title: Critical role of cyclooxygenase-2 activation in pathogenesis of hydronephrosis caused by lactational exposure of mice to dioxin.
abstract: Congenital hydronephrosis is a serious disease occurring among infants and children. Besides the intrinsic genetic factors, in utero exposure to a xenobiotic, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), has been suggested to induce hydronephrosis in rodents owing to anatomical obstruction in the ureter. Here, we report that hydronephrosis induced in mouse pups exposed lactationally to TCDD is not associated with anatomical obstruction, but with abnormal alterations in the subepithelial mesenchyma of the ureter. In the kidneys of these pups, the expressions of a battery of inflammatory cytokines including monocyte chemoattractant protein (MCP)-1, tumor necrosis factor alpha (TNFalpha) and interleukin (IL)-1beta were up-regulated as early as postnatal day (PND) 7. The amounts of cyclooxygenase (COX)-2 mRNA and protein as well as prostaglandin E2 (PGE(2)) were conspicuously up-regulated in an arylhydrocarbon-receptor-dependent manner in the TCDD-induced hydronephrotic kidney, with a subsequent down-regulation of the gene expressions of Na+ and K+ transporters, NKCC2 and ROMK. Daily administration of a COX-2 selective inhibitor to newborns until PND 7 completely abrogated the TCDD-induced PGE(2) synthesis and gene expressions of inflammatory cytokines and electrolyte transporters, and eventually prevented the onset of hydronephrosis. These findings suggest an essential role of COX-2 in mediating the TCDD action of inducing hydronephrosis through the functional impairment rather than the anatomical blockade of the ureter.
authors.affiliation: Research Center for Environmental Risk, National Institute for Environmental Studies, Tsukuba 305-8506, Japan. nishimura.noriko@nies.go.jp
authors.forename: Noriko
authors.initials: N
authors.lastname: Nishimura
authors.forename: Fumio
authors.initials: F
authors.lastname: Matsumura
authors.forename: Christopher F A
authors.initials: CF
authors.lastname: Vogel
authors.forename: Hisao
authors.initials: H
authors.lastname: Nishimura
authors.forename: Junzo
authors.initials: J
authors.lastname: Yonemoto
authors.forename: Wataru
authors.initials: W
authors.lastname: Yoshioka
authors.forename: Chiharu
authors.initials: C
authors.lastname: Tohyama
mesh_terms: D000818:Animals; D000833:Animals, Suckling / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism* / Q000502:physiology; D004147:Dioxins / Q000633:toxicity; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D005260:Female; D006869:Hydronephrosis / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology; D007774:Lactation / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D018811:Maternal Exposure / Q000009:adverse effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D011247:Pregnancy
chemical_list: D004147:Dioxins; D000072317:Polychlorinated Dibenzodioxins; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2