Pyrethroid Insecticide Cypermethrin Accelerates Pubertal Onset in Male Mice via Disrupting Hypothalamic-Pituitary-Gonadal Axis
Pyrethroid Insecticide Cypermethrin Accelerates Pubertal Onset in Male Mice via Disrupting Hypothalamic-Pituitary-Gonadal Axis
复制标题
拟除虫菊酯杀虫剂氯氰菊酯通过破坏下丘脑-垂体-性腺轴加速雄性小鼠青春期的开始
DOI：
10.1021/acs.est.7b02739
复制
发表时间：
2017
影响因子：
11.4
通讯作者：
Liu Jing
中科院分区：
文献类型：
--
作者：
Ye Xiaoqing;Li Feixue;Zhang Jianyun;Ma Huihui;Ji Dapeng;Huang Xin;Curry Thomas E. Jr.;Liu Weiping;Liu Jing
拟除虫菊酯是一类在世界范围内广泛使用的杀虫剂，已被确定为内分泌干扰物(EDCs)。我们最近的流行病学研究报告了在中国男孩中，拟除虫菊酯类农药暴露增加与促性腺激素水平升高和青春期发育较早之间的关系。在这项研究中，我们进一步研究了最普遍的拟除虫菊酯杀虫剂之一的氯氰菊酯(CP)对雄性动物模型下丘脑-垂体-性腺(HPG)轴和青春期开始的影响。出生后早期暴露于环境相关剂量的CP(0.5、5和50μg/kg CP)显著加快了雄性小鼠的青春期开始年龄。给予CP可使雄性小鼠血清黄体生成素(LH)、卵泡刺激素(FSH)和睾酮水平呈剂量依赖性升高。CP对下丘脑促性腺激素释放激素(GnRH)基因表达无明显影响，但高浓度CP可刺激GnRH脉冲频率。CP可诱导促性腺激素分泌及促性腺激素亚单位基因[绒毛膜促性腺激素α(CGα)、促黄体生成素β、促性腺激素β]的表达。CP刺激睾丸间质细胞睾酮生成和类固醇生成相关基因[类固醇合成急性调节基因(STAR)和细胞色素p450，家族11，A亚家族，多肽1(Cyp11a1)]的表达。CP诱导的HPG轴成熟与下丘脑钠通道、垂体促性腺激素和睾丸间质细胞钙通道的干扰有关。我们在动物模型中建立的发现进一步证明了拟除虫菊酯暴露的生物学合理性，它可能是导致男性青春期提前的潜在环境因素。
Pyrethroids, a class of insecticides that are widely used worldwide, have been identified as endocrine-disrupting chemicals (EDCs). Our recent epidemiological study reported on an association of increased pyrethroids exposure with elevated gonadotropins levels and earlier pubertal development in Chinese boys. In this study, we further investigated the effects of cypermethrin (CP), one of the most ubiquitous pyrethroid insecticides, on hypothalamic–pituitary–gonadal (HPG) axis and pubertal onset in male animal models. Early postnatal exposure to CP at environmentally relevant doses (0.5, 5, and 50 μg/kg CP) significantly accelerated the age of puberty onset in male mice. Administration of CP induced a dose-dependent increase in serum levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH) and testosterone in male mice. CP did not affect gonadotropin-releasing hormone (GnRH) gene expression in the hypothalamus, but CP at higher concentrations stimulated GnRH pulse frequency. CP could induce the secretion of LH and FSH, as well as the expression of gonadotropin subunit genes [chorionic gonadotropin α (CGα), LHβ, and FSHβ] in pituitary gonadotropes. CP stimulated testosterone production and the expression of steroidogenesis-related genes [steroidogenic acute regulatory (StAR) and Cytochrome p 450, family 11, subfamily A, polypeptide 1 (CYP11A1)] in testicular Leydig cells. The interference with hypothalamic sodium channels as well as calcium channels in pituitary gonadotropes and testicular Leydig cells was responsible for CP-induced HPG axis maturation. Our findings established in animal models provide further evidence for the biological plausibility of pyrethroid exposure as a potentially environmental contributor to earlier puberty in males.