CYCLOOXYGENASE-2 AS A CRITICAL FACTOR THAT LINK DIOXIN EXPOSURE, AHR SIGNALING AND TOCIXITY PHENOTYPE IN NEWBORN MICE
Arylhydrocarbon receptor has been known to play an essential role in producing a variety of toxicities, but the target molecule responsible for such toxicities is largely unknown. We found that lactational exposure to dioxins induced increase in cyclooxygenase 2 (COX-2) activity, suppressed Na, K and Cl ion-transporter genes and increased inflammatory cytokines, such as IL-1β, followed eventually by the onset of hydronephrosis. Since these alterations as well as hydronephrosis can be suppressed with administration of a COX-2 selective inhibitor, COX-2 was found to be an essential factor to produce hydronephrosis in newborn mouse pups. We next studied whether the induction of COX-2 is a sufficient factor to produce this disease state. To this end, we administered lithium, a COX-2-inducing chemical, to newborn mice for the first 3 weeks after delivery. Treatment of LiCl caused a significant increase in COX-2 mRNA. Urinary osmolarity of LiCl-treated neonates was significantly lower than that of control neonate. Because of a very narrow safety margin of LiCl, most of the Li-treated neonates died during the second week of age. However, a severe degree of hydronephrosis was found in the surviving mice. Taken together, we conclude that COX-2 upregulation is a sufficient factor to produce hydronephrosis.
Yoshioka W Akagi T Matsumura F Nishimura N Tohyama C
Laboratory of Environmental Health Sciences,Center for Disease Biology and Integrative Medicine,Grad Department of Environmental Toxicology and Center for Environmental Health Sciences,University of Ca Research Center for Environmental Risk,National Institute for Environmental Studies,Tsukuba 305-0043 Laboratory of Environmental Health Sciences,Center for Disease Biology and Integrative Medicine,Grad
国际会议
北京
英文
1-6
2009-08-24（万方平台首次上网日期，不代表论文的发表时间）