| First Author | Fujisawa N | Year | 2018 |
| Journal | Arch Toxicol | Volume | 92 |
| Issue | 2 | Pages | 789-801 |
| PubMed ID | 29043426 | Mgi Jnum | J:325438 |
| Mgi Id | MGI:6873902 | Doi | 10.1007/s00204-017-2081-z |
| Citation | Fujisawa N, et al. (2018) Roles of cytosolic phospholipase A2alpha in reproductive and systemic toxicities in 2,3,7,8-tetrachlorodibenzo-p-dioxin-exposed mice. Arch Toxicol 92(2):789-801 |
| abstractText | 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 A2alpha (cPLA2alpha), toxicological significance of this signaling pathway remains elusive. Herein, we investigated the roles of cPLA2alpha in TCDD toxicities using cPLA2alpha-null mice. In a first set of experiments, pregnant mice were orally administered TCDD at a dose of 40 mug/kg on gestation day (GD) 12.5, and fetuses were collected on GD 18 for subsequent analyses. The number of live male fetuses of cPLA2alpha-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 cPLA2alpha-null fetuses regardless of sex, and kidney expression levels of the inflammatory cytokines interleukin-1beta and tumor necrosis factor-alpha were increased in a cPLA2alpha-dependent manner in TCDD-exposed fetuses. In a second set of experiments, following intraperitoneal administration of TCDD at 50 mug/kg, body weight of the male adult mice was decreased within 2 days in wild-type mice but was not changed in cPLA2alpha-null mice. In addition, TCDD-induced lipid accumulation in the livers of cPLA2alpha-null mice was at an intermediate level compared with TCDD-exposed wild-type and vehicle-control mice. In conclusion, the present results show that cPLA2alpha 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. |
