Relationships of DNA Methylation, Methyl-Donor Rich Diet, and Physical Activity with Pubertal Timing and Tempo among Mexican Adolescents

Abstract

Variations in pubertal timing and tempo have implications for the risk of adult diseases. Influences on the timing of pubertal onset and pace of pubertal progression have been widely discussed, but the underlying biological mechanisms remain unclear. Epigenetic modifications, the study of heritable changes in gene expression that does not involve changes to the underlying DNA sequence, are known to regulate developmental processes; thus, puberty, known to be one developmentally plastic phase, could be potentially affected.

Given that gene expression changes mediated by DNA methylation, may play a role in pubertal tempo regulation, availability of methyl donor nutrients also could affect these pathways.We conducted a population-based analysis using the Mexico City birth cohort, ELEMENT, to deepen our understanding of the link between developmental epigenetic processes and pubertal trajectory.

In Aim 1, we investigated the association of peripubertal blood DNA methylation at LINE-1 repetitive elements, and growth-related candidate loci IGF2, H19, HSD11B2 with pubertal timing and tempo, and observed gene-specific, sex-specific results. Among boys, a percent DNA methylation increase of HSD11B2 was associated with earlier pubarche. Increases in IGF2 DNA methylation were associated with later onset but faster progression of genital development in boys. Among girls, percent increase in DNA methylation of H19 was associated with later onset of breast development.

In Aim 2, we examined first trimester maternal and adolescent diet patterns that may be associated with DNA methylation at LINE-1 repetitive elements in adolescence. We used LASSO to calculate an Epigenetics-Associated Diet Score (EADS) for each pattern; then tested the associations of these scores with pubertal status. We observed associations between maternal EADS and pubertal onset, but not pubertal progression. Each standard deviation (SD) higher maternal EADS was associated with higher odds of later onset of menarche. In contrast, we observed associations between adolescent EADS and pubertal progression, but not pubertal onset. For each SD higher adolescent EADS, there was increased odds of slower genital progression, and slower testicular development in boys.

In Aim 3, we used an isotemporal substitution paradigm and regression models to examine the association of different physical activity intensities with reproductive hormones (testosterone, cortisol, progesterone, and androstenedione concentrations), DNA methylation (LINE-1 repetitive elements and the genes H19, HSD11B2, and PPARA), and Tanner stages in both boys and girls. Results suggested that substituting 30 minutes of sedentary behavior for moderate physical activity per day was associated with lower testosterone levels in boys, while a 30-minute increase in sedentary behavior was associated with higher progesterone levels in girls. Substituting 30 minutes of sedentary behavior for vigorous physical activity per day was associated with higher percent of HSD11B2 DNA methylation in boys, while a 30-minute increase in sedentary behavior was associated with lower percent of HSD11B2 DNA methylation.

Findings from this dissertation suggested that modifications in peripubertal DNA methylation may influence pubertal outcomes. Epigenetic-associated diet and accelerometer-measured physical activity may also influence reproductive hormones and pubertal status in a sex-, timing- and intensity-specific manner. This is the first and only population-based study so far that conducted a full examination of global and gene-specific DNA methylation with pubertal onset and progression in both sexes. In order to examine whether the findings are generalizable, future studies should consider recruiting a larger sample size with longitudinal design and repeated measurements.