway and Functional Disruption via a ceRNA Network

Di(2‐ethylhexyl) phthalate (DEHP), a widely used plasticizer, crosses the placental barrier and disrupts fetal development, though its precise mechanisms remain poorly defined. To assess its placental effects, pregnant mice were treated daily with 40 μg/kg DEHP, and placental alterations were systematically evaluated through histopathological examination, Western blot analysis, and whole‐transcriptome sequencing. DEHP exposure reduced the total placental area, disrupted the decidual and spongiotrophoblast layers, and disorganized vascular structures. Concurrently, protein levels of Bax, p53, and Caspase‐3 were significantly elevated, while Bcl‐2 expression decreased, indicating mitochondrial apoptosis mediated by the PI3K/Akt–p53 pathway. Transcriptomic profiling further revealed widespread dysregulation of mRNAs and noncoding RNAs, enriched in processes involving the Notch signaling pathway, cholesterol metabolism, hormone response, and oxygen transport. Construction of a ceRNA network suggested that miR‐6538 may contribute to placental dysfunction by regulating Tmcc2 and Susd2. These findings elucidate a novel mechanism through which DEHP impairs placental structure and function via apoptotic signaling and RNA regulatory networks, offering important insights into its reproductive toxicity.