One-carbon metabolism during the menstrual cycle and pregnancy

Author summaryOne-carbon metabolism, in which one-carbon groups are transferred between compounds, is an important part of metabolism that is found in all eukaryotic cells. It includes reactions that are crucial for cell division and the reaction that methylates DNA, the basis for epigenetics. In mammals, many enzymes of one-carbon metabolism are affected by the sex hormones testosterone and estrogen and, since estrogen varies during the menstrual cycle, one-carbon metabolites and velocities change a lot during the cycle in menstruating women. We have created a mathematical model of hepatic one-carbon metabolism to investigate these changes during the menstrual cycle and during pregnancy. The model's predictions are consistent with the experimental and clinical literature. The model can be used to conduct in silico experiments to test hypotheses about the effects of possible therapeutic interventions. The model explains why women have lower homocysteine than men, which is important because homocysteine is a major biomarker for cardio-vascular disease. The model also explains why homocysteine is not a good biomarker for vitamin B-12, vitamin B-6, and folate deficiencies, despite claims in the literature that it is a good biomarker. The mathematical model is available and can be used by other researchers. Many enzymes in one-carbon metabolism (OCM) are up- or down-regulated by the sex hormones which vary diurnally and throughout the menstrual cycle. During pregnancy, estradiol and progesterone levels increase tremendously to modulate physiological changes in the reproductive system. In this work, we extend and improve an existing mathematical model of hepatic OCM to understand the dynamic metabolic changes that happen during the menstrual cycle and pregnancy due to estradiol variation. In particular, we add the polyamine drain on S-adenosyl methionine and the direct effects of estradiol on the enzymes cystathionine beta-synthase (CBS), thymidylate synthase (TS), and dihydrofolate reductase (DHFR). We show that the homocysteine concentration varies inversely with estradiol concentration, discuss the fluctuations in 14 other one-carbon metabolites and velocities throughout the menstrual cycle, and draw comparisons with the literature. We then use the model to study the effects of vitamin B-12, vitamin B-6, and folate deficiencies and explain why homocysteine is not a good biomarker for vitamin deficiencies. Additionally, we compute homocysteine throughout pregnancy, and compare the results with experimental data. Our mathematical model explains how numerous homeostatic mechanisms in OCM function and provides new insights into how homocysteine and its deleterious effects are influenced by estradiol. The mathematical model can be used by others for further in silico experiments on changes in one-carbon metabolism during the menstrual cycle and pregnancy.