Evaluation and comparison of nine growth and development-based measures of pubertal timing.

BACKGROUND: Pubertal timing is heritable, varies between individuals, and has implications for life-course health. There are many different indicators of pubertal timing, and how they relate to each other is unclear. Our aim was to quantitatively compare nine indicators of pubertal timing. METHODS: We used data from questionnaires and height, weight, and bone measurements from ages 7-17 y in a population-based cohort of 4267 females and 4251 males to compare nine growth and development-based indicators of pubertal timing. We summarise age of each indicator, their phenotypic and genetic correlations, and how they relate to established genetic risk score (GRS) for puberty timing, and phenotypic childhood body composition measures. RESULTS: We show that pubic hair in males (mean: 12.6 y) and breasts in females (11.5 y) are early indicators of puberty, and voice breaking (14.2 y) and menarche (12.7 y) are late indicators however, there is substantial variation between individuals in pubertal age. All indicators show evidence of positive phenotypic intercorrelations (e.g., r = 0.49: male genitalia and pubic hair ages), and positive genetic intercorrelations. An age at menarche GRS positively associates with all other pubertal age indicators (e.g., difference in female age at peak height velocity per SD higher GRS: 0.24 y, 95%CI: 0.21 to 0.26), as does an age at voice breaking GRS (e.g., difference in age at male axillary hair: 0.11 y, 0.07 to 0.15). Higher childhood fat mass and lean mass associated with earlier puberty timing. CONCLUSIONS: Our findings provide insights into the measurements of the timing of pubertal growth and development and illustrate value of various pubertal timing indicators in life-course research.

Age of puberty varies between individuals and can affect a person's future health. We obtained information from 8500 British children as they progressed through puberty. We compared nine measures of pubertal timing. We found that the appearance of pubic hair in boys and breasts in girls are early indicators of puberty, and that voice change and onset of menstruation are late indicators. However, there was also substantial variability between individuals in age of puberty. All puberty measures were correlated with each other and related to an individual's adult body mass index, as well as to their childhood muscle and fat mass. Our findings are useful information for health care workers and researchers who are interested in assessing and studying puberty.

Prenatal Urban Environment and Blood Pressure Trajectories From Childhood to Early Adulthood.

Background: Prenatal urban environmental exposures have been associated with blood pressure in children. The dynamic of these associations across childhood and later ages is unknown. Objectives: The purpose of this study was to assess associations of prenatal urban environmental exposures with blood pressure trajectories from childhood to early adulthood. Methods: Repeated measures of systolic blood pressure (SBP) and diastolic blood pressure (DBP) were collected in up to 7,454 participants from a UK birth cohort. Prenatal urban exposures (n = 43) covered measures of noise, air pollution, built environment, natural spaces, traffic, meteorology, and food environment. An exposome-wide association study approach was used. Linear spline mixed-effects models were used to model associations of each exposure with trajectories of blood pressure. Replication was sought in 4 independent European cohorts (up to 9,261). Results: In discovery analyses, higher humidity was associated with a faster increase (mean yearly change in SBP for an interquartile range increase in humidity: 0.29 mm Hg/y, 95% CI: 0.20-0.39) and higher temperature with a slower increase (mean yearly change in SBP per interquartile range increase in temperature: -0.17 mm Hg/y, 95% CI: -0.28 to -0.07) in SBP in childhood. Higher levels of humidity and air pollution were associated with faster increase in DBP in childhood and slower increase in adolescence. There was little evidence of an association of other exposures with change in SBP or DBP. Results for humidity and temperature, but not for air pollution, were replicated in other cohorts. Conclusions: Replicated findings suggest that higher prenatal humidity and temperature could modulate blood pressure changes across childhood.

Ultra-processed foods, adiposity and risk of head and neck cancer and oesophageal adenocarcinoma in the European Prospective Investigation into Cancer and Nutrition study: a mediation analysis.

PURPOSE: To investigate the role of adiposity in the associations between ultra-processed food (UPF) consumption and head and neck cancer (HNC) and oesophageal adenocarcinoma (OAC) in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. METHODS: Our study included 450,111 EPIC participants. We used Cox regressions to investigate the associations between the consumption of UPFs and HNC and OAC risk. A mediation analysis was performed to assess the role of body mass index (BMI) and waist-to-hip ratio (WHR) in these associations. In sensitivity analyses, we investigated accidental death as a negative control outcome. RESULTS: During a mean follow-up of 14.13 ± 3.98 years, 910 and 215 participants developed HNC and OAC, respectively. A 10% g/d higher consumption of UPFs was associated with an increased risk of HNC (hazard ratio [HR] = 1.23, 95% confidence interval [CI] 1.14-1.34) and OAC (HR = 1.24, 95% CI 1.05-1.47). WHR mediated 5% (95% CI 3-10%) of the association between the consumption of UPFs and HNC risk, while BMI and WHR, respectively, mediated 13% (95% CI 6-53%) and 15% (95% CI 8-72%) of the association between the consumption of UPFs and OAC risk. UPF consumption was positively associated with accidental death in the negative control analysis. CONCLUSIONS: We reaffirmed that higher UPF consumption is associated with greater risk of HNC and OAC in EPIC. The proportion mediated via adiposity was small. Further research is required to investigate other mechanisms that may be at play (if there is indeed any causal effect of UPF consumption on these cancers).

Mediators of the association between childhood body mass index and educational attainment: Analysis of a UK prospective cohort study.

BACKGROUND: Higher body mass index (BMI) in childhood is associated with lower academic achievement. OBJECTIVE: To explore potential pathways linking childhood BMI with educational attainment. METHODS: Using data from the Avon Longitudinal Study of Parents and Children prospective cohort study (N = 6949), we assessed the association between BMI z-scores at 11.7 years and educational attainment at 16 (General Certificate of Secondary Education [GCSE] results). Depressive symptoms, externalizing behaviours, bullying and school enjoyment were considered as potential mediators. Mediators were examined individually and jointly using sequential causal mediation. RESULTS: Higher BMI z-scores were associated with lower GCSE scores (females ß = -3.47 95% CI -5.54, -1.41 males ß = -4.33 95% CI -6.73, -1.94). Together, bullying, externalizing symptoms, depressive symptoms and school enjoyment mediated 41.9% of this association in females, and 23.3% in males. In males, evidence for mediation was weak (confidence intervals for all indirect effects spanned the null). In both females and males, most of the mediation was driven by externalizing symptoms. CONCLUSIONS: The detrimental effect of higher BMI on educational attainment appears to be partly explained by externalizing behaviours, particularly in females. Interventions to support behavioural problems may help the academic achievement of children with a higher body weight.

Genome-wide association study meta-analysis identifies three novel loci for circulating anti-Müllerian hormone levels in women.

STUDY QUESTION: Can additional genetic variants for circulating anti-Müllerian hormone (AMH) levels be identified through a genome-wide association study (GWAS) meta-analysis including a large sample of premenopausal women? SUMMARY ANSWER: We identified four loci associated with AMH levels at P < 5 × 10-8: the previously reported MCM8 locus and three novel signals in or near AMH, TEX41 and CDCA7. WHAT IS KNOWN ALREADY: AMH is expressed by antral stage ovarian follicles in women, and variation in age-specific circulating AMH levels has been associated with disease outcomes. However, the physiological mechanisms underlying these AMH-disease associations are largely unknown. STUDY DESIGN, SIZE, DURATION: We performed a GWAS meta-analysis in which we combined summary statistics of a previous AMH GWAS with GWAS data from 3705 additional women from three different cohorts. PARTICIPANTS/MATERIALS, SETTING, METHODS: In total, we included data from 7049 premenopausal female participants of European ancestry. The median age of study participants ranged from 15.3 to 48 years across cohorts. Circulating AMH levels were measured in either serum or plasma samples using different ELISA assays. Study-specific analyses were adjusted for age at blood collection and population stratification, and summary statistics were meta-analysed using a standard error-weighted approach. Subsequently, we functionally annotated GWAS variants that reached genome-wide significance (P < 5 × 10-8). We also performed a gene-based GWAS, pathway analysis and linkage disequilibrium score regression and Mendelian randomization (MR) analyses. MAIN RESULTS AND THE ROLE OF CHANCE: We identified four loci associated with AMH levels at P < 5 × 10-8: the previously reported MCM8 locus and three novel signals in or near AMH, TEX41 and CDCA7. The strongest signal was a missense variant in the AMH gene (rs10417628). Most prioritized genes at the other three identified loci were involved in cell cycle regulation. Genetic correlation analyses indicated a strong positive correlation among single nucleotide polymorphisms for AMH levels and for age at menopause (rg = 0.82, FDR = 0.003). Exploratory two-sample MR analyses did not support causal effects of AMH on breast cancer or polycystic ovary syndrome risk, but should be interpreted with caution as they may be underpowered and the validity of genetic instruments could not be extensively explored. LARGE SCALE DATA: The full AMH GWAS summary statistics will made available after publication through the GWAS catalog (https://www.ebi.ac.uk/gwas/). LIMITATIONS, REASONS FOR CAUTION: Whilst this study doubled the sample size of the most recent GWAS, the statistical power is still relatively low. As a result, we may still lack power to identify more genetic variants for AMH and to determine causal effects of AMH on, for example, breast cancer. Also, follow-up studies are needed to investigate whether the signal for the AMH gene is caused by reduced AMH detection by certain assays instead of actual lower circulating AMH levels. WIDER IMPLICATIONS OF THE FINDINGS: Genes mapped to the MCM8, TEX41 and CDCA7 loci are involved in the cell cycle and processes such as DNA replication and apoptosis. The mechanism underlying their associations with AMH may affect the size of the ovarian follicle pool. Altogether, our results provide more insight into the biology of AMH and, accordingly, the biological processes involved in ovarian ageing. STUDY FUNDING/COMPETING INTEREST(S): Nurses' Health Study and Nurses' Health Study II were supported by research grants from the National Institutes of Health (CA172726, CA186107, CA50385, CA87969, CA49449, CA67262, CA178949). The UK Medical Research Council and Wellcome (217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC. This publication is the work of the listed authors, who will serve as guarantors for the contents of this article. A comprehensive list of grants funding is available on the ALSPAC website (http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf). Funding for the collection of genotype and phenotype data used here was provided by the British Heart Foundation (SP/07/008/24066), Wellcome (WT092830M and WT08806) and UK Medical Research Council (G1001357). M.C.B., A.L.G.S. and D.A.L. work in a unit that is funded by the University of Bristol and UK Medical Research Council (MC_UU_00011/6). M.C.B.'s contribution to this work was funded by a UK Medical Research Council Skills Development Fellowship (MR/P014054/1) and D.A.L. is a National Institute of Health Research Senior Investigator (NF-0616-10102). A.L.G.S. was supported by the study of Dynamic longitudinal exposome trajectories in cardiovascular and metabolic non-communicable diseases (H2020-SC1-2019-Single-Stage-RTD, project ID 874739). The Doetinchem Cohort Study was financially supported by the Ministry of Health, Welfare and Sports of the Netherlands. The funder had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. Ansh Labs performed the AMH measurements for the Doetinchem Cohort Study free of charge. Ansh Labs was not involved in the data analysis, interpretation or reporting, nor was it financially involved in any aspect of the study. R.M.G.V. was funded by the Honours Track of MSc Epidemiology, University Medical Center Utrecht with a grant from the Netherlands Organization for Scientific Research (NWO) (022.005.021). The Study of Women's Health Across the Nation (SWAN) has grant support from the National Institutes of Health (NIH), DHHS, through the National Institute on Aging (NIA), the National Institute of Nursing Research (NINR) and the NIH Office of Research on Women's Health (ORWH) (U01NR004061; U01AG012505, U01AG012535, U01AG012531, U01AG012539, U01AG012546, U01AG012553, U01AG012554, U01AG012495). The SWAN Genomic Analyses and SWAN Legacy have grant support from the NIA (U01AG017719). The Generations Study was funded by Breast Cancer Now and the Institute of Cancer Research (ICR). The ICR acknowledges NHS funding to the NIHR Biomedical Research Centre. The content of this manuscript is solely the responsibility of the authors and does not necessarily represent official views of the funders. The Sister Study was funded by the Intramural Research Program of the National Institutes of Health (NIH), National Institute of Environmental Health Sciences (Z01-ES044005 to D.P.S.); the AMH assays were supported by the Avon Foundation (02-2012-065 to H.B. Nichols and D.P.S.). The breast cancer genome-wide association analyses were supported by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research, the 'Ministère de l'Économie, de la Science et de l'Innovation du Québec' through Genome Québec and grant PSR-SIIRI-701, The National Institutes of Health (U19 CA148065, X01HG007492), Cancer Research UK (C1287/A10118, C1287/A16563, C1287/A10710) and The European Union (HEALTH-F2-2009-223175 and H2020 633784 and 634935). All studies and funders are listed in Michailidou et al. (Nature, 2017). F.J.M.B. has received fees and grant support from Merck Serono and Ferring BV. D.A.L. has received financial support from several national and international government and charitable funders as well as from Medtronic Ltd and Roche Diagnostics for research that is unrelated to this study. N.S. is scientific consultant for Ansh Laboratories. The other authors declare no competing interests.

LongITools: Dynamic longitudinal exposome trajectories in cardiovascular and metabolic noncommunicable diseases.

The current epidemics of cardiovascular and metabolic noncommunicable diseases have emerged alongside dramatic modifications in lifestyle and living environments. These correspond to changes in our "modern" postwar societies globally characterized by rural-to-urban migration, modernization of agricultural practices, and transportation, climate change, and aging. Evidence suggests that these changes are related to each other, although the social and biological mechanisms as well as their interactions have yet to be uncovered. LongITools, as one of the 9 projects included in the European Human Exposome Network, will tackle this environmental health equation linking multidimensional environmental exposures to the occurrence of cardiovascular and metabolic noncommunicable diseases.

Abuse in Childhood and Cardiometabolic Health in Early Adulthood: Evidence From the Avon Longitudinal Study of Parents and Children.

Background Although childhood abuse has been consistently associated with cardiovascular disease in later adulthood, its associations with cardiometabolic health in younger adults are poorly understood. We assessed associations between childhood physical, sexual, and psychological abuse and cardiometabolic outcomes at 18 and 25 years. Methods and Results We used data on 3223 participants of the ALSPAC (Avon Longitudinal Study of Parents and Children). Exposure to childhood abuse was self-reported retrospectively at 22 years. We used linear regression to assess the associations between childhood abuse and cardiometabolic outcomes at 18 and 25 years. At 18 years, physical (ß 1.35 kg/m2; 95% CI, 0.66-2.05), sexual (ß 0.57 kg/m2; 95% CI 0.04-1.11), and psychological (ß 0.47 kg/m2; 95% CI 0.01-0.92) abuse were associated with higher body mass index. Physical abuse was also associated with lower high-density lipoprotein cholesterol (ß -0.07 mmol/L; 95% CI, -0.13 to -0.01) and higher C-reactive protein (31%; 95% CI, 1%-69%), and sexual abuse was associated with higher heart rate (ß 1.92 bpm; 95% CI 0.26-3.58). At age 25, all 3 types of abuse were additionally associated with higher insulin, and sexual abuse was associated with lower cholesterol (-0.14 mmol/L; 95% CI, -0.26 to -0.01). The age at which abuse occurred (<11or 11-17 years) had little influence on the associations, and when sex differences were evident, associations were stronger in men. Conclusions Childhood abuse is associated with negative cardiometabolic outcomes even by young adulthood. Further follow-up will determine whether associations strengthen across the life course and whether sex differences persist, which is essential for targeting effective screening programs and early interventions in those who suffered abuse in childhood.

Do inflammation and adiposity mediate the association of diet quality with depression and anxiety in young adults?

BACKGROUND & AIMS: Diet quality has been inversely associated with depression, but less is known about its association with anxiety and about the mechanisms involved in the association between diet and mental health. This study aimed to assess the associations of diet quality with major depressive disorder (MDD) and generalized anxiety disorder (GAD) in young adults, and to explore whether inflammation, indexed by interleukin-6 (IL-6) and C-reactive protein (CRP), and body mass index (BMI) mediate this association. METHODS: We used data of 3331 participants from the 1993 Pelotas Birth Cohort (Brazil). Data on dietary intake and inflammatory markers were assessed at 18 years, and information on mental disorders was obtained at both 18 and 22 years. A food frequency questionnaire was used to assess dietary intake, and diet quality was estimated using the Brazilian Healthy Eating Index - Revised (BHEI-R). The occurrence of MDD and GAD was assessed using the Mini International Neuropsychiatric Interview (MINI), conducted by psychologists. The associations of diet quality, BMI and inflammatory markers with mental disorders were explored using logistic regression. The mediation analysis was performed using structural equation modelling. RESULTS: A one standard deviation increase in the diet quality score at age 18 years was associated with both lower levels of CRP (-0.06 mg/L; 95% CI: -0.10; -0.008) at 18 years and 23% lower odds of MDD at 22 years (OR: 0.77; 95% CI: 0.61; 0.97). No association was found between diet quality score and both BMI and GAD. Obesity was associated with higher odds of MDD, but CRP and IL-6 were not associated with MDD or GAD. Our results provide no evidence that inflammatory markers and BMI mediate the association between diet quality and MDD in young adults. CONCLUSIONS: A better diet quality is associated with lower occurrence of MDD among young adults, but we did not find evidence that inflammatory markers and BMI mediate this association.

Purple pitanga fruit (Eugenia uniflora L.) protects against oxidative stress and increase the lifespan in Caenorhabditis elegans via the DAF-16/FOXO pathway.

Pitanga, a fruit of the pitangueira tree (Eugenia uniflora L.), is native to Brazil and has a high antioxidant capacity due to the elevated amount of anthocyanins. The present study aimed to investigate the chemical composition of the purple pitanga fruit and to evaluate its antioxidant effect in the nematode Caenorhabditis elegans. We observed that the ethanolic extract of purple pitanga did not cause any toxic effects but notably increased worm lifespan. The extract improved the survival, reproduction and lifespan of the worms in pre- and post-exposure to stressors H2O2 and juglone, as well as improved the lifespan of the oxidative stress hypersensitive strain mev-1. Notably, PPE extract decreased reactive oxygen species by DCF-DA probe and protein carbonyl content from worms stressed with H2O2. The extract also affected the expression of superoxide dismutase SOD-3 and heat shock protein HSP-16.2 levels, daf 16 target genes that modulate lifespan and antioxidant metabolism. In addition, we demonstrate that these effects are dependent on DAF-16, as PPE extract did not provide protection in daf-16 mutants. Therefore, these results suggest that PPE significantly protected against oxidative stress modulating daf-16 target genes.

Age of sexual initiation and depression in adolescents: Data from the 1993 Pelotas (Brazil) Birth Cohort.

BACKGROUND: Studies have shown that sexual initiation at earlier ages increases the risk of depressive symptoms in adolescents. However, little is known about its association with major depressive episode (MDE). METHODS: The association between age of sexual initiation and MDE at 18 years was assessed in the 1993 Pelotas Birth Cohort using multiple logistic regression. Sexual initiation characteristics (age and type of partner) were assessed at the 15- and 18-years follow-up. The age of sexual initiation was evaluated in categories (11-14, 15-16, 17+ years). The type of partner was categorized into: boyfriend/ girlfriend, casual partner and other. MDE was assessed using the Mini International Neuropsychiatric Interview (MINI). RESULTS: From the 4027 adolescents assessed, the prevalence of MDE was higher in females (10.1%) than in males (3.4%), and 66.7% of the males and 58.6% of the females reported sexual initiation up to 16 years (p < 0.001). Female adolescents who had sexual initiation <17 years had higher odds of MDE (15-16 years: OR 2.29; 11-14 years: OR 2.23), however no association was found for males. The type of partner in the first sexual intercourse was not associated to depression. LIMITATIONS: Possibility of recall bias on the age of sexual initiation, and low statistical power for some analyses. CONCLUSIONS: A positive association between age of sexual initiation and MDE was observed only in females. More investigation is needed to understand the mechanisms through which age of sexual initiation can affect the risk of depression and whether the association persists in adulthood.