Translationally relevant mouse model of early life cancer and chemotherapy exposure results in brain and small intestine cytokine responses: A potential link to cognitive deficits.
Translationally relevant mouse model of early life cancer and chemotherapy exposure results in brain and small intestine cytokine responses: A potential link to cognitive deficits.
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早期生命癌症和化疗暴露的翻译相关小鼠模型会导致大脑和小肠细胞因子反应：与认知缺陷的潜在联系。
DOI：
10.1016/j.bbi.2021.10.003
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发表时间：
2022-01
期刊：
影响因子：
--
通讯作者：
Reyes TM
中科院分区：
文献类型：
--
作者：
Konsman JP;Laaker CJ;Lloyd KR;Hiltz A;Smith BL;Smail MA;Reyes TM
急性淋巴细胞白血病（ALL）是最常见的儿童癌症，其幸存者患长期认知问题（包括执行功能缺陷）的风险增加。化疗药物甲氨蝶呤（MTX）用于治疗大多数ALL患者，并与认知缺陷密切相关。为了解决生命早期癌症化疗如何导致认知缺陷，我们开发了一种与白血病生存相关的小鼠模型，该模型使小鼠在生命早期暴露于白血病细胞和化疗药物（长春新碱和MTX，以及亚叶酸救援）。几周后，使用新物体识别（识别记忆）和5选择系列反应时间任务（执行功能）对雄性和雌性小鼠进行测试。在化疗后急性和认知测试后慢性评估前额叶皮层和小肠中促炎、白色物质和突触相关分子的基因表达。早期癌症化疗暴露导致成年雄性小鼠的识别、记忆和执行功能缺陷。趋化因子Ccl 2的前额皮质表达急性增加，而促炎细胞因子肿瘤坏死因子-α的小肠表达急性（两种性别）和慢性（仅雄性）均升高。小肠炎症与前额叶皮质促炎和突触基因表达变化以及执行功能缺陷相关。总的来说，这些数据表明，目前的方案产生了一个强大的小鼠模型，在其中研究白血病幸存者的认知缺陷，并表明小肠炎症可能是一个新的贡献者的早期生活化疗的不良CNS后果。
Survivors of acute lymphoblastic leukemia (ALL), the most common childhood cancer, are at increased risk for long-term cognitive problems, including executive function deficits. The chemotherapeutic agent methotrexate (MTX) is used to treat most ALL patients, and is closely associated with cognitive deficits. To address how early life cancer chemotherapy leads to cognitive deficits, we developed a translationally relevant mouse model of leukemia survival that exposed mice to leukemic cells and chemotherapeutic drugs (vincristine and MTX, with leucovorin rescue) in early life. Male and female mice were tested several weeks later using novel object recognition (recognition memory) and 5-choice serial reaction time task (executive function). Gene expression of proinflammatory, white matter and synapse-associated molecules was assessed in the prefrontal cortex and small intestine both acutely after chemotherapy and chronically after cognitive testing. Early life cancer-chemotherapy exposure resulted in recognition memory and executive function deficits in adult male mice. Prefrontal cortex expression of the chemokine Ccl2 was increased acutely, while small intestine expression of the proinflammatory cytokine tumor necrosis factor-alpha was elevated both acutely (both sexes) and chronically (males only). Inflammation in the small intestine was correlated with prefrontal cortical proinflammatory and synaptic gene expression changes, as well as to executive function deficits. Collectively, these data indicate that the current protocol results in a robust mouse model in which to study cognitive deficits in leukemia survivors, and suggest that small intestine inflammation may represent a novel contributor to adverse CNS consequences of early life chemotherapy.
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DOI：
10.1016/s2352-3026(16)30110-7
发表时间：
2016-10
期刊：
The Lancet. Haematology
影响因子：
--
作者：
Cheung YT;Sabin ND;Reddick WE;Bhojwani D;Liu W;Brinkman TM;Glass JO;Hwang SN;Srivastava D;Pui CH;Robison LL;Hudson MM;Krull KR
通讯作者：
Krull KR
影响因子：
5.2
作者：
Garcia-Hernandez V;Quiros M;Nusrat A
通讯作者：
Nusrat A
影响因子：
2.7
作者：
CARLI, M;ROBBINS, TW;EVERITT, BJ
通讯作者：
EVERITT, BJ
影响因子：
3.2
作者：
BRANSKI, D;LEBENTHAL, E;HATCH, TF
通讯作者：
HATCH, TF
影响因子：
1.9
作者：
Insel, Kathleen C.;Hockenberry, Marilyn J.;Moore, Ida M. (Ki)
通讯作者：
Moore, Ida M. (Ki)