Department of Oncology and Diagnostic Sciences, University of Maryland Dental School Baltimore, MD, USA ; Marlene and Stuart Greenebaum Cancer Center, University of Maryland Baltimore, MD, USA.
Front Cell Neurosci. 2013 May 9;7:69. doi: 10.3389/fncel.2013.00069. eCollection 2013.
Anabolic-androgenic steroids (AAS) are lipophilic hormones often taken in excessive quantities by athletes and bodybuilders to enhance performance and increase muscle mass. AAS exert well known toxic effects on specific cell and tissue types and organ systems. The attention that androgen abuse has received lately should be used as an opportunity to educate both athletes and the general population regarding their adverse effects. Among numerous commercially available steroid hormones, very few have been specifically tested for direct neurotoxicity. We evaluated the effects of supraphysiological doses of methandienone and 17-α-methyltestosterone on sympathetic-like neuron cells. Vitality and apoptotic effects were analyzed, and immunofluorescence staining and western blot performed. In this study, we demonstrate that exposure of supraphysiological doses of methandienone and 17-α-methyltestosterone are toxic to the neuron-like differentiated pheochromocytoma cell line PC12, as confirmed by toxicity on neurite networks responding to nerve growth factor and the modulation of the survival and apoptosis-related proteins ERK, caspase-3, poly (ADP-ribose) polymerase and heat-shock protein 90. We observe, in contrast to some previous reports but in accordance with others, expression of the androgen receptor (AR) in neuron-like cells, which when inhibited mitigated the toxic effects of AAS tested, suggesting that the AR could be binding these steroid hormones to induce genomic effects. We also note elevated transcription of neuritin in treated cells, a neurotropic factor likely expressed in an attempt to resist neurotoxicity. Taken together, these results demonstrate that supraphysiological exposure to the AAS methandienone and 17-α-methyltestosterone exert neurotoxic effects by an increase in the activity of the intrinsic apoptotic pathway and alterations in neurite networks.
合成代谢雄激素类固醇（AAS）是脂溶性激素，常被运动员和健美运动员大量服用，以提高运动表现和增加肌肉质量。AAS 对特定的细胞和组织类型以及器官系统产生众所周知的毒性作用。最近对雄激素滥用的关注应该被用来作为一个机会，向运动员和普通民众宣传其不良影响。在众多市售的类固醇激素中，只有极少数经过了直接神经毒性的专门测试。我们评估了超生理剂量的美雄酮和 17-α-甲基睾丸酮对交感神经元样细胞的影响。分析了活力和凋亡效应，并进行了免疫荧光染色和 Western blot。在这项研究中，我们证明了超生理剂量的美雄酮和 17-α-甲基睾丸酮暴露对神经元样分化的嗜铬细胞瘤 PC12 细胞系有毒性，这一点可以通过对神经生长因子反应的神经突网络的毒性和对生存和凋亡相关蛋白 ERK、caspase-3、多聚（ADP-核糖）聚合酶和热休克蛋白 90 的调节来证实。我们观察到，与一些先前的报告相反，但与其他报告一致，神经元样细胞中存在雄激素受体（AR）的表达，当抑制 AR 时，减轻了测试的 AAS 的毒性作用，这表明 AR 可能与这些类固醇激素结合，诱导基因组效应。我们还注意到，在处理过的细胞中，神经滋养素的转录水平升高，这是一种神经营养因子，可能是为了抵抗神经毒性而表达的。总之，这些结果表明，超生理暴露于 AAS 美雄酮和 17-α-甲基睾丸酮通过增加内在凋亡途径的活性和改变神经突网络来发挥神经毒性作用。
