Department of Biological Sciences, University of Calgary, 2500 University Drive NW, Calgary, Alberta, T2N 1N4, Canada.
Department of Biological Sciences, University of Calgary, 2500 University Drive NW, Calgary, Alberta, T2N 1N4, Canada.
Environ Pollut. 2021 Apr 1;274:116535. doi: 10.1016/j.envpol.2021.116535. Epub 2021 Jan 20.
Ubiquitous use of antidepressants has resulted in increased concentrations of these pharmaceuticals in waterways receiving municipal wastewater effluent. Amongst these, venlafaxine, a selective serotonin and norepinephrine reuptake inhibitor, is commonly found at concentrations surpassing 1 ppb in surface waters. We recently showed that the deposition of venlafaxine in zebrafish (Danio rerio) embryos impacts neural development in the hypothalamus, suggesting the possibility of neuroendocrine disruptions due to this antidepressant. Here, we tested the hypothesis that early developmental exposure to venlafaxine disrupts the long-term functioning of the hypothalamus-pituitary-interrenal (HPI) axis in zebrafish. Embryos (1-4 cell stage) were injected with either 0, 1, or 10 ng venlafaxine, and the ontogeny of cortisol content, as well as changes in cortisol levels following a stressor in larvae and adults were assessed across 3 generations. Zygotic venlafaxine exposure did not affect the ontogeny of cortisol production, but there was a disruption in the cortisol response to stressor exposure, which was also evident in multiple generations. In the F generation, venlafaxine exposure did not affect cortisol levels in response to stressor exposure in larvae, but adult females, and not males, showed an attenuated cortisol response compared to control fish. This reduction in cortisol levels in the females was rescued by stimulation with adrenocorticotropic hormone, suggesting that the disruption was at the level of the hypothalamus-pituitary axis. Venlafaxine-mediated disruption in HPI axis functioning was also evident in the F and F generations, including impaired cortisol responses to a stressor in adult female and larval fish, respectively. Taken together, our results suggest that venlafaxine is an endocrine disruptor, and early developmental exposure to this antidepressant may have long-term and generational consequences on cortisol stress axis activity in zebrafish.
无处不在的抗抑郁药使用导致这些药物在接收城市废水的水道中的浓度增加。其中，文拉法辛，一种选择性 5-羟色胺和去甲肾上腺素再摄取抑制剂，通常在地表水中的浓度超过 1 皮克/分升。我们最近表明，文拉法辛在斑马鱼（Danio rerio）胚胎中的沉积会影响下丘脑的神经发育，这表明这种抗抑郁药可能会引起神经内分泌紊乱。在这里，我们测试了这样一个假设，即早期发育暴露于文拉法辛会破坏斑马鱼下丘脑-垂体-肾上腺（HPI）轴的长期功能。胚胎（1-4 细胞期）分别注射 0、1 或 10ng 文拉法辛，并在 3 个世代中评估皮质醇含量的个体发生以及幼虫和成年鱼中应激后皮质醇水平的变化。合子文拉法辛暴露不会影响皮质醇产生的个体发生，但皮质醇对应激暴露的反应受到干扰，这在多个世代中也很明显。在 F 代中，文拉法辛暴露不会影响幼虫应激时皮质醇水平，但成年雌性鱼而不是雄性鱼与对照鱼相比，皮质醇反应减弱。这种雌性鱼皮质醇水平的降低可以通过促肾上腺皮质激素刺激得到挽救，这表明这种干扰发生在下丘脑-垂体轴的水平。F 和 F 代中的 HPI 轴功能障碍也明显受到文拉法辛的影响，包括成年雌性鱼和幼鱼对应激的皮质醇反应受损。总之，我们的结果表明文拉法辛是一种内分泌干扰物，早期发育暴露于这种抗抑郁药可能会对斑马鱼皮质醇应激轴活性产生长期和代际影响。
