Roles of cytosolic phospholipase A₂α in reproductive and systemic toxicities in...

Exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induces a variety of toxicities upon binding of TCDD to aryl hydrocarbon receptor. Although this binding upregulates the synthesis of prostaglandins and their related lipid mediators via cytosolic phospholipase A₂α (cPLA₂α), toxicological significance of this signaling pathway remains elusive. Herein, we investigated the roles of cPLA₂α in TCDD toxicities using cPLA₂α-null mice. In a first set of experiments, pregnant mice were orally administered TCDD at a dose of 40 μg/kg on gestation day (GD) 12.5, and fetuses were collected on GD 18 for subsequent analyses. The number of live male fetuses of cPLA₂α-null type was significantly less than that of wild-type in TCDD-exposed litters. TCDD-induced hydronephrosis was more severe in wild-type fetuses than in cPLA₂α-null fetuses regardless of sex, and kidney expression levels of the inflammatory cytokines interleukin-1β and tumor necrosis factor-α were increased in a cPLA₂α-dependent manner in TCDD-exposed fetuses. In a second set of experiments, following intraperitoneal administration of TCDD at 50 μg/kg, body weight of the male adult mice was decreased within 2 days in wild-type mice but was not changed in cPLA₂α-null mice. In addition, TCDD-induced lipid accumulation in the livers of cPLA₂α-null mice was at an intermediate level compared with TCDD-exposed wild-type and vehicle-control mice. In conclusion, the present results show that cPLA₂α is involved in TCDD-induced body weight loss, lipid accumulation in the liver, fetal hydronephrosis, and cytokine gene expression, and that the molecular basis of TCDD toxicity differs considerably between target tissues and life stages.