Ichimura Ryohei, Takahashi Miwa, Morikawa Tomomi, Inoue Kaoru, Maeda Jun, Usuda Kento, Yokosuka Makoto, Watanabe Gen, Yoshida Midori
Division of Pathology, National Institute of Health Science, 1-18-1 Kamiyoga, Setagaya, Tokyo 158-8501, Japan; Laboratory of Veterinary Physiology, Department of Veterinary Medicine, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo 183-8509, Japan; Development Research, Pharmaceutical Research Center, Mochida Pharmaceutical Co., Ltd., 722 Jimba-aza-Uenohara, Gotemba, Shizuoka 412-8524, Japan.
Division of Pathology, National Institute of Health Science, 1-18-1 Kamiyoga, Setagaya, Tokyo 158-8501, Japan.
Reprod Toxicol. 2015 Jan;51:145-56. doi: 10.1016/j.reprotox.2015.01.004. Epub 2015 Jan 20.
Neonatal exposure to 17alpha-ethynylestradiol (EE) causes delayed effect, a late-occurring irreversible damage to reproductive functions characterized by the early onset of age-matched abnormal estrous cycling. To clarify the involvement of a hypothalamic key cycling regulator KiSS1/GPR54 in the delayed effect, we investigated artificially induced LH surges and KiSS1 mRNA expression in the anteroventral periventricular nucleus (AVPV) of cycling young adult rats neonatally exposed to EE, and compared these parameters to those in about 5 months old middle-aged rats. KiSS1 mRNA expression, the number of KiSS1-positive cells and KiSS1/ERα co-expressing cells in the AVPV decreased in both EE-exposed and middle-aged rats. The peak area and levels of LH surge dose-dependently decreased in EE-exposed rats, and reduction was more evident in middle-aged rats. These results indicate that the prior attenuation of KiSS1 and consequent depression of LH surges plays a key role in the onset of abnormal estrous cycling in the delayed effect.
新生大鼠暴露于17α-乙炔雌二醇（EE）会产生延迟效应，即对生殖功能造成后期出现的不可逆损害，其特征为与年龄匹配的异常发情周期提前开始。为了阐明下丘脑关键周期调节因子KiSS1/GPR54在延迟效应中的作用，我们研究了新生期暴露于EE的成年发情期年轻大鼠前腹侧室周核（AVPV）中人工诱导的促黄体生成素（LH）峰及KiSS1 mRNA表达，并将这些参数与约5月龄中年大鼠的参数进行比较。在暴露于EE的大鼠和中年大鼠中，AVPV中KiSS1 mRNA表达、KiSS1阳性细胞数量以及KiSS1/雌激素受体α（ERα）共表达细胞数量均减少。在暴露于EE的大鼠中，LH峰的峰值面积和水平呈剂量依赖性降低，且在中年大鼠中降低更为明显。这些结果表明，KiSS1的预先衰减以及随之而来的LH峰抑制在延迟效应中异常发情周期的发生中起关键作用。
