The Timing and Duration of Folate Restriction Differentially Impacts Colon Carcinogenesis

Abstract

Diet plays a crucial role in the development of colorectal cancer (CRC). Of particular importance, folate, present in foods and supplements, is a crucial modulator of CRC risk. The role of folate, and, specifically, the synthetic variant, folic acid, in the primary prevention of CRC has not been fully elucidated. Animal studies varied considerably in the timing, duration, and supplementation of folates, leading to equivocal results. Our work attempts to isolate these variables to ascertain the role of folic acid in CRC initiation, as we previously demonstrated that folate restriction conferred protection against CRC initiation in a β-pol haploinsufficient mouse model. Here we demonstrated that prior adaptation to folate restriction altered the response to carcinogen exposure in wild-type C57BL/6 mice. Mice adapted to folate restriction for 8 weeks were protected from CRC initiation compared to mice placed on folate restriction for 1 week, irrespective of antibiotic supplementation. Through analyses of mTOR signaling, DNA methyltransferase, and DNA repair, we have identified factors that may play a critical role in the differential responses to folate restriction. Furthermore, the timing and duration of folate restriction altered these pathways differently in the absence of carcinogenic insult. These results represent novel findings, as we were able to show that, in the same model and under controlled conditions, folate restriction produced contrasting results depending on the timing and duration of the intervention.