The effect of in utero folic acid supplementation on an early biomarker of mammary tumors

2120

Background: Epidemiologic studies suggest that dietary intake and blood levels of folate may be inversely related to breast cancer risk. However, more recent epidemiologic evidence has indicated that a high folate intake, especially from supplements, may increase the risk of breast cancer. The prenatal period is critical to the development of the mammary gland, and an increase in intrauterine folic acid exposure may have an impact on the offspring’s breast cancer risk. We therefore investigated the effect of folic acid supplementation provided in utero and during lactation on an early biomarker of mammary tumors. The incidence of mammary tumors is positively correlated with the number of highly proliferative and undifferentiated terminal end buds (TEBs) in rodent models.
 Methods: Female Sprague-Dawley rats were placed on either a control diet (2mg folic acid/kg diet) or a supplemented diet (5mg) for 3 weeks prior to breeding and remained on the diet throughout pregnancy and lactation. Female pups (n=10) from each maternal diet group were placed on the control diet at 21 days of age. At 50 days of age, the number of TEBs, terminal ducts (TD), alveolar buds (AB), and lobules in the pups were determined. Organ weights, weight gain, and plasma folate level were also determined.
 Results: At weaning plasma folate concentration accurately reflected maternal dietary folic acid levels (p<0.001). At 50 days of age, pups from dams on the supplemented diet had significantly higher plasma folate concentrations (p=0.011). Dietary folate intake positively correlated with plasma folate levels at both 21 and 50 days (p<0.001 and p=0.008, respectively). Pups from the supplemented dams had a significantly lower number of TEBs per mm2 (p=0.014) and a higher number of AB (p=0.004) than the pups from dams on the control diet. Dietary folate had a negative correlation with the number of TEBs (p=0.012) and a positive correlation with AB number (p=0.002). There was no significant difference in the number of TD and lobules between the groups. Uterus weight (g/100g body weight) was significantly lower (p=0.05) and liver weight (g/100g body weight) was greater (p=0.053) in the pups from supplemented dams. Liver weight was positively correlated with dietary folate (p=0.046). There was no difference in ovary weight. Pups from the supplemented dams weighed less at weaning (p=0.023) and also had less body weight gain (p=0.004).
 Conclusions: Notwithstanding the limitations associated with this model, our data suggest that folic acid supplementation provided in utero and during lactation could potentially lower mammary tumor risk in the offspring. However, the effect of maternal folic acid supplementation may not be the only factor contributing to the observed protective effect. Further studies in appropriate mammary tumor models are warranted to elucidate the effect of folic acid supplementation during pregnancy on the risk of mammary tumors in the offspring.