Decreasing the number of children that develop cancer is hampered by a lack of clear understanding of its causes. To achieve the long-term objective of reducing the number of children who develop malignancy, it is first necessary to define causes. Evidence from observational studies suggests that prenatal vitamin supplementation may be protective for several childhood cancers, including medulloblastoma. Some evidence indicates that folic acid, a major component of prenatal vitamins, may be mediating the protective effect, however this is not entirely clear due to the inherent limitations of case-control studies, including the difficulty of assessing past pregnancy exposures. The primary aim of this project is to establish whether maternal dietary folic acid level during the peri-gestational period (in and around pregnancy) can influence the incidence and rate of medulloblastoma development in offspring in a highly controlled experimental setting using the transgenic mouse model, Ptc1. Our rationale is that if folic acid can modulate tumor incidence, the mechanism can then be determined, which will ultimately enhance understanding of how pediatric brain tumors develop from the earliest stages as a result of maternal nutrient levels and other environmental exposures. The secondary aim is to establish whether maternal dietary folic acid level can influence genetic selection in a mouse model. This knowledge could have important implications regarding selective pressure that may occur as a result of folic acid fortification programs that have been instituted in many countries.
The specific aims of this project will be accomplished by randomizing female wild- type mice (C57BL/6) to three different previously tested doses of dietary folic acid prior to mating with transgenic Ptc1 heterozygous males that are predisposed to medulloblastoma. The mice will be maintained on the diets through weaning of their offspring and the offspring will be genotyped and followed for medulloblastoma development. Statistical differences between dietary groups in the frequencies of heterozygote offspring and brain tumors that develop over nine months will be determined by chi-square tests. Differences in the rate of tumor development will be assessed using Kaplan-Meier survival analyses. The significance of the proposed research is that it will help bridge a gap in knowledge from human epidemiology studies by determining in a controlled experimental setting whether maternal dietary folic acid level can affect the incidence of medulloblastoma in a well-characterized transgenic mouse model.
The proposed research is an important first step in gaining a basic understanding of whether maternal exposures during pregnancy play a role in the subsequent development of childhood malignancy. Specifically, this project will determine if peri-gestational folic acid supplementation can influence the risk of medulloblastoma in a controlled experimental setting using a vertebrate animal model. The relevance to public health is that if the factors that cause malignancy can be defined, biological mechanisms can then be determined, and public health strategies can be implemented to reduce the overall burden of childhood cancer.
| Been, Raha A; Ross, Julie A; Nagel, Christian W et al. (2013) Perigestational dietary folic acid deficiency protects against medulloblastoma formation in a mouse model of nevoid basal cell carcinoma syndrome. Nutr Cancer 65:857-65 |
