Critical role of microsomal prostaglandin E synthase-1 in the hydronephrosis caused by lactational exposure to dioxin in mice
Critical role of microsomal prostaglandin E synthase-1 in the hydronephrosis caused by lactational exposure to dioxin in mice
复制标题
微粒体前列腺素E合酶1在小鼠哺乳期接触二恶英引起的肾积水中的关键作用
DOI：
10.1093/toxsci/kfs115
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发表时间：
2012
期刊：
影响因子：
--
通讯作者：
Tohyama C
中科院分区：
文献类型：
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作者：
Yoshioka W;Aida-Yasuoka K;Fujisawa N;Kawaguchi T;Ohsako S;Hara S;Uematsu S;Akira S;Tohyama C
通过哺乳暴露于2，3，7，8-四氯二苯并对二恶英（TCDD）的新生小鼠肾脏诱导的肾积水是TCDD致畸性的敏感且特征性的标志。我们以前发现，环氧化酶-2（考克斯-2）的活性诱导的哺乳期TCDD暴露的小鼠新生儿肾脏所需的这种毒性。考克斯-2是环氧合酶的诱导型，负责产生前列腺素（PGs）和血栓素。PGE 2是一种前列腺素，在接触TCDD的小鼠幼崽中升高。在这项研究中，我们研究了微粒体前列腺素E合酶-1（mPGES-1），一种可诱导形式的PGE 2合酶，在TCDD诱导的肾积水中的作用。母鼠给予10 μg TCDD/kg剂量可增加mPGES-1野生型幼鼠的mPGES-1信使RNA丰度、尿PGE 2水平和肾积水发生率。在纯合子mPGES-1基因敲除（KO）小鼠，相反，TCDD诱导的肾积水被抑制，证明了mPGES-1在反应中的重要作用。PGES-1基因的缺失也抑制了TCDD暴露幼鼠尿PGE 2水平接近基础水平。总之，哺乳期TCDD暴露后mPGES-1上调是TCDD诱导的小鼠新生儿肾积水的一个致病因素。
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. PGE2, 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 PGE2synthase, in TCDD-induced hydronephrosis. A dose of 10 μg TCDD/kg to dams increased mPGES-1 messenger RNA abundance, urinary PGE2levels, 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 themPGES-1gene also suppressed urinary PGE2level 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.