The role of prostaglandin E2 receptor EP1 in 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced neonatal hydronephrosis in mice

Abstract Prostaglandin E 2 (PGE 2 ) is a critical factor in the pathogenesis of dioxin-induced neonatal hydronephrosis. Since the PGE 2 receptor has four subtypes, EP1 − EP4, this study was aimed to challenge the hypothesis that at least one of the four subtypes is responsible for the pathogenesis of dioxin-induced hydronephrosis. To this end, we used mouse pups, with a C57BL/6 J background, genetically lacking EP1, EP2, or EP3, and wild-type pups in whom EP4 was suppressed by administering ONO-AE3-208 (ONO), an EP4 antagonist, from postnatal day 1 (PND 1) to PND 13. To expose the pups to 2,3,7,8-tetrachlorodibenzo- p -dioxin (TCDD) via lactation, the dams were administered TCDD at an oral dose of 20 μg/kg on PND 1. The pups’ urine and kidneys were collected on PND 14 for urinalysis and histological examination, respectively. We found that the incidence of hydronephrosis was 80% in the EP1 +/+ group, but was markedly reduced to 28.6% in the EP1 –/– group despite the fact that PGE 2 concentration in the urine was similarly increased in the both groups. In contrast, the incidence of hydronephrosis was 80% and 100% in the EP2 +/+ and EP2 –/– groups, respectively, and 88.9% and 100% in the EP3 +/+ and EP3 –/– groups, respectively. With regard to EP4, the incidence of hydronephrosis in vehicle (saline)-treated groups and ONO-treated was 88.9% and 100%, respectively. Therefore, we concluded that among PGE 2 receptor subtypes, EP1 plays a predominant role in the onset of TCDD-induced neonatal hydronephrosis in mouse pups.