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The impact of zinc and folic acid supplementation on sperm DNA methylation: results from the folic acid and zinc supplementation randomized clinical trial (FAZST).

Division of Urology, Department of Surgery, University of Utah School of Medicine, Salt Lake City, Utah; Department of Cell Biology and Physiology, Brigham Young University, Provo, Utah; Andrology and IVF Laboratories, University of Utah School of Medicine, Salt Lake City, Utah. Division of Urology, Department of Surgery, University of Utah School of Medicine, Salt Lake City, Utah; Andrology and IVF Laboratories, University of Utah School of Medicine, Salt Lake City, Utah. Division of Urology, Department of Surgery, University of Utah School of Medicine, Salt Lake City, Utah; Andrology and IVF Laboratories, University of Utah School of Medicine, Salt Lake City, Utah; Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, Utah. Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland. Biostatistics and Bioinformatics Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland. IVF and Andrology Laboratories, Center for Advanced Reproductive Care, Iowa City, Iowa. The Emmes Company, LLC, Rockville, Maryland. Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, University of Utah School of Medicine, Salt Lake City, Utah. Andrology and IVF Laboratories, University of Utah School of Medicine, Salt Lake City, Utah. Division of Urology, Department of Surgery, University of Utah School of Medicine, Salt Lake City, Utah. Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland. Electronic address: mumfords@mail.nih.gov.

Fertility and sterility. 2022;(1):75-85
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Abstract

OBJECTIVE To determine if 6-month folic acid (5 mg) and zinc (30 mg) supplementation impacts sperm DNA methylation patterns. DESIGN A multicenter, double-blind, block randomized, placebo-controlled trial titled "The Folic Acid and Zinc Supplementation Trial (FAZST)." SETTING Infertility care centers. PATIENT(S): Male partners (18 years and older) from heterosexual couples (female partners aged 18-45 years) seeking fertility treatment were recruited. INTERVENTION(S): Men were randomized 1:1 to receive folic acid (5 mg) and elemental zinc (30 mg) (n = 713) or a matching placebo (n = 757) daily for 6 months. MAIN OUTCOME MEASURE(S): Sperm DNA methylation was analyzed using the EPIC methylation array (Illumina) at 6 months. Differential sperm DNA methylation was assessed at multiple levels (regional, single cytosine phosphate guanine, etc.). We additionally assessed the impact of supplementation on epigenetic age. RESULT(S): No significant differences were identified between the treatment and placebo groups although some trends appeared to be present. To determine if these trends were noteworthy, we implemented various permutations and found that the patterns we identified were no more than would be expected by random chance. CONCLUSION(S): The data presented here strongly suggest that this supplementation regimen is not effective at altering sperm DNA methylation. These data comport well with previous findings from the FAZST study that found no impact of supplementation on basic semen analysis parameters or live birth. CLINICAL TRIAL REGISTRATION NUMBER ClinicalTrials.gov Identifier: NCT01857310.

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MeSH terms : DNA Methylation ; Folic Acid ; Zinc