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Developmental Effect of Endocrine Disruptors on Fish and Mice

内分泌干扰物对鱼和小鼠发育的影响

基本信息

批准号：
11839022
负责人：
IGUCHI Taisen
金额：
$ 2.62万
依托单位：
Okazaki National Research Institutes (2000)Yokohama City University (1999)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2000
项目状态：
已结题

项目摘要

Bisphenol-A (BPA), an estrogenic chemical, was given to pregnant mice and Japanese monkey and studied transplacental transfer. BPA was foun in fetal brain, liver and other organs in 30 min in mice and 1 h in monkey suggesting that BPA can be easily cross the placenta. BPA and a synthetic estrogen, diethylstilbestrol (DES), were given to pregnant mice and studied fertility and various abnormalities in female offspring. DES induced sterility, polyovular follicles in ovary and persistent stratification of vaginal epithelium, but not BPA.Hoxa-9 and a-10 genes in Mullerian duct were downregulated by DES in the fetal period suggesting the close correlation to uterine changes in DES-exposed mice. In order to study low dose issue of BPA, 2 and 20μg/kg body weight of BPA and 0.02-2μg/kg of DES were given to day 10 to 17 of pregnancy. In 20μg BPA-and all DES-exposed female offspring showed significantly early vaginal opening and lower body weight as compared to controls. This results suggest that there is a low dose effect of BPA, however, the mechanism underlie is still unclear. Neonatal DES treatment induced hypospadias in female mice, fusion of urethra and vaginal lumen at lower position of vagina, where apoptosis was observed. The critical period in induction of hypospadias was 7 days after birth. Neonatally BPA (150μg) treated female mice showed persistent estrus, and ovary-independent vaginal changes.In order to study estrogenic agents on development of fish, Fundulus heteroclitus embryos were exposed to estradiol. Various malformations, including sex ratio change were induced by estradiol. Estrogen receptor α and β were cloned and ER expression during development were analysed. FTZ-F1 gene was also cloned from Fundulus. In zebrafish, gonad develops to ovary by ca 20 days after hatching then a half of fish develop testis from the ovary. During testis formation, apoptosis of oocytes occurred in the ovary.

双酚A（BPA），一种雌激素化学品，给予怀孕的小鼠和日本猴，并研究了经胎盘转移。BPA在小鼠胎脑、肝脏等器官中的检出时间为30 min，在猴胎脑、肝脏等器官中的检出时间为1 h，提示BPA可轻易通过胎盘。BPA和一种合成雌激素己烯雌酚（DES）被给予怀孕的老鼠，研究雌性后代的生育能力和各种异常情况。DES可诱导小鼠不孕、卵巢多卵卵泡和阴道上皮持续分层，但对BPA无明显影响。胚胎期DES可下调苗勒管Hoxa-9和a-10基因表达，提示DES暴露小鼠子宫变化与之密切相关。为了研究BPA的低剂量问题，在妊娠第10 ~ 17天分别给予2和20μg/kg BPA和0.02 ~ 2μg/kg DES。与对照组相比，20μg BPA和所有DES暴露的雌性后代显示出明显的早期阴道开放和较低的体重。这一结果表明BPA存在低剂量效应，但其机制尚不清楚。DES处理诱导雌性小鼠尿道下裂，阴道下部尿道与阴道腔融合，可见细胞凋亡。先天性尿道下裂的诱发临界期为生后7天。为研究雌激素对鱼类胚胎发育的影响，将雌激素（150μg）处理的异基底胚胎暴露于雌二醇（E2）中，观察雌激素对鱼类胚胎发育的影响。雌激素可引起各种畸形，包括性比改变。克隆雌激素受体α和β，并分析发育过程中ER的表达。FTZ-F1基因也是从Fundulus中克隆出来的。在斑马鱼中，性腺在孵化后约20天发育成卵巢，然后一半的鱼从卵巢发育成睾丸。在睾丸形成过程中，卵巢中的卵母细胞发生凋亡。