One-carbon metabolism during the menstrual cycle and pregnancy

• Main Authors: Frederik Nijhout, H. (Author), Kim, R. (Author), Reed, M.C (Author)
• Format: Article
• Language: English
• Published: Public Library of Science 2021
• Subjects: ademetionine; Article; B12 deficiency; carbon; Carbon; carbon metabolism; computer model; concentration (parameter); contraceptive agent; controlled study; cyanocobalamin; cystathionine beta synthase; dihydrofolate reductase; enzyme inhibition; enzyme substrate; estradiol; Estradiol; female; Female; folic acid; Folic Acid; folic acid deficiency; glutathione; homeostasis; homocysteine; Homocysteine; human; Humans; male; mathematical model; menstrual cycle; Menstrual Cycle; metabolism; molecular dynamics; pregnancy; Pregnancy; pyridoxine deficiency; S-Adenosylmethionine; thymidylate synthase; Vitamin B 12
• Online Access: View Fulltext in Publisher

 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 β-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 B12, vitamin B6, 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. © 2021 Kim et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.