Kim Hannah, Nakajima Tadaaki, Hayashi Shinji, Chambon Pierre, Watanabe Hajime, Iguchi Taisen, Sato Tomomi
International Graduate School of Arts and Sciences, Yokohama City University, Yokohama, Japan.
Biol Reprod. 2009 Nov;81(5):1002-9. doi: 10.1095/biolreprod.108.070599. Epub 2009 Jun 24.
In mice, neonatal exposure to a synthetic estrogen, diethylstilbestrol (DES), induces polyovular follicles, which contain two or more oocytes per ovarian follicle. We reported previously that the estrogen receptor beta (ESR2) mediates DES signaling in polyovular follicle induction. However, the specific mechanism of polyovular follicle induction has not yet been clarified. Folliculogenesis in rodents begins soon after birth, accompanied by programmed oocyte death and germ cell loss. In this study, the effects of DES on oocyte death and on mRNA expression of genes thought to be involved in polyovular follicle induction were analyzed during a crucial period of folliculogenesis in the ovary of C57BL/6J, Fas(lpr/lpr) (lacking cell death receptor, FAS), and Esr2 knockout (Esr2 KO) mice. Neonatal DES exposure reduced programmed oocyte death in C57BL/6J mice; however, this reduction was not observed in Esr2 KO mice. In control Fas(lpr/lpr) mice, the oocyte apoptotic index was significantly lower than that in the control C57BL/6J mice. However, the polyovular follicle incidence in control 20-day-old Fas(lpr/lpr) mice was similar to that in the control C57BL/6J mice. Moreover, DES exposure changed mRNA expression of inhibin-alpha (Inha) in 2-day-old C57BL/6J mice. These results suggest that inhibition of oocyte death by DES through ESR2 may be one of the triggers for polyovular follicle induction. The FAS system is also involved in neonatal oocyte death; however, reduction of oocyte death is not sufficient for polyovular follicle induction. The combination of increased Inha mRNA and reduction of oocyte death in the ovaries of mice by DES through ESR2 might be correlated with polyovular follicle induction.
在小鼠中，新生期暴露于合成雌激素己烯雌酚（DES）会诱导多卵卵泡的形成，每个卵巢卵泡中含有两个或更多个卵母细胞。我们之前报道过，雌激素受体β（ESR2）介导DES在多卵卵泡诱导中的信号传导。然而，多卵卵泡诱导的具体机制尚未阐明。啮齿动物的卵泡发生在出生后不久就开始了，伴随着程序性卵母细胞死亡和生殖细胞丢失。在本研究中，分析了DES对C57BL/6J、Fas(lpr/lpr)（缺乏细胞死亡受体FAS）和Esr2基因敲除（Esr2 KO）小鼠卵巢卵泡发生关键期卵母细胞死亡以及被认为参与多卵卵泡诱导的基因mRNA表达的影响。新生期暴露于DES可减少C57BL/6J小鼠的程序性卵母细胞死亡；然而，在Esr2 KO小鼠中未观察到这种减少。在对照Fas(lpr/lpr)小鼠中，卵母细胞凋亡指数显著低于对照C57BL/6J小鼠。然而，20日龄对照Fas(lpr/lpr)小鼠的多卵卵泡发生率与对照C57BL/6J小鼠相似。此外，DES暴露改变了2日龄C57BL/6J小鼠中抑制素α（Inha）的mRNA表达。这些结果表明，DES通过ESR2抑制卵母细胞死亡可能是多卵卵泡诱导的触发因素之一。FAS系统也参与新生期卵母细胞死亡；然而，卵母细胞死亡的减少不足以诱导多卵卵泡的形成。DES通过ESR2使小鼠卵巢中Inha mRNA增加和卵母细胞死亡减少的组合可能与多卵卵泡诱导相关。
