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Effect of maternal and postweaning folic acid supplementation on colorectal cancer risk in the offspring
  1. Karen K Y Sie1,
  2. Alan Medline2,3,
  3. Jacobine van Weel4,
  4. Kyoung-Jin Sohn5,
  5. Sang-Woon Choi6,
  6. Ruth Croxford7,
  7. Young-In Kim1,5,8,9
  1. 1Department of Nutritional Sciences, University of Toronto, Toronto, Ontario, Canada
  2. 2Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
  3. 3Department of Pathology, Humber River Regional Hospital, Toronto, Ontario, Canada
  4. 4Faculty of Medicine, University of Utrecht, The Netherlands
  5. 5Department of Medicine, University of Toronto, Toronto, Ontario, Canada
  6. 6Vitamin and Carcinogenesis Laboratory, Jean Mayer USDA Human Nutrition Research Center on Ageing at Tufts University, Boston, Massachusetts, USA
  7. 7Statistical Consultant, Toronto, Ontario, Canada
  8. 8Division of Gastroenterology, Department of Medicine, St. Michael's Hospital, Toronto, Ontario, Canada
  9. 9The Keenan Research Center, the Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada
  1. Correspondence to Young-In Kim, St. Michael's Hospital, 16CC-038, 30 Bond Street, Toronto, Ontario, Canada, M5B 1W8; youngin.kim{at}utoronto.ca

Abstract

Background 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.

Methods 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.

Results 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.

Conclusions 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.

  • Folate
  • folic acid
  • maternal supplementation
  • colorectal cancer
  • animal model
  • colorectal cancer
  • dietary - colon cancer
  • folic acid
  • methylation
  • vitamins

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Footnotes

  • See Paper, p 1695

  • Presented in part at the 2008 American Association for Cancer Research Meeting, San Diego, CA, USA, April 2008 and published in abstract form in the Proceedings of the American Association for Cancer Research 2008;68:abst 2098.

  • Funding The Canadian Cancer Society (Grant # 017078; to YIK); Canadian Institutes of Heath Research (Grant # 14126; to YIK); Canadian Graduate Scholarships Master's Award from the Canadian Institutes of Health Research (to KKYS).

  • Competing interests None.

  • Ethics approval Animal experimentation was approved by the Animal Care Committee of the University of Toronto, in accordance with the guidelines of the Canadian Council on Animal Care.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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