Identifying a Novel Role for X-prolyl Aminopeptidase (Xpnpep) 2 in CrVI-Induced Adverse Effects on Germ Cell Nest Breakdown and Follicle Development in Rats
Identifying a Novel Role for X-prolyl Aminopeptidase (Xpnpep) 2 in CrVI-Induced Adverse Effects on Germ Cell Nest Breakdown and Follicle Development in Rats
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DOI：
10.1095/biolreprod.114.125708
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发表时间：
2015-03-01
影响因子：
3.6
通讯作者：
Burghardt, Robert C.
中科院分区：
文献类型：
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作者：
Banu, Sakhila K.;Stanley, Jone A.;Burghardt, Robert C.
环境暴露于内分泌干扰物（EDCs）是卵巢早衰（POF）的原因之一。六价铬（CrVI）是一种重金属EDC，广泛应用于50多个行业，包括Chrome、焊接、木材加工和制革。美国环境保护署最近的数据表明，美国几个城市的饮用水中铬含量增加，这可能使居民容易出现各种健康问题。最近，我们证明，妊娠期暴露于六价铬导致POF的F1后代。本研究旨在确定CrVI诱导POF的分子机制。从妊娠日（GD）9.5至GD 14.5，通过饮用水对妊娠大鼠给予25 ppm重铬酸钾，并通过经胎盘转移使胎儿暴露于CrVI。在胚胎日（艾德）15.5、艾德17.5、出生后第1天（PND）、PND 4或PND 25从胎仔或幼仔中取出卵巢，并进行各种分析。结果显示，妊娠期暴露于CrVI：1）生殖细胞/卵母细胞凋亡和晚期生殖细胞巢（GCN）分解增加; 2）在GCN分解期间，人类POF标志物X-脯氨酰氨基肽酶（Xpnpep）2增加; 3）出生后卵泡发育期间Xpnpe 2减少; 4）Xpnpe 2与Col 3和Col 4的共定位增加。我们还发现，Xpnpep 2负调控的表达Col 1，Col 3和Col 4在所有的发展阶段的研究。因此，CrVI通过靶向Xpnpep 2推进GCN分解并增加F1雌性后代中的卵泡闭锁。
Environmental exposure to endocrine-disrupting chemicals (EDCs) is one cause of premature ovarian failure (POF). Hexavalent chromium (CrVI) is a heavy metal EDC widely used in more than 50 industries, including chrome plating, welding, wood processing, and tanneries. Recent data from U.S. Environmental Protection Agency indicate increased levels of Cr in drinking water from several American cities, which potentially predispose residents to various health problems. Recently, we demonstrated that gestational exposure to CrVI caused POF in F1 offspring. The current study was performed to identify the molecular mechanism behind CrVI-induced POF. Pregnant rats were treated with 25 ppm of potassium dichromate from Gestational Day (GD) 9.5 to GD 14.5 through drinking water, and the fetuses were exposed to CrVI through transplacental transfer. Ovaries were removed from the fetuses or pups on Embryonic Day (ED) 15.5, ED 17.5, Postnatal Day (PND) 1, PND 4, or PND 25, and various analyses were performed. Results showed that gestational exposure to CrVI: 1) increased germ cell/oocyte apoptosis and advanced germ cell nest (GCN) breakdown; 2) increased X-prolyl aminopeptidase (Xpnpep) 2, a POF marker in humans, during GCN breakdown; 3) decreased Xpnpep2 during postnatal follicle development; and 4) increased colocalization of Xpnpep2 with Col3 and Col4. We also found that Xpnpep2 inversely regulated the expression of Col1, Col3, and Col4 in all the developmental stages studied. Thus, CrVI advanced GCN breakdown and increased follicle atresia in F1 female progeny by targeting Xpnpep2.