Maternal folic acid depletion during early pregnancy increases sensitivity to squamous tumor formation in the offspring in mice
Maternal folic acid depletion during early pregnancy increases sensitivity to squamous tumor formation in the offspring in mice
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DOI：
10.1017/s2040174419000217
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发表时间：
2019-12-01
影响因子：
1.7
通讯作者：
Nakashima, Manabu
中科院分区：
文献类型：
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作者：
Kawakubo-Yasukochi, Tomoyo;Morioka, Masahiko;Nakashima, Manabu
人们普遍认为，营养不良会影响后代未来患生活方式相关疾病的风险，这表明表观遗传机制的参与。由于叶酸（FA）是调节DNA甲基化所必需的营养素，我们试图确定母亲在怀孕早期摄入FA如何影响后代的肿瘤敏感性。从交配前2 - 3天至受孕后7天，母鼠维持FA耗竭（FA（-））或正常（2 mg FA/kg; FA（+））饮食，并对其后代进行化学致瘤攻击，皮肤使用7，12-二甲基苯并[a]蒽和佛波醇12-肉豆蔻酸酯13-乙酸酯，舌头使用4-硝基喹啉N-氧化物。在两种鳞状组织中，FA（-）母鼠的后代肿瘤发生比FA（+）母鼠的后代进展更快。值得注意的是，在FA（-）后代的皮肤中，圆柱瘤病（Cyld）的表达和活性由于其启动子区域中DNA甲基化状态的改变而降低，这导致FA（-）后代中肿瘤发生增加并伴有炎症。因此，我们得出结论，母亲在怀孕早期FA不足，能够促进肿瘤的进展，在后代通过调节DNA甲基化，如Cyld。此外，我们提出，第一次，“先天性”子宫营养的第三个原因的肿瘤发生除了已知的原因遗传易感性和后天环境因素。
Gestational nutrition is widely recognized to affect an offspring's future risk of lifestyle-related diseases, suggesting the involvement of epigenetic mechanisms. As folic acid (FA) is a nutrient essential for modulating DNA methylation, we sought to determine how maternal FA intake during early pregnancy might influence tumor sensitivity in an offspring. Dams were maintained on a FA-depleted (FA(-)) or normal (2 mg FA/kg; FA(+)) diet from 2 to 3 days before mating to 7 days post-conception, and their offspring were challenged with chemical tumorigenesis using 7,12-dimethylbenz[a)anthracene and phorbol 12-myristate 13-acetate for skin and 4-nitroquinoline N-oxide for tongue. In both squamous tissues, tumorigenesis was more progressive in the offspring from FA(-) than FA(+) dams. Notably, in the skin of FA(-) offspring, the expression and activity of cylindromatosis (Cyld) were decreased due to the altered DNA methylation status in its promoter region, which contributed to increased tumorigenesis coupled with inflammation in the FA(-) offspring. Thus, we conclude that maternal FA insufficiency during early pregnancy is able to promote neoplasm progression in the offspring through modulating DNA methylation, such as Cyld. Moreover, we propose, for the first time, "innate" utero nutrition as the third cause of tumorigenesis besides the known causes-hereditary predisposition and acquired environmental factors.