Asenius, Karin Ingrid Fredrika; (2019) The impact of paternal metabolic health on sperm DNA methylation and fetal growth. Doctoral thesis (Ph.D), UCL (University College London).

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Text Fredrika Asenius The Impact of Paternal Metabolic Health on Sperm DNA Methylation and Fetal Growth.pdf - Accepted Version Download (21MB) | Preview

Abstract

Low birth weight is associated with cardiovascular disease and T2DM in later life. Paternal obesity and T2DM have been associated with an increased risk of fathering low birthweight offspring. Obesity is associated with epigenetic changes in blood, but few studies have replicated DNA methylation differences found in obese subjects. Animal studies have shown that obesity and insulin resistance are associated with DNA methylation changes in sperm, which in turn could mediate intergenerational effects. Such findings are lacking in humans. My PhD explored the association between paternal metabolic traits and the birth weight of his offspring. I then investigated whether DNA methylation signatures in spermatozoa of obese fathers could underlie any observed association with his offspring birthweight. First, I performed a prospective cohort study of 500 mother-father-offspring trios to identify paternal metabolic traits associated with an increased risk of fathering low birth weight offspring. Out of 390 trios, including 64 obese men and 48 growth restricted offspring, I did not discover any significant paternal metabolic traits associated with fathering low-birthweight offspring. However, I found that paternal (own) birth weight is associated with the birth weight of his offspring. This suggests that paternal genetic factors are more influential in determining his offspring’s growth in utero than are factors acquired during his lifetime. Second, I performed a systematic review of studies that had investigated DNA methylation in human sperm. From this review, I summarised current knowledge and generated recommendations for future research. I then performed the largest characterisation of matched human sperm and blood samples to date using the most comprehensive DNA methylation profiling array, the MethylationEPIC array. Results showed that the DNA methylomes of sperm and blood are highly discordant and in effect completely uncorrelated. Future studies of intergenerational effects will have to study germ cells, rather than blood. Lastly, I attempted to validate previously-identified DNA methylation signatures associated with male obesity. Despite comparing 96 well-characterised obese men with 96 lean men, I was unable to replicate any previously identified differentially methylated CpG sites associated with obesity, in their blood. In a linear regression model, I identified two CpG sites, cg07037944 and cg26651978, as being suggestive of an association with BMI. These results will contribute to a larger cohort study of 1000 obese and 1000 lean men that aims to identify a robust and reproducible DNA methylation profile associated with obesity. In conclusion, this thesis did not prove my pre-determined hypotheses. However, it does present findings which advance our understanding of the intriguing possibility that acquired parental metabolic phenotype may influence offspring birthweight through intergenerational inheritance of epigenetic marks.

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