Association of Periconception Paternal Body Mass Index With Persistent Changes in DNA Methylation of Offspring in Childhood

Nudrat Noor, Andres Cardenas, Sheryl L Rifas-Shiman, Hui Pan, Jonathan M Dreyfuss, Emily Oken, Marie-France Hivert, Tamarra James-Todd, Mary-Elizabeth Patti, Elvira Isganaitis, Nudrat Noor, Andres Cardenas, Sheryl L Rifas-Shiman, Hui Pan, Jonathan M Dreyfuss, Emily Oken, Marie-France Hivert, Tamarra James-Todd, Mary-Elizabeth Patti, Elvira Isganaitis

Abstract

Importance: While prenatal nutrition and maternal obesity are recognized as important contributors to epigenetic changes and childhood obesity, the role of paternal obesity in the epigenome of offspring has not been well studied.

Objectives: To test whether periconception paternal body mass index (BMI) is associated with DNA methylation patterns in newborns, to examine associations between maternal and paternal BMI and the epigenome of offspring, and to examine persistence of epigenetic marks at ages 3 and 7 years.

Design, setting, and participants: Project Viva is a prebirth cohort study of mothers and children including 2128 live births that enrolled mothers from April 1999 to July 2002 and followed offspring to adolescence. This study analyzed the subset of participants with available data on paternal BMI and DNA methylation in offspring blood in the newborn period, at age 3 years, and at age 7 years. Data were analyzed from July 2017 to October 2019.

Exposures: The primary exposure was paternal periconception BMI; associations were adjusted for maternal prepregnancy BMI and stratified according to maternal BMI above or below 25.

Main outcomes and measures: The primary outcome was genome-wide DNA methylation patterns in offspring blood collected at birth, age 3 years, and age 7 years.

Results: A total of 429 father-mother-infant triads were included. The mean (SD) periconception paternal BMI was 26.4 (4.0) and mean maternal prepregnancy BMI was 24.5 (5.2); 268 fathers had BMI greater than or equal to 25 (mean [SD], 28.5 [3.3]) and 161 had BMI less than 25 (mean [SD], 22.8 [1.8]). Paternal BMI greater than or equal to 25 was associated with increased offspring birth weight compared with paternal BMI less than 25 (mean [SD] z score, 0.38 [0.91] vs 0.11 [0.96]; P = .004). Cord blood DNA methylation at 9 CpG sites was associated with paternal BMI independent of maternal BMI (q < .05). Methylation at cg04763273, between TFAP2C and BMP7, decreased by 5% in cord blood with every 1-unit increase in paternal BMI (P = 3.13 × 10-8); hypomethylation at this site persisted at ages 3 years and 7 years. Paternal BMI was associated with methylation at cg01029450 in the promoter region of the ARFGAP3 gene; methylation at this site was also associated with lower infant birth weight (β = -0.0003; SD = 0.0001; P = .03) and with higher BMI z score at age 3 years.

Conclusions and relevance: In this study, paternal BMI was associated with DNA methylation, birth weight, and childhood BMI z score in offspring.

Conflict of interest statement

Conflict of Interest Disclosures: Ms Rifas-Shiman reported receiving grants from the National Institutes of Health during the conduct of the study. Dr Oken reported receiving grants from the National Institutes of Health during the conduct of the study. Dr Patti reported receiving grants from the National Institutes of Health, research grants from Xeris and Dexcom, personal fees from Fractyl, Eiger Pharmaceuticals, and Avolynt, and research supplies from Insulet during the conduct of the study, all outside the submitted work. Dr Isganaitis reported receiving grants from the National Institute of Child Health and Human Development, the National Institute of Diabetes and Digestive and Kidney Diseases, and AstraZeneca during the conduct of the study. No other disclosures were reported.

Figures

Figure 1.. Epigenome-wide DNA Methylation Analyses for…
Figure 1.. Epigenome-wide DNA Methylation Analyses for Association of Paternal Body Mass Index (BMI) With Cord Blood DNA Methylation
A, The exposure for model 1 was paternal BMI (calculated as weight in kilograms divided by height in meters squared) adjusted for maternal prepregnancy BMI and other covariates. B, The exposure for model 2 was paternal BMI restricted to mothers with prepregnancy BMI 25 or greater. The x-axis shows the chromosomal location, while the y-axis shows the negative log10P value for the association between paternal BMI and methylation (M-value) at a given CpG locus (ie, greater −log10(P) indicates greater strength of association). The orange line indicates Bonferroni-adjusted genome-wide significance; blue line, false discovery rate (FDR) q less than .05.
Figure 2.. Association of Paternal Periconception Body…
Figure 2.. Association of Paternal Periconception Body Mass Index (BMI) and Cord Blood DNA Methylation for 9 Top-Ranking CpG Sites
The x-axis shows paternal BMI (calculated as weight in kilograms divided by height in meters squared) and the y-axis shows DNA methylation (M-value). Results are adjusted for maternal prepregnancy BMI, maternal age, gestational weight gain, household income, maternal education, maternal smoking, maternal alcohol use, marital status, infant’s sex, race/ethnicity, gestational age at delivery, mode of delivery, birth weight, batch effects, and estimated nucleated cell types from cord blood (percentage of CD8+ lymphocytes, CD4+ lymphocytes, natural killer cells, monocytes, B-cells, granulocytes, and nucleated red blood cells). Results are shown for cg17206978 near CENPA (A), cg12837919 near LSAMP (B), cg19846622 near MSX1 (C), cg15687147 near FAM190A (D), cg26544752 near CDH10 (E), cg07908498 near SORCS3 (F), cg22355517 near PDE3A (G), cg04763273 near TFAP2C (H), and cg01029450 near ARFGAP3 (I). All CpG loci had false discovery rate q less than .05.

References

    1. Gluckman PD, Hanson MA, Cooper C, Thornburg KL. Effect of in utero and early-life conditions on adult health and disease. N Engl J Med. 2008;359(1):-. doi:10.1056/NEJMra0708473
    1. Barker DJ, Gluckman PD, Godfrey KM, Harding JE, Owens JA, Robinson JS. Fetal nutrition and cardiovascular disease in adult life. Lancet. 1993;341(8850):938-941. doi:10.1016/0140-6736(93)91224-A
    1. Taveras EM. Childhood obesity risk and prevention: shining a lens on the first 1000 days. Child Obes. 2016;12(3):159-161. doi:10.1089/chi.2016.0088
    1. Radford EJ, Ito M, Shi H, et al. . In utero undernourishment perturbs the adult sperm methylome and intergenerational metabolism. Science. 2014;345(6198):1255903. doi:10.1126/science.1255903
    1. Jimenez-Chillaron JC, Isganaitis E, Charalambous M, et al. . Intergenerational transmission of glucose intolerance and obesity by in utero undernutrition in mice. Diabetes. 2009;58(2):460-468. doi:10.2337/db08-0490
    1. Martínez D, Pentinat T, Ribó S, et al. . In utero undernutrition in male mice programs liver lipid metabolism in the second-generation offspring involving altered Lxra DNA methylation. Cell Metab. 2014;19(6):941-951. doi:10.1016/j.cmet.2014.03.026
    1. Carone BR, Fauquier L, Habib N, et al. . Paternally induced transgenerational environmental reprogramming of metabolic gene expression in mammals. Cell. 2010;143(7):1084-1096. doi:10.1016/j.cell.2010.12.008
    1. Ng SF, Lin RC, Laybutt DR, Barres R, Owens JA, Morris MJ. Chronic high-fat diet in fathers programs β-cell dysfunction in female rat offspring. Nature. 2010;467(7318):963-966. doi:10.1038/nature09491
    1. Wei Y, Yang CR, Wei YP, et al. . Paternally induced transgenerational inheritance of susceptibility to diabetes in mammals. Proc Natl Acad Sci U S A. 2014;111(5):1873-1878. doi:10.1073/pnas.1321195111
    1. de Castro Barbosa T, Ingerslev LR, Alm PS, et al. . High-fat diet reprograms the epigenome of rat spermatozoa and transgenerationally affects metabolism of the offspring. Mol Metab. 2015;5(3):184-197. doi:10.1016/j.molmet.2015.12.002
    1. Mao Z, Xia W, Chang H, Huo W, Li Y, Xu S. Paternal BPA exposure in early life alters Igf2 epigenetic status in sperm and induces pancreatic impairment in rat offspring. Toxicol Lett. 2015;238(3):30-38. doi:10.1016/j.toxlet.2015.08.009
    1. Wu L, Lu Y, Jiao Y, et al. . Paternal psychological stress reprograms hepatic gluconeogenesis in offspring. Cell Metab. 2016;23(4):735-743. doi:10.1016/j.cmet.2016.01.014
    1. Dias BG, Ressler KJ. Parental olfactory experience influences behavior and neural structure in subsequent generations. Nat Neurosci. 2014;17(1):89-96. doi:10.1038/nn.3594
    1. Donkin I, Versteyhe S, Ingerslev LR, et al. . Obesity and bariatric surgery drive epigenetic variation of spermatozoa in humans. Cell Metab. 2016;23(2):369-378. doi:10.1016/j.cmet.2015.11.004
    1. Soubry A, Guo L, Huang Z, et al. . Obesity-related DNA methylation at imprinted genes in human sperm: results from the TIEGER study. Clin Epigenetics. 2016;8:51. doi:10.1186/s13148-016-0217-2
    1. Kühnen P, Handke D, Waterland RA, et al. . Interindividual variation in DNA methylation at a putative POMC metastable epiallele is associated with obesity. Cell Metab. 2016;24(3):502-509. doi:10.1016/j.cmet.2016.08.001
    1. Soubry A, Murphy SK, Wang F, et al. . Newborns of obese parents have altered DNA methylation patterns at imprinted genes. Int J Obes (Lond). 2015;39(4):650-657. doi:10.1038/ijo.2013.193
    1. Soubry A, Schildkraut JM, Murtha A, et al. . Paternal obesity is associated with IGF2 hypomethylation in newborns: results from a Newborn Epigenetics Study (NEST) cohort. BMC Med. 2013;11:29. doi:10.1186/1741-7015-11-29
    1. Oken E, Baccarelli AA, Gold DR, et al. . Cohort profile: Project Viva. Int J Epidemiol. 2015;44(1):37-48. doi:10.1093/ije/dyu008
    1. Centers for Disease Control and Prevention Growth charts. . Accessed October 29, 2019.
    1. Sharp GC, Lawlor DA, Richmond RC, et al. . Maternal pre-pregnancy BMI and gestational weight gain, offspring DNA methylation and later offspring adiposity: findings from the Avon Longitudinal Study of Parents and Children. Int J Epidemiol. 2015;44(4):1288-1304. doi:10.1093/ije/dyv042
    1. Oldereid NB, Wennerholm UB, Pinborg A, et al. . The effect of paternal factors on perinatal and paediatric outcomes: a systematic review and meta-analysis. Hum Reprod Update. 2018;24(3):320-389. doi:10.1093/humupd/dmy005
    1. Magnus MC, Olsen SF, Granstrom C, et al. . Paternal and maternal obesity but not gestational weight gain is associated with type 1 diabetes. Int J Epidemiol. 2018;47(2):417-426. doi:10.1093/ije/dyx266
    1. Anderson RE, Hanson HA, Thai D, et al. . Do paternal semen parameters influence the birth weight or BMI of the offspring? a study from the Utah Population Database. J Assist Reprod Genet. 2018;35(5):793-799. doi:10.1007/s10815-018-1154-0
    1. Wenke AK, Bosserhoff AK. Roles of AP-2 transcription factors in the regulation of cartilage and skeletal development. FEBS J. 2010;277(4):894-902. doi:10.1111/j.1742-4658.2009.07509.x
    1. Pastor WA, Liu W, Chen D, et al. . TFAP2C regulates transcription in human naive pluripotency by opening enhancers. Nat Cell Biol. 2018;20(5):553-564. doi:10.1038/s41556-018-0089-0
    1. Townsend KL, Suzuki R, Huang TL, et al. . Bone morphogenetic protein 7 (BMP7) reverses obesity and regulates appetite through a central mTOR pathway. FASEB J. 2012;26(5):2187-2196. doi:10.1096/fj.11-199067
    1. Tseng YH, Kokkotou E, Schulz TJ, et al. . New role of bone morphogenetic protein 7 in brown adipogenesis and energy expenditure. Nature. 2008;454(7207):1000-1004. doi:10.1038/nature07221
    1. Shiba Y, Kametaka S, Waguri S, Presley JF, Randazzo PA. ArfGAP3 regulates the transport of cation-independent mannose 6-phosphate receptor in the post-Golgi compartment. Curr Biol. 2013;23(19):1945-1951. doi:10.1016/j.cub.2013.07.087
    1. Liu X, Zhang C, Xing G, Chen Q, He F. Functional characterization of novel human ARFGAP3. FEBS Lett. 2001;490(1-2):79-83. doi:10.1016/S0014-5793(01)02134-2
    1. Obinata D, Takayama K, Urano T, et al. . ARFGAP3, an androgen target gene, promotes prostate cancer cell proliferation and migration. Int J Cancer. 2012;130(10):2240-2248. doi:10.1002/ijc.26224
    1. Hou M, Stukenborg JB, Nurmio M, et al. . Ontogenesis of Ap-2γ expression in rat testes. Sex Dev. 2011;5(4):188-196. doi:10.1159/000328822
    1. Khosronezhad N, Colagar AH, Jorsarayi SG. T26248G-transversion mutation in exon7 of the putative methyltransferase Nsun7 gene causes a change in protein folding associated with reduced sperm motility in asthenospermic men. Reprod Fertil Dev. 2015;27(3):471-480. doi:10.1071/RD13371
    1. Harris T, Marquez B, Suarez S, Schimenti J. Sperm motility defects and infertility in male mice with a mutation in Nsun7, a member of the Sun domain-containing family of putative RNA methyltransferases. Biol Reprod. 2007;77(2):376-382. doi:10.1095/biolreprod.106.058669
    1. Ingerslev LR, Donkin I, Fabre O, et al. . Endurance training remodels sperm-borne small RNA expression and methylation at neurological gene hotspots. Clin Epigenetics. 2018;10:12. doi:10.1186/s13148-018-0446-7
    1. Soto SM, Blake AC, Wesolowski SR, et al. . Myoblast replication is reduced in the IUGR fetus despite maintained proliferative capacity in vitro. J Endocrinol. 2017;232(3):475-491. doi:10.1530/JOE-16-0123
    1. Swali A, McMullen S, Hayes H, Gambling L, McArdle HJ, Langley-Evans SC. Cell cycle regulation and cytoskeletal remodelling are critical processes in the nutritional programming of embryonic development. PLoS One. 2011;6(8):e23189. doi:10.1371/journal.pone.0023189
    1. Dudley KJ, Sloboda DM, Connor KL, Beltrand J, Vickers MH. Offspring of mothers fed a high fat diet display hepatic cell cycle inhibition and associated changes in gene expression and DNA methylation. PLoS One. 2011;6(7):e21662. doi:10.1371/journal.pone.0021662
    1. Radford EJ, Isganaitis E, Jimenez-Chillaron J, et al. . An unbiased assessment of the role of imprinted genes in an intergenerational model of developmental programming. PLoS Genet. 2012;8(4):e1002605. doi:10.1371/journal.pgen.1002605
    1. Oliva R. Protamines and male infertility. Hum Reprod Update. 2006;12(4):417-435. doi:10.1093/humupd/dml009
    1. Terashima M, Barbour S, Ren J, Yu W, Han Y, Muegge K. Effect of high fat diet on paternal sperm histone distribution and male offspring liver gene expression. Epigenetics. 2015;10(9):861-871. doi:10.1080/15592294.2015.1075691
    1. Guo F, Yan L, Guo H, et al. . The transcriptome and DNA methylome landscapes of human primordial germ cells. Cell. 2015;161(6):1437-1452. doi:10.1016/j.cell.2015.05.015
    1. Reik W, Dean W, Walter J. Epigenetic reprogramming in mammalian development. Science. 2001;293(5532):1089-1093. doi:10.1126/science.1063443
    1. Burke MA, Carman KG. You can be too thin (but not too tall): social desirability bias in self-reports of weight and height. Econ Hum Biol. 2017;27(Pt A):198-222. doi:10.1016/j.ehb.2017.06.002
    1. Sørensen TIa, Ajslev TA, Ängquist L, Morgen CS, Ciuchi IG, Davey Smith G. Comparison of associations of maternal peri-pregnancy and paternal anthropometrics with child anthropometrics from birth through age 7 y assessed in the Danish National Birth Cohort. Am J Clin Nutr. 2016;104(2):389-396. doi:10.3945/ajcn.115.129171
    1. Patel R, Martin RM, Kramer MS, et al. . Familial associations of adiposity: findings from a cross-sectional study of 12,181 parental-offspring trios from Belarus. PLoS One. 2011;6(1):e14607. doi:10.1371/journal.pone.0014607

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