Neurobiology Research Unit, University Hospital Rigshospitalet, Building 9201, Juliane Maries Vej 24, 2100 Copenhagen, Denmark.
Neurotoxicology. 2013 Jul;37:154-62. doi: 10.1016/j.neuro.2013.04.012. Epub 2013 May 6.
Early life exposure to endocrine disruptors is considered to disturb normal development of hormone sensitive parameters and contribute to advanced puberty and reduced fecundity in humans. Kisspeptin is a positive regulator of the hypothalamic-pituitary-gonadal axis, and plays a key role in the initiation of puberty. In the adult, Kiss1 gene expression occurs in two hypothalamic nuclei, namely the anteroventral periventricular nucleus (AVPV) and the arcuate nucleus (ARC), which are differentially regulated by peripheral sex steroid hormones. In this study we determined the effects on puberty onset and Kiss1 mRNA levels in each of the two nuclei after long-term perinatal exposure of rats to ethinyl oestradiol (EE2) or to five different pesticides, individually and in a mixture. Rat dams were per orally administered with three doses of EE2 (5, 15 or 50 μg/kg/day) or with the pesticides epoxiconazole, mancozeb, prochloraz, tebuconazole, and procymidone, alone or in a mixture of the five pesticides at three different doses. Kiss1 mRNA expression was determined in the AVPV and in the ARC of the adult male and female pups in the EE2 experiment, and in the adult female pups in the pesticide experiment. We find that perinatal EE2 exposure did not affect Kiss1 mRNA expression in this study designed to model human exposure to estrogenic compounds, and we find only minor effects on puberty onset. Further, the Kiss1 system does not exhibit persistent changes and puberty onset is not affected after perinatal exposure to a pesticide mixture in this experimental setting. However, we find that the pesticide mancozeb tends to increase Kiss1 expression in the ARC, presumably through neurotoxic mechanisms rather than via classical endocrine disruption, calling for increased awareness that Kiss1 expression can be affected by environmental pollutants through multiple mechanisms.
早期生活中接触内分泌干扰物被认为会干扰激素敏感参数的正常发育，并导致人类青春期提前和生育能力下降。Kisspeptin 是下丘脑-垂体-性腺轴的正调节剂，在青春期启动中发挥关键作用。在成年期，Kiss1 基因表达发生在两个下丘脑核中，即前腹侧室旁核（AVPV）和弓状核（ARC），它们受外周性激素的差异调节。在这项研究中，我们确定了长期围产期暴露于雌二醇（EE2）或单独或混合的五种不同农药后，对青春期起始和两个核中的 Kiss1 mRNA 水平的影响。大鼠母鼠经口给予三种剂量的 EE2（5、15 或 50μg/kg/天）或单独或混合五种农药（环氧氯丙烷、代森锰锌、百菌清、戊唑醇和丙环唑），三种不同剂量。在 EE2 实验中，测定了成年雄性和雌性幼鼠 AVPV 和 ARC 中的 Kiss1 mRNA 表达，在农药实验中，测定了成年雌性幼鼠中的 Kiss1 mRNA 表达。我们发现，在设计用于模拟人类暴露于雌激素化合物的本研究中，围产期 EE2 暴露并未影响 Kiss1 mRNA 表达，并且对青春期起始的影响很小。此外，在这种实验环境中，围产期接触农药混合物不会导致 Kiss1 系统出现持续变化和青春期起始受到影响。然而，我们发现农药代森锰锌倾向于增加 ARC 中的 Kiss1 表达，推测这是通过神经毒性机制而不是通过经典的内分泌干扰，这呼吁提高认识，即 Kiss1 表达可能会受到环境污染物的影响通过多种机制。
