University of Massachusetts Amherst, Department of Psychological & Brain Sciences, Amherst, MA 01003, USA; Neuroscience and Behavior Graduate Program, University of Massachusetts, Amherst, MA 01003, USA.
University of Massachusetts Amherst, Department of Psychological & Brain Sciences, Amherst, MA 01003, USA.
Horm Behav. 2023 Jan;147:105281. doi: 10.1016/j.yhbeh.2022.105281. Epub 2022 Nov 23.
Aromatase inhibitors (AIs) are a class of drugs commonly given to patients with estrogen receptor (ER)-dependent breast cancers to reduce estrogenic stimulation. However, AIs like Letrozole are associated with negative side effects such as cognitive deficits, sleep disturbances and hot flashes. We have previously shown that these negative effects can be recapitulated in common marmosets (Callithrix jacchus) treated with Letrozole (20 μg daily) for 4 weeks and that marmosets treated with Letrozole show increased levels of estradiol in the hippocampus (Gervais et al., 2019). In order to better understand the mechanisms through which AIs affect cognitive function and increase steroid levels in the hippocampus, we used bulk, paired-end RNA-sequencing to examine differentially expressed genes among Letrozole-treated (LET; n = 8) and vehicle-treated (VEH; n = 8) male and female animals. Gene ontology results show significant reduction across hundreds of categories, some of the most significant being inflammatory response, stress response, MHC Class II protein complex binding, T-cell activation, carbohydrate binding and signaling receptor binding in LET animals. GSEA results indicate that LET females, but not LET males, show enrichment for hormonal gene sets. Based on the transcriptional changes observed, we conclude that AIs may differentially affect the sexes in part due to processes mediated by the CYP-450 superfamily. Ongoing studies will further investigate the longitudinal effects of AIs on behavior and whether AIs increase the risk of stress-induced neurodegeneration.
芳香酶抑制剂（AIs）是一类常用于治疗雌激素受体（ER）依赖性乳腺癌患者的药物，以减少雌激素刺激。然而，像来曲唑（Letrozole）这样的 AI 与认知缺陷、睡眠障碍和热潮红等负面副作用相关。我们之前已经表明，这些负面影响可以在接受来曲唑（20μg/天）治疗 4 周的普通狨猴（Callithrix jacchus）中重现，并且来曲唑治疗的狨猴海马体中的雌二醇水平升高（Gervais 等人，2019）。为了更好地理解 AI 影响认知功能和增加海马体中类固醇水平的机制，我们使用 bulk、配对末端 RNA-seq 来检查接受来曲唑治疗（LET；n=8）和接受载体治疗（VEH；n=8）的雄性和雌性动物之间差异表达的基因。GO 结果显示数百个类别显著减少，其中一些最重要的类别是炎症反应、应激反应、MHC II 类蛋白复合物结合、T 细胞激活、碳水化合物结合和信号受体结合。GSEA 结果表明 LET 雌性动物而非 LET 雄性动物显示激素基因集富集。基于观察到的转录变化，我们得出结论，AI 可能会因 CYP-450 超家族介导的过程而在一定程度上对性别产生不同的影响。正在进行的研究将进一步调查 AI 对行为的长期影响，以及 AI 是否会增加应激诱导的神经退行性变的风险。
