Di-n-Butyl Phthalate Disrupts the Expression of Genes Involved in Cell Cycle and Apoptotic Pathways in Mouse Ovarian Antral Follicles
Di-n-Butyl Phthalate Disrupts the Expression of Genes Involved in Cell Cycle and Apoptotic Pathways in Mouse Ovarian Antral Follicles
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DOI：
10.1095/biolreprod.112.105122
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发表时间：
2013-01-01
影响因子：
3.6
通讯作者：
Flaws, Jodi A.
中科院分区：
文献类型：
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作者：
Craig, Zelieann R.;Hannon, Patrick R.;Flaws, Jodi A.
邻苯二甲酸二丁酯（DBP）存在于许多消费品中，如婴儿、美容和医疗产品。一些研究表明，DBP对啮齿动物有生殖毒性，但没有研究评估其对卵巢卵泡的影响。因此，我们使用卵泡培养系统来评估DBP对窦卵泡生长、细胞周期和凋亡基因表达、细胞周期分期、闭锁和17 β -雌二醇（E-2）产生的影响。从成年CD-1小鼠中分离出窦卵泡，并将其暴露于1,10,100和1000 μ g/ml DBP中24或168小时。随着时间的推移，载药或1-100 μ g/ml DBP处理的卵泡会生长，但1000 μ g/ml DBP会显著抑制卵泡的生长。不考虑对卵泡生长的影响，dbp处理的卵泡中细胞周期蛋白D2、E1、A2和B1的mRNA表达减少，p21表达增加。DBP对促凋亡基因Bax、Bad和Bok的表达没有影响，但DBP 1000 μ g/ml使Bid水平升高，使抗凋亡基因Bcl2水平降低。dbp处理的卵泡在G(1)期细胞数量明显增加，S期细胞数量明显减少，并呈现G期细胞数量减少的趋势(2)。虽然舒张压在24小时内不影响E-2的产生和闭锁，但舒张压在96小时后降低了E-2水平，并在168小时后发生闭锁。这些数据表明，舒张压作用于胃窦卵泡，改变细胞周期和凋亡因子的表达，导致细胞周期停滞，降低E-2，并引发闭锁，这取决于剂量。
Di-n-butyl phthalate (DBP) is present in many consumer products, such as infant, beauty, and medical products. Several studies have shown that DBP causes reproductive toxicity in rodents, but no studies have evaluated its effects on ovarian follicles. Therefore, we used a follicle culture system to evaluate the effects of DBP on antral follicle growth, cell cycle and apoptosis gene expression, cell cycle staging, atresia, and 17 beta-estradiol (E-2) production. Antral follicles were isolated from adult CD-1 mice and exposed to DBP at 1, 10, 100, and 1000 mu g/ml for 24 or 168 h. Follicles treated with vehicle or DBP at 1-100 mu g/ml grew over time, but DBP at 1000 mu g/ml significantly suppressed follicle growth. Regardless of effect on follicle growth, DBP-treated follicles had decreased mRNA for cyclins D2, E1, A2, and B1 and increased p21. Levels of the proapoptotic genes Bax, Bad, and Bok were not altered by DBP treatment, but DBP 1000 mu g/ml increased levels of Bid and decreased levels of the antiapoptotic gene Bcl2. DBP-treated follicles contained significantly more cells in G(1) phase, significantly less cells in S, and exhibited a trend for fewer cells in G(2). Although DBP did not affect E-2 production and atresia at 24 h, follicles treated with DBP had reduced levels of E-2 at 96 h and underwent atresia at 168 h. These data suggest that DBP targets antral follicles and alters the expression of cell cycle and apoptosis factors, causes cell cycle arrest, decreases E-2, and triggers atresia, depending on dose.