Maternal smoking during pregnancy has been found to influence newborn DNA methylation in genes involved in fundamental developmental processes. It is pertinent to understand the degree to which the offspring methylome is sensitive to the intensity and duration of prenatal smoking. An investigation of the persistence of offspring methylation associated with maternal smoking and the relative roles of the intrauterine and postnatal environment is also warranted. In the Avon Longitudinal Study of Parents and Children, we investigated associations between prenatal exposure to maternal smoking and offspring DNA methylation at multiple time points in approximately 800 mother–offspring pairs. In cord blood, methylation at 15 CpG sites in seven gene regions (AHRR, MYO1G, GFI1, CYP1A1, CNTNAP2, KLF13 and ATP9A) was associated with maternal smoking, and a dose-dependent response was observed in relation to smoking duration and intensity. Longitudinal analysis of blood DNA methylation in serial samples at birth, age 7 and 17 years demonstrated that some CpG sites showed reversibility of methylation (GFI1, KLF13 and ATP9A), whereas others showed persistently perturbed patterns (AHRR, MYO1G, CYP1A1 and CNTNAP2). Of those showing persistence, we explored the effect of postnatal smoke exposure and found that the major contribution to altered methylation was attributed to a critical window of in utero exposure. A comparison of paternal and maternal smoking and offspring methylation showed consistently stronger maternal associations, providing further evidence for causal intrauterine mechanisms. These findings emphasize the sensitivity of the methylome to maternal smoking during early development and the long-term impact of such exposure.

Exposure to early-life adversity is known to predict DNA methylation (DNAm) patterns that may be related to psychiatric risk. However, few studies have investigated whether adversity has time-dependent effects based on the age at exposure. Using a two-stage structured life course modeling approach, we tested the hypothesis that there are sensitive periods when adversity induces greater DNAm changes. We tested this hypothesis in relation to two alternatives: an accumulation hypothesis, in which the effect of adversity increases with the number of occasions exposed, regardless of timing; and a recency model, in which the effect of adversity is stronger for more proximal events. Data came from the Accessible Resource for Integrated Epigenomic Studies, a subsample of mother-child pairs from the Avon Longitudinal Study of Parents and Children (n = 691-774). After covariate adjustment and multiple testing correction, we identified 38 CpG sites that were differentially methylated at 7 years of age following exposure to adversity. Most loci (n = 35) were predicted by the timing of adversity, namely exposures before 3 years of age. Neither the accumulation nor recency of the adversity explained considerable variability in DNAm. A standard epigenome-wide association study of lifetime exposure (vs. no exposure) failed to detect these associations. The developmental timing of adversity explains more variability in DNAm than the accumulation or recency of exposure. Very early childhood appears to be a sensitive period when exposure to adversity predicts differential DNAm patterns. Classification of individuals as exposed versus unexposed to early-life adversity may dilute observed effects.

Background: Evidence suggests that in utero exposure to undernutrition and overnutrition might affect adiposity in later life. Epigenetic modification is suggested as a plausible mediating mechanism. Methods: We used multivariable linear regression and a negative control design to examine offspring epigenome-wide DNA methylation in relation to maternal and offspring adiposity in 1018 participants. Results: Compared with neonatal offspring of normal weight mothers, 28 and 1621 CpG sites were differentially methylated in offspring of obese and underweight mothers, respectively [false discovert rate (FDR)-corrected P-value < 0.05), with no overlap in the sites that maternal obesity and underweight relate to. A positive association, where higher methylation is associated with a body mass index (BMI) outside the normal range, was seen at 78.6% of the sites associated with obesity and 87.9% of the sites associated with underweight. Associations of maternal obesity with offspring methylation were stronger than associations of paternal obesity, supporting an intrauterine mechanism. There were no consistent associations of gestational weight gain with offspring DNA methylation. In general, sites that were hypermethylated in association with maternal obesity or hypomethylated in association with maternal underweight tended to be positively associated with offspring adiposity, and sites hypomethylated in association with maternal obesity or hypermethylated in association with maternal underweight tended to be inversely associated with offspring adiposity. Conclusions: Our data suggest that both maternal obesity and, to a larger degree, underweight affect the neonatal epigenome via an intrauterine mechanism, but weight gain during pregnancy has little effect. We found some evidence that associations of maternal underweight with lower offspring adiposity and maternal obesity with greater offspring adiposity may be mediated via increased DNA methylation.

Low energy availability (EA) is suspected to be the underlying cause of both the Female Athlete Triad and the more recently defined syndrome, Relative Energy Deficiency in Sport (RED-S). The International Olympic Committee (IOC) defined RED-S as a syndrome of health and performance impairments resulting from an energy deficit. While the importance of adequate EA is generally accepted, few studies have attempted to understand whether low EA is associated with the health and performance consequences posited by the IOC. Objective The purpose of this cross-sectional study was to examine the association of low EA with RED-S health and performance consequences in a large clinical population of female athletes. Methods One thousand female athletes (15–30 years) completed an online questionnaire and were classified as having low or adequate EA. The associations between low EA and the health and performance factors listed in the RED-S models were evaluated using chi-squared test and the odds ratios were evaluated using binomial logistic regression (p<0.05). Results Athletes with low EA were more likely to be classified as having increased risk of menstrual dysfunction, poor bone health, metabolic issues, haematological detriments, psychological disorders, cardiovascular impairment and gastrointestinal dysfunction than those with adequate EA. Performance variables associated with low EA included decreased training response, impaired judgement, decreased coordination, decreased concentration, irritability, depression and decreased endurance performance. Conclusion These findings demonstrate that low EA measured using self-report questionnaires is strongly associated with many health and performance consequences proposed by the RED-S models.

DNA methylation-based biomarkers of aging are highly correlated with actual age. Departures of methylation-estimated age from actual age can be used to define epigenetic measures of child development or age acceleration (AA) in adults. Very little is known about genetic or environmental determinants of these epigenetic measures of aging. We obtained DNA methylation profiles using Infinium HumanMethylation450 BeadChips across five time-points in 1018 mother–child pairs from the Avon Longitudinal Study of Parents and Children. Using the Horvath age estimation method, we calculated epigenetic age for these samples. AA was defined as the residuals from regressing epigenetic age on actual age. AA was tested for associations with cross-sectional clinical variables in children. We identified associations between AA and sex, birth weight, birth by caesarean section and several maternal characteristics in pregnancy, namely smoking, weight, BMI, selenium and cholesterol level. Offspring of non-drinkers had higher AA on average but this difference appeared to resolve during childhood. The associations between sex, birth weight and AA found in ARIES were replicated in an independent cohort (GOYA). In children, epigenetic AA measures are associated with several clinically relevant variables, and early life exposures appear to be associated with changes in AA during adolescence. Further research into epigenetic aging, including the use of causal inference methods, is required to better our understanding of aging.

Objectives The menstrual cycle can affect sports participation and exercise performance. There are very few data on specific menstrual cycle symptoms (symptoms during various phases of the cycle, not only during menstruation) experienced by exercising women. We aimed to characterise the most common symptoms, as well as the number and frequency of symptoms, and evaluate whether menstrual cycle symptoms are associated with sporting outcomes. Methods 6812 adult women of reproductive age (mean age: 38.3 (8.7) years) who were not using combined hormonal contraception were recruited via the Strava exercise app user database and completed a 39-part survey. Respondents were from seven geographical areas, and the questions were translated and localised to each region (Brazil, n=892; France, n=1355; Germany, n=839; Spain, n=834; UK and Ireland, n=1350; and USA, n=1542). The survey captured exercise behaviours, current menstrual status, presence and frequency of menstrual cycle symptoms, medication use for symptoms, perceived effects of the menstrual cycle on exercise and work behaviours, and history of hormonal contraception use. We propose a novel Menstrual Symptom index (MSi) based on the presence and frequency of 18 commonly reported symptoms (range 0–54, where 54 would correspond to all 18 symptoms each occurring very frequently). Results The most prevalent menstrual cycle symptoms were mood changes/anxiety (90.6%), tiredness/fatigue (86.2%), stomach cramps (84.2%) and breast pain/tenderness (83.1%). After controlling for body mass index, training volume and age, the MSi was associated with a greater likelihood of missing or changing training (OR=1.09 (CI 1.08 to 1.10); p≤0.05), missing a sporting event/competition (OR=1.07 (CI 1.06 to 1.08); p≤0.05), absenteeism from work/academia (OR=1.08 (CI 1.07 to 1.09); p≤0.05) and use of pain medication (OR=1.09 (CI 1.08 to 1.09); p≤0.05). Conclusion Menstrual cycle symptoms are very common in exercising women, and women report that these symptoms compromise their exercise participation and work capacity. The MSi needs to be formally validated (psychometrics); at present, it provides an easy way to quantify the frequency of menstrual cycle symptoms.