Zearalenone Disrupts the Placental Barrier via Integrated Stress Response Activation in Mice and Human Trophoblast Cells

Zearalenone (ZEA) contaminates various food crops and water systems worldwide. We investigate whether gestational ZEA exposure disrupts the placental barrier and elucidates its underlying mechanisms. This study employed a mouse model and human trophoblast cells. We found that ZEA accumulated in mouse placental tissue. Compared with the well-defined tight junctions observed in controls, ZEA disrupted placental barrier integrity. Consistent with the morphological disruption, ZEA significantly downregulated the expression of placental barrier proteins. Furthermore, ZEA elevated fetal glucocorticoid levels by suppressing placental 11β-HSD2 protein expression and enzymatic activity. Mechanistically, ZEA inhibited placental protein synthesis via integrated stress response (ISR) activation. ISR inhibition attenuated ZEA-induced disruption of the placental barrier and downregulation of barrier proteins, and ameliorated adverse pregnancy outcomes. Our results suggest that ZEA causes placental barrier disruption and adverse pregnancy outcomes through triggering ISR. These mechanistic insights into ZEA's developmental toxicity may guide protective strategies for human and animal health.