Folate dietary insufficiency and folic acid supplementation similarly impair metabolism and compromise hematopoiesis
Curtis J. Henry,
Travis Nemkov,
Matias Casás-Selves,
Ganna Bilousova,
Vadym Zaberezhnyy,
Kelly C. Higa,
Natalie J. Serkova,
Kirk C. Hansen,
Angelo D’Alessandro,
James DeGregori
Affiliations
Curtis J. Henry
Department of Biochemistry and Molecular Genetics, University of Colorado AMC, Aurora, CO, USA;Department of Immunology and Microbiology, University of Colorado AMC, Aurora, CO, USA
Travis Nemkov
Department of Biochemistry and Molecular Genetics, University of Colorado AMC, Aurora, CO, USA
Matias Casás-Selves
Department of Biochemistry and Molecular Genetics, University of Colorado AMC, Aurora, CO, USA
Ganna Bilousova
Department of Dermatology and Charles C. Gates Center for Regenerative Medicine, University of Colorado AMC, Aurora, CO, USA
Vadym Zaberezhnyy
Department of Biochemistry and Molecular Genetics, University of Colorado AMC, Aurora, CO, USA
Kelly C. Higa
Department of Immunology and Microbiology, University of Colorado AMC, Aurora, CO, USA
Natalie J. Serkova
Department of Anesthesiology, University of Colorado AMC, Aurora, CO, USA
Kirk C. Hansen
Department of Biochemistry and Molecular Genetics, University of Colorado AMC, Aurora, CO, USA
Angelo D’Alessandro
Department of Biochemistry and Molecular Genetics, University of Colorado AMC, Aurora, CO, USA
James DeGregori
Department of Biochemistry and Molecular Genetics, University of Colorado AMC, Aurora, CO, USA;Department of Immunology and Microbiology, University of Colorado AMC, Aurora, CO, USA;Department of Medicine, Section of Hematology, University of Colorado AMC, Aurora, CO, USA;Department of Pediatrics, Section of Hematology/Oncology, University of Colorado AMC, Aurora, CO, USA
While dietary folate deficiency is associated with increased risk for birth defects and other diseases, evidence suggests that supplementation with folic acid can contribute to predisposition to some diseases, including immune dysfunction and cancer. Herein, we show that diets supplemented with folic acid both below and above the recommended levels led to significantly altered metabolism in multiple tissues in mice. Surprisingly, both low and excessive dietary folate induced similar metabolic changes, which were particularly evident for nucleotide biosynthetic pathways in B-progenitor cells. Diet-induced metabolic changes in these cells partially phenocopied those observed in mice treated with anti-folate drugs, suggesting that both deficiency and excessive levels of dietary folic acid compromise folate-dependent biosynthetic pathways. Both folate deficiency and excessive dietary folate levels compromise hematopoiesis, resulting in defective cell cycle progression, persistent DNA damage, and impaired production of lymphocytes. These defects reduce the reconstitution potential in transplantation settings and increase radiation-induced mortality. We conclude that excessive folic acid supplementation can metabolically mimic dietary folate insufficiency, leading to similar functional impairment of hematopoiesis.
