Abstract 2098: The effect of in utero folic acid supplementation on colorectal cancer risk in the offspring in a chemical carcinogen rodent model
Authors: Sie Karen K , Medline Alan , Sohn Kyoung-Jin , Croxford Ruth , Kim Young-In 
Published: May 2019

Abstract
Background: Epidemiologic studies suggest that dietary intake and blood levels of folate are inversely related to colorectal cancer (CRC) risk. However, animal studies and recent human intervention trials have suggested that although folate supplementation may decrease the risk of developing de novo CRC, folate supplementation may promote the progression of existing, undiagnosed preneoplastic lesions in the colorectum to CRC. Total intake and blood levels of folate in North America have dramatically increased over the past decade owing to mandatory folic acid (FA; the synthetic form of folate) fortification and 30-40% of the population taking multivitamins containing FA. It is unknown whether high folate in the intrauterine environment may affect CRC risk in the offspring. We therefore investigated the effect of FA supplementation provided in utero and postnatally on CRC risk in the offspring in the azoxymethane (AOM) rat model of CRC.
Methods: Female Sprague-Dawley rats were placed on either a control diet (2mg FA/kg diet) or a supplemented diet (5mg FA) for 3 weeks prior to breeding, and remained on the diet throughout pregnancy and lactation. Male pups from each maternal diet group were randomized to either the control or supplemented diet (n=55 per group) at weaning (21 days of age). At 5 and 6 weeks of age, 2 weekly s.c. injections of AOM were given. At 34 weeks of age, all rats were sacrificed and tumor incidence, multiplicity and burden as well as plasma folate and homocysteine (Hcy; an accurate inverse indicator of folate status) and liver folate concentrations were determined.
Results: Plasma and liver folate concentrations accurately reflected dietary FA levels (p&lt;0.001), and a significant interaction was found between maternal and pup diets (p&lt; 0.02). Plasma Hcy was lower in pups fed the 5mg diet (p=0.036). Maternal FA supplementation significantly decreased the risk of developing CRC in the offspring (p=0.003) whereas postnatal FA supplementation had no significant effect. Pups from dams on the control diet had a nearly 3-fold increased risk of developing CRC compared with those from dams on FA supplementation (odds ratio=2.78; 95% CI, 1.41-5.50). There was no significant effect of interaction between maternal and pup diets on CRC incidence. Total number of tumors and sum of tumor diameter were significantly different among the diet groups (p=0.014 and p=0.006, respectively) with FA supplemented pups from dams on the control diet bearing a higher number of tumors and a larger tumor diameter than other groups (p&lt;0.03).
Conclusions: Notwithstanding the limitations associated with this model, our data suggest that FA supplementation provided in utero, but not postnatally, may protect the offspring from developing CRC. Although FA supplementation may promote the progression of established precursors of CRC, FA supplementation may decrease the risk of developing de novo CRC.