Roles of cytosolic phospholipase A₂? in reproductive and systemic toxicities in 2,3,7,8-tetrachlorodibenzo-p-dioxin-exposed mice.

ABSTRACT: 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 A₂? (cPLA₂?), toxicological significance of this signaling pathway remains elusive. Herein, we investigated the roles of cPLA₂? in TCDD toxicities using cPLA₂?-null mice. In a first set of experiments, pregnant mice were orally administered TCDD at a dose of 40 ?g/kg on gestation day (GD) 12.5, and fetuses were collected on GD 18 for subsequent analyses. The number of live male fetuses of cPLA₂?-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 cPLA₂?-null fetuses regardless of sex, and kidney expression levels of the inflammatory cytokines interleukin-1? and tumor necrosis factor-? were increased in a cPLA₂?-dependent manner in TCDD-exposed fetuses. In a second set of experiments, following intraperitoneal administration of TCDD at 50 ?g/kg, body weight of the male adult mice was decreased within 2 days in wild-type mice but was not changed in cPLA₂?-null mice. In addition, TCDD-induced lipid accumulation in the livers of cPLA₂?-null mice was at an intermediate level compared with TCDD-exposed wild-type and vehicle-control mice. In conclusion, the present results show that cPLA₂? 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.

SUBMITTER: Fujisawa N 

PROVIDER: S-EPMC5818604 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature