Critical Role of Microsomal Prostaglandin E Synthase-1 in the Hydronephrosis Caused by Lactational Exposure to Dioxin in Mice

Abstract

Hydronephrosis induced in the kidney of neonatal mice exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) via lactation is a sensitive and characteristic hallmark of TCDD teratogenicity. We previously found that cyclooxygenase-2 (COX-2) activity induced in mouse neonate kidneys by lactational TCDD exposure is required for this toxicity. COX-2 is an inducible form of cyclooxygenase and is responsible for producing prostaglandins (PGs) and thromboxane. PGE(2), a prostaglandin, is elevated in TCDD-exposed mouse pups. In this study, we investigated the role of microsomal prostaglandin E synthase-1 (mPGES-1), an inducible form of PGE(2) synthase, in TCDD-induced hydronephrosis. A dose of 10 μg TCDD/kg to dams increased mPGES-1 messenger RNA abundance, urinary PGE(2) levels, and the incidence of hydronephrosis in mPGES-1 wild-type pups. In homozygous mPGES-1 knockout (KO) mice, in contrast, TCDD-induced hydronephrosis was suppressed, demonstrating an essential role of mPGES-1 in the response. Lack of the mPGES-1 gene also suppressed urinary PGE(2) level to near the basal level in TCDD-exposed pups. In conclusion, mPGES-1 upregulation upon lactational TCDD exposure is a causal factor for TCDD-induced hydronephrosis in mouse neonates.

Predominant Role of Cytosolic Phospholipase A2α in Dioxin-induced Neonatal Hydronephrosis in Mice

“…This time point was chosen because TCDD-induced increase in urinary PGE 2 , and upregulation of enzymes responsible for the PGE 2 production, COX-2 and mPGES-1, are prominent on PND 71320. In female TCDD-exposed WT pups, COX-2 mRNA abundance, mPGES-1 mRNA abundance, and urinary PGE 2 concentration were significantly increased 5.5, 6.1, and 13.3 fold, respectively, compared with those in the control pups (Fig.…”

“…We analyzed expression of several genes the deficiency of which have been reported to induce hydronephrosis282930 and that are downregulated in the kidney of mouse pups exposed to TCDD1320. In female pups on PND 7, expression of mRNAs of electrolyte transporters, Na-K-Cl cotransporter 2 (NKCC2) and renal outer medullary K channel (ROMK), were significantly downregulated in the TCDD-exposed WT pups (46% and 32%, respectively) compared with those in the vehicle-treated WT pups (Figs.…”

“…COX-2 is an inducible form of cyclooxygenase, which converts arachidonic acid to prostaglandin H 2 (PGH 2 ). Microsomal prostaglandin E synthase-1 (mPGES-1) transforms PGH 2 to prostaglandin E 2 (PGE 2 ) and is required for TCDD-induced hydronephrosis, as demonstrated by the lack of hydronephrosis in mPGES-1-null mice20. These studies indicate that PGE 2 production, mediated by COX-2 and mPGES-1, plays a key role in the onset of TCDD-induced hydronephrosis.…”

“…Several genes in addition to that for AhR have been shown to be involved in dioxin toxicity19. Among them, genes encoding enzymes for the production of prostaglandins are responsible for the onset of TCDD-induced neonatal hydronephrosis in mice1320. AhR-dependent upregulation of COX-2 plays a critical role in the onset of hydronephrosis induced by lactational exposure to TCDD in mice.…”

Yusho and its latest findings—A review in studies conducted by the Yusho Group

“…Lactational exposure to TCDD in the neonatal period as well as exposure in utero induces tetrogenicity. TCDD via lactation induced up-regulation of cyclooxygenase (COX)-2, a rate-limiting enzyme for prostaglandin synthesis, and increased prostaglandin E2 synthesis in an AhR-dependent manner, resulted in abnormal morphology in the ureteral subepithelial mesenchyma of mice (Nishimura et al, 2008;Yoshioka et al, 2012). TCDD also induced circulation failure in zebrafish embryos, such as reduction of blood flow in the brain (Teraoka et al, 2009) or precardiac edema (Teraoka et al, 2014) through the COX-2-thromboxane pathway.…”