Methylsulfonylmethane Serves as a Donor of Methyl Groups for Methylation of DNA in Human Liver HepaRG Cells

Abstract

Methylsulfonylmethane (MSM), a natural organosulfur compound, is a popular dietary supplement sold both as a single product and as a constituent of multi-ingredient products. It has been postulated that MSM may serve as a donor for methyl groups for various cellular processes; however, studies have yet to demonstrate this. Therefore, the goal of this study was to determine whether or not MSM, supplemented to fully differentiated human HepaRG cells at physiologically-relevant concentrations, can serve as a donor for methyl groups for DNA methylation. For this purpose, methyl groups in the MSM molecule were labeled with deuterium (deuterated) and incorporation of the labeled 5-methylcytosine into the HepaRG cell DNA was evaluated using liquid chromatography/mass spectrometry (LC-MS/MS). We report that MSM supplementation resulted in significant incorporation of deuterated product into DNA in a time- and dose-dependent fashion. These changes were not associated with increased 5-methylcytosine content, did not result in changes of DNA methylation or re-distribution of DNA methylation patterns between the retrotransposons LINE-1 and HERV18, and were not associated with cytotoxicity. In conclusion, short-term supplementation with MSM in vitro demonstrates that MSM can serve as a donor of methyl groups for methylation of DNA, but does not affect the levels of DNA methylation globally and does not lead to redistribution of the DNA methylation patterns within the most abundant repetitive elements. Future studies will be needed to validate these findings in vivo and to investigate whether or not MSM can restore normal DNA methylation patterns within the hypomethylated phenotype.

Keywords:

• dietary supplements
• DNA methylation
• LINE-1
• methylsulfonylmethane

Acknowledgements

The authors would like to thank Christopher Fettes for his excellent editorial services.

Disclosure statement

This study, in part, was funded by Bergstrom Nutrition (Vancouver, WA, USA). The funder had no role in the design of the study; in the collection, analyses or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.No other potential conflict of interest was reported by the authors.

Additional information

Funding

This research was funded by Bergstrom Nutrition (Vancouver, WA, USA), Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health under grant number P20GM109096; Clinical and Translational Science Awards UL1TR000039 and KL2TR000063; and the Arkansas Biosciences Institute.

Notes on contributors

Kirsten Clement

Kirsten Clement is a research associate at the Department of Environmental Health Sciences and the Center for Dietary Supplements Research at the University of Arkansas for Medical Sciences, Fay W. Boozman College of Public Health. Her main interests are devoted to development of in vitro and microphysiological systems for safety and efficacy testing of nutrients and dietary supplements.

Mitchell R. McGill

Mitchell R. McGill is an Assistant Professor in the Department of Environmental Health Sciences at the University of Arkansas for Medical Sciences, Fay W. Boozman College of Public Health. He is an expert in xenobiotic-induced liver injury with emphasis on both preclinical models and clinical biomarkers. He has authored nearly 100 peer-reviewed publications and a dozen book chapters on the topic of liver injury. He also serves as a drug safety consultant for the pharmaceutical industry and is a practicing board-certified clinical chemist.

Isabelle R. Miousse

Isabelle Racine Miousse is an Assistant Professor in the Department of Biochemistry and Molecular Biology at the University of Arkansas for Medical Sciences. She received her Ph.D. from McGill University in Canada on the metabolism of one-carbon groups. She specializes in epigenetics, with a focus on how environmental and dietary factors linked to cancer affect DNA and histone methylation. Her lab investigates how the supply and metabolism of the methyl donor methionine modulates these responses and alters cancer development.

Sean G. Young

Sean Young is an Assistant Professor in the Department of Environmental Health Sciences at the University of Arkansas for Medical Sciences, Fay W. Boozman College of Public Health. Sean is a medical geographer, with training in geographic information systems, data science, and data visualization. His interests focus on spatial analysis of human-environment interactions and disease ecology across a wide range of public health topics, including accessibility to cancer screening and treatment, spatio-temporal modeling of emerging infectious diseases, and creating risk indices for prescription opioid misuse, among others.

Stepan Melnyk

Stepan Melnyk is a Director of the Core Metabolomics Laboratory at Arkansas Children’s Research Institute. With both an MD and PhD, three decades of his biomedical research career have been dedicated to studying metabolic consequences of oxidative stress, including detection of oxidative damaged biomolecules (3-nitrotyrosine, glutathione), DNA adducts (5-methylcytosine/5-hydroxymethylcytosine, 8-oxo-dG) and universal methylation reaction donor S-Adenosylmethionine (SAM), and development of analytical techniques (HPLC, LC-MS) for those purposes. Stepan has an exceptional list of collaborations on a variety of important biomedical topics (i.e., cancer, autism, congenital cardiac pathology in children, etc.) presented in 120+ peer reviewed journal articles with a high citation index.

Igor Koturbash

Igor Koturbash is an Associate Professor and Chair, Department of Environmental Health Sciences and Co-Director of the Center for Dietary Supplements Research at the University of Arkansas for Medical Sciences, Fay W. Boozman College of Public Health. Igor has a long-lasting interest in diet and dietary supplements and their impact on human health. Therefore, the major focus of his research is safety, efficacy and mechanisms of action of dietary supplements and understanding how diet and dietary supplements can modulate tissue response to cancer therapy. Igor is heavily involved in a number of safety and efficacy studies on various dietary supplements and herbs, including methionine supplementation, green tea extract and cannabidiol (CBD), to name a few. Igor has published 100+ peer-reviewed articles and book chapters and his research has received uninterrupted extramural funding from various sources since the beginning of his independent career.