Chakrabarti Shami, Wagh Chanchal, Bagnall-Moreau Ciara, Uddin Fathema, Reiser Joshua, Salas-Ramirez Kaliris, Ahles Tim, Hubbard Karen
Department of Biology, The City College of New York, New York, NY, 10031, USA.
Columbia Center of Translational Immunology, Columbia University, New York, NY, 10032, USA.
Sci Rep. 2025 Jul 1;15(1):20681. doi: 10.1038/s41598-025-07419-2.
Chemotherapy can cause several long-term side effects that can affect cancer survivors' quality of life-, notably cognitive decline in response to select chemotherapeutic agents. Studies using both human patients and animal models have been employed to determine the regions of the brain that are subject to the most considerable changes, furthermore, elucidating possible molecular mechanisms of chemotherapy-induced cognitive impairment (CICI). However, the reason behind the differences in symptoms and duration of CICI between patients have yet to be identified. This study focused on understanding whether the systemic delivery of doxorubicin and cyclophosphamide (AC chemotherapeutics) causes any epigenetic factors to change in the female rat prefrontal cortex (PFC), possibly providing an insight into the variability of clinical manifestations of CICI. We evaluated DNA methylation levels and patterns in the PFC after AC-chemotherapy administration. We also demonstrated changes in histone deacetylase and acetyl transferase activity levels in the murine PFC in response to treatment. Despite no change in the global DNA methylation level, we found that several genes related to neuronal development and maintenance were differentially methylated in the promoter and exon regions in the rat PFC. Our study showed a significant increase in the expression of the de novo DNA methyl transferase DNMT3a compared to the control.
化疗会引发多种长期副作用，这些副作用会影响癌症幸存者的生活质量，尤其是某些化疗药物会导致认知能力下降。针对人类患者和动物模型开展的研究已用于确定大脑中受影响最为显著的区域，此外，还能阐明化疗诱发认知障碍（CICI）的可能分子机制。然而，患者之间CICI症状和持续时间存在差异的原因尚未明确。本研究聚焦于了解阿霉素和环磷酰胺（AC化疗药物）的全身给药是否会导致雌性大鼠前额叶皮质（PFC）中的任何表观遗传因素发生变化，这可能有助于深入了解CICI临床表现的变异性。我们评估了AC化疗给药后PFC中的DNA甲基化水平和模式。我们还证明了小鼠PFC中组蛋白脱乙酰酶和乙酰转移酶活性水平在治疗后的变化。尽管总体DNA甲基化水平没有变化，但我们发现大鼠PFC中与神经元发育和维持相关的几个基因在启动子和外显子区域存在差异甲基化。我们的研究表明，与对照组相比，从头DNA甲基转移酶DNMT3a的表达显著增加。
