Department of Nutritional Sciences, University of Toronto, Toronto, Ontario, Canada.
Gut. 2011 Dec;60(12):1687-94. doi: 10.1136/gut.2011.238782. Epub 2011 May 11.
Intrauterine and early life exposure to folic acid has significantly increased in North America owing to folic acid fortification, widespread supplemental use and periconceptional folic acid supplementation. The effect of maternal and postweaning folic acid supplementation on colorectal cancer risk in the offspring was investigated.
Female rats were placed on a control or supplemental (2.5× the control) diet prior to mating and during pregnancy and lactation. At weaning, male pups from each maternal diet group were randomised to the control or supplemental diet (n=55 per each of the four maternal/pup diet groups) for 31 weeks and colorectal cancer was induced by azoxymethane at 5 weeks of age. At necropsy, colorectal cancer parameters as well as colorectal epithelial proliferation, apoptosis and global DNA methylation were determined in the offspring.
Maternal, but not postweaning, folic acid supplementation significantly reduced the odds of colorectal adenocarcinoma by 64% in the offspring (OR 0.36; 95% CI 0.18 to 0.71; p=0.003). Pups from the dams fed the control diet that were given postweaning folic acid supplementation had significantly higher tumour multiplicity and burden than other groups (p<0.05). Maternal and postweaning folic acid supplementation interacted in a manner that decreased rectal epithelial proliferation (p<0.05). Both maternal and postweaning folic acid supplementation significantly decreased DNA damage in the rectum (p<0.05). Maternal folic acid supplementation significantly increased (p=0.007), whereas postweaning supplementation significantly decreased (p<0.001), colorectal global DNA methylation.
The data suggest for the first time that maternal folic acid supplementation at the level equivalent to the average postfortification total folate intake in North America and to that recommended to women at reproductive age protects against the development of colorectal cancer in the offspring. This protective effect may be mediated in part by increased global DNA methylation and decreased epithelial proliferation and DNA damage in the colorectum.
由于叶酸强化、广泛补充使用和围孕期叶酸补充，北美的宫内和生命早期暴露于叶酸的水平显著增加。本研究旨在调查母体和断奶后叶酸补充对后代结直肠癌风险的影响。
雌性大鼠在交配前、妊娠和哺乳期给予对照或补充（对照的 2.5 倍）饮食。断奶时，每个母体饮食组的雄性幼崽随机分为对照或补充饮食组（每组 4 个母体/幼崽饮食组，每组 55 只），并接受 31 周的饮食，5 周龄时用偶氮甲烷诱导结直肠癌。尸检时，检测后代的结直肠癌参数以及结直肠上皮增殖、凋亡和全基因组 DNA 甲基化。
母体而非断奶后叶酸补充可使后代结直肠腺癌的发生几率显著降低 64%（OR 0.36；95%CI 0.18 至 0.71；p=0.003）。给予断奶后叶酸补充的对照组母鼠所产幼崽的肿瘤多发性和负担明显高于其他组（p<0.05）。母体和断奶后叶酸补充以一种相互作用的方式降低直肠上皮增殖（p<0.05）。母体和断奶后叶酸补充均显著降低直肠 DNA 损伤（p<0.05）。母体叶酸补充显著增加（p=0.007），而断奶后补充显著降低（p<0.001）结直肠全基因组 DNA 甲基化。
本研究首次表明，北美的平均叶酸强化后总叶酸摄入量和推荐给育龄妇女的叶酸补充水平的母体叶酸补充可预防后代结直肠癌的发生。这种保护作用可能部分通过增加全基因组 DNA 甲基化以及减少结直肠上皮增殖和 DNA 损伤来介导。
