Abnormal folate metabolism causes age-, sex- and parent-of-origin-specific haematological defects in mice.

Abstract

The importance of the vitamin folate (also known as folic acid) in erythrocyte formation, maturation, and/or longevity is apparent since folate deficiency in humans causes megaloblastic anemia. Megaloblastic anemia is a type of macrocytic anemia whereby erythrocytes are enlarged and fewer in number. Folate metabolism is required for thymidine synthesis and the one-carbon metabolism, though its specific role in erythropoiesis is not well understood. MTRR is a key enzyme necessary for the progression of folate metabolism since knocking down the Mtrr gene in mice results in hyperhomocysteinemia and global DNA hypomethylation. We demonstrate here that abnormal folate metabolism in mice caused by Mtrr gt/gt homozygosity leads to haematopoietic phenotypes that are sex- and age-dependent. Specifically, Mtrr gt/gt female mice displayed macrocytic anemia, which might be due to defective erythroid differentiation at the exclusion of hemolysis. This was associated with increased renal Epo mRNA expression, hypercellular bone marrow, and splenic extramedullary haematopoiesis. In contrast, the male response differed since Mtrr gt/gt male mice were not anemic but did display erythrocytic macrocytosis and lymphopenia. Regardless of sex, these phenotypes were late-onset. Remarkably, we also show that when either parent carries an Mtrr gt allele, a haematological defect results in their adult wildtype daughters. However, the specific phenotype was dependent upon the sex of the parent. For instance, wildtype daughters of Mtrr +/gt females displayed normocytic anemia. In contrast, wildtype daughters of Mtrr +/gt males exhibited erythrocytic microcytosis not associated with anemia. Therefore, abnormal folate metabolism affects adult haematopoiesis in an age-, sex-, and parent-specific manner.