Department of Biomedical Sciences, Colorado State University, Fort Collins, CO, USA.
J Neuroendocrinol. 2010 Jun;22(6):518-26. doi: 10.1111/j.1365-2826.2010.01973.x. Epub 2010 Mar 2.
Developmental exposure to the agricultural fungicide vinclozolin can impair reproductive function in male rabbits and was previously found to decrease the number of immunoreactive-gonadotrophin-releasing hormone (GnRH) neurones in the region of the organum vasculosum of the lamina terminalis and rostral preoptic area by postnatal week (PNW) 6. In the present study, in an aim to further examine the disruption of GnRH neurones by foetal vinclozolin exposure, pregnant rabbits were dosed orally with vinclozolin, flutamide or carrot paste vehicle for the last 2 weeks of gestation. Offspring were euthanised at birth (males and females), PNW 6 (females), PNW 26 (adult males) or PNW 30 (adult females) of age. At birth and in adults, brains were sectioned and processed for immunoreactive GnRH. The numbers of immunoreactive GnRH neuronal perikarya were significantly decreased in vinclozolin-treated rabbits at birth and in adult littermates. By contrast, there was an increase in GnRH immunoreactivity in the terminals in the region of the median eminence. Analysis of PNW 6 female brains by radioimmunoassay revealed a two-fold increase in GnRH peptide content in the mediobasal hypothalamus in vinclozolin-treated rabbits. This finding was complemented by immunofluorescence analyses, which revealed a 2.8-fold increase in GnRH immunoreactivity in the median eminence of vinclozolin compared to vehicle-treated females at PNW 30. However, there was no difference between treatment groups in the measures of reproduction that were evaluated: ejaculation latency, conception rates or litter size. These results indicate that sub-acute, prenatal vinclozolin treatment is sufficient to create perdurable alterations in the GnRH neuronal network that forms an important input into the reproductive axis. Finally, the effect of vinclozolin on the GnRH neuronal network was not comparable to that of flutamide, suggesting that vinclozolin was not acting through anti-androgenic mechanisms.
发育暴露于农业杀真菌剂 vinclozolin 可损害雄性兔子的生殖功能，先前的研究发现，它会导致终器血管体区和视前区吻端的 GnRH 神经元数量减少，这是在出生后第 6 周（PNW）发现的。在本研究中，为了进一步研究胎儿暴露于 vinclozolin 对 GnRH 神经元的破坏作用，妊娠兔子在妊娠的最后 2 周经口给予 vinclozolin、氟他胺或胡萝卜糊剂载体处理。后代在出生时（雄性和雌性）、PNW 6（雌性）、PNW 26（成年雄性）或 PNW 30（成年雌性）时被安乐死。在出生时和成年时，对大脑进行切片并进行 GnRH 免疫反应处理。在出生时和成年同窝仔中，vinclozolin 处理的兔子的 GnRH 神经元胞体的数量显著减少。相比之下，在正中隆起区域的末端处，GnRH 免疫反应性增加。对 PNW 6 雌性大脑进行放射免疫测定分析显示，在 vinclozolin 处理的兔子的中脑基底部下丘脑 GnRH 肽含量增加了两倍。免疫荧光分析补充了这一发现，与 vehicle 处理的雌性相比，在 PNW 30 时，vinclozolin 处理的雌性在正中隆起处的 GnRH 免疫反应性增加了 2.8 倍。然而，在评估的繁殖指标方面，治疗组之间没有差异：射精潜伏期、受孕率或产仔数。这些结果表明，亚急性、产前 vinclozolin 处理足以在形成生殖轴重要输入的 GnRH 神经元网络中产生持久的改变。最后，vinclozolin 对 GnRH 神经元网络的影响与 flutamide 不同，这表明 vinclozolin 不是通过抗雄激素机制起作用的。
