Ichimura Ryohei, Takahashi Miwa, Morikawa Tomomi, Inoue Kaoru, Kuwata Kazunori, 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.
Neurotoxicology. 2016 Sep;56:64-75. doi: 10.1016/j.neuro.2016.07.003. Epub 2016 Jul 6.
Selective estrogen receptor modulators (SERMs) are a class of therapeutic chemicals which present tissue-specific estrogen receptor modulating activity. Neonatal exposure to SERMs has been reported to adversely affect central nervous system development, however, mechanism and involvement of hypothalamic kisspeptin neurone in this impairment remains undetermined. To clarify this uncertainty, neonates from female Donryu rats were subcutaneously injected with raloxifene (RLX) at 0.1, 1, and 10mg/kg or tamoxifen (TMX) at 10mg/kg on postnatal day 0, and then hypothalamic KiSS1 mRNA expression and gonadotropin levels were investigated during young adulthood and estrous cycling was monitored until middle age. Treatment with RLX or TMX at 10mg/kg significantly depressed luteinizing hormone surge levels and KiSS1 mRNA expression in the anteroventral periventricular nucleus (AVPV), the control center of estrous cyclicity. The 10mg/kg TMX group also showed decreased levels of follicle-stimulating hormone and KiSS1 mRNA expression in the arcuate nucleus (ARC). Early cessation of normal estrous cycling was observed in the 10mg/kg RLX group, while the estrous cycle in the 10mg/kg TMX group had ceased by the start of the analysis. The same dose of tamoxifen or raloxifene had either weak-estrogenic or anti-estrogenic activity on the uterus, respectively; however, treatment in adulthood with both SERMs did not affect KiSS1 mRNA expression in either the AVPV or ARC in the present study. These results indicate that neonatal exposure to SERMs could disrupt neuroendocrine development and postnatal reproductive function through the alteration of kisspeptin neurons.
选择性雌激素受体调节剂（SERMs）是一类具有组织特异性雌激素受体调节活性的治疗性化学物质。据报道，新生儿接触SERMs会对中枢神经系统发育产生不利影响，然而，下丘脑促性腺激素释放激素神经元在这种损伤中的机制和作用仍未确定。为了澄清这一不确定性，在出生后第0天，给雌性唐利玉大鼠的新生仔鼠皮下注射0.1、1和10mg/kg的雷洛昔芬（RLX）或10mg/kg的他莫昔芬（TMX），然后在成年早期研究下丘脑KiSS1 mRNA表达和促性腺激素水平，并监测动情周期直至中年。10mg/kg的RLX或TMX处理显著降低了促黄体生成素激增水平以及动情周期控制中心腹内侧视前核（AVPV）中的KiSS1 mRNA表达。10mg/kg的TMX组还显示弓状核（ARC）中促卵泡生成素水平和KiSS1 mRNA表达降低。在10mg/kg的RLX组中观察到正常动情周期提前停止，而在10mg/kg的TMX组中，在分析开始时动情周期就已经停止。相同剂量的他莫昔芬或雷洛昔芬分别对子宫具有弱雌激素或抗雌激素活性；然而，在本研究中，成年期用这两种SERMs处理均不影响AVPV或ARC中的KiSS1 mRNA表达。这些结果表明，新生儿接触SERMs可能通过改变促性腺激素释放激素神经元来破坏神经内分泌发育和产后生殖功能。
