Worldwide the number of children and adolescents with risk factors for cardiovascular disease such as obesity and high blood pressure is increasing. Prevention strategies to reduce blood pressure and obesity are a national and international public health priority.
The relationships between diet and obesity and cardiovascular risk factors such as high blood pressure have been studied in adult populations but there are fewer corresponding studies in adolescents.
This project aims to
• Explore the relationships between diet, body size and adiposity, blood pressure and biomarkers for cardiovascular health (such as serum lipids and serum tocopherols) in UK adolescents from the ALSPAC cohort.
• Determine aspects of diet that increase children’s and adolescents’ likelihood of future obesity and high blood pressure.
• Develop a dietary based risk tool to identify groups of young people at high risk of future obesity during their teenage years.

It is widely accepted that early life influences shape our development and health and behavioural outcomes across the lifecourse. Epigenetic mechanisms are increasingly implicated in these complex interactions and provide a key to understanding (i) what aspects of our environment impact upon gene regulation, (ii) how our environment and way of living become embodied in human biology, over what time frame and with what degree of persistence and (iii) how social and biological inequality may influence development and health.

Environmental chemicals which are known to interfere with the intra-cellular signalling and regulatory effects of human hormones (particularly the male and female sex hormones, respectively androgen and estrogen) are collectively termed endocrine disrupting chemicals (EDCs). Exposure to anti-androgenic EDCs, especially during critical perinatal developmental period, is thought to have broad biological effects, possibly contributing to increased risk of congenital malformations of the reproductive tract and male infertility. However, detailed mechanistic characterisation of the impacts of exposure to EDCs, especially to broad regulatory features such as epigenetic modifications, has yet to be performed.

This project builds upon a substantial foundation of epigenetic research in richly
characterised longitudinal cohort studies to explore how early life EDC exposures may perturb the epigenome. We will utilise the Avon Longitudinal Study of Parents and Children, which currently has the most extensive collection of longitudinal epigenetic data of any birth cohort study in the world, as a platform to address the impact of EDC exposures. Specifically, we will utilize the exposure measurements of the CONTAMED (contaminant mixtures and human reproductive health) study which previously measured several potential EDCs (paracetamol, dichloro-anilines, phthalate metabolites, bisphenol A, triclosan, o-phenylphenol, and parabens) in three different types of biological samples (urine, plasma, placenta), to understand how these compounds influence epigenetic signatures and downstream outcomes.

Approximately 7% of children who start primary school in the UK have language difficulties. Children with a diagnosed language disorder have worse mental health compared to those without. Moreover, nearly 40% of children with a speech and language disability have experienced abuse (emotional, physical, & sexual), which is 4 times higher than children with no disability. Despite the serious implications, children with language difficulties often go un-noticed.

The project will identify the pathways that lead depression during adolescence. For example, it may be that children with high genetic risk for language difficulties, who experience childhood abuse, go on to have language difficulties, which then leads to depression during adolescence. If this were to be the case, it would allow for clinical psychologists and speech therapists to work with victims of childhood abuse to improve their language ability with a view to reducing the associated mental health difficulties.

Understanding the role of genetic language risk in the pathways from childhood abuse to depression symptoms in adolescence will inform targeted language based interventions for the most vulnerable children.

The "metabolome" refers to the entire array of small molecules (metabolites) of different types that are found in the body. Metabolites may be exogenous (e.g. from diet, drugs), or endogenous, reflecting the substrates, intermediates and products of biochemical reactions. Metabolites include amino acids, peptides, lipids and lipoproteins, organic acids and carbohydrates, as well as many smaller molecules.

Proton nuclear magnetic resonance (NMR) metabolomics, in contrast to the other main analytical tool (mass spectrometry), gives information regarding a few hundred larger intact molecules whose physiological roles are largely at least partly understood. NMR has higher reproducibility than mass spectrometry.

The Brainshake platform (https://www.brainshake.fi/biomarkers) allows simultaneous analysis of ~230 NMR metabolites on serum or plasma. This technology is increasingly applied to large adult cohorts, identifying metabolites individually and in combination that are strongly predictive of disease risk of various kinds, in particular cardiovascular. There are much fewer data in children, with only one published study to date. This reported the relationship between GlycA (a composite marker of inflammation derived from the NMR analysis) and obesity and fitness in early adolescence (Ref).

With local collaborators we have recently obtained Brainshake metabolomic data for two population-based cohorts (and a number of smaller groups of children) in Victoria, Australia, and are seeking to combine these data with other large series internationally in order to characterise the age-related development of the metabolome across childhood in normal healthy children. This will provide important information that will enable us and others to interpret the significance of metabolomic data from a range of clinical populations. As far as we are aware (including personal communication with Peter Wurtz of Brainshake), the age- and sex-related profile of the metabolome across childhood is largely unknown.

Substance use and substance abuse occur at much higher levels in populations with mental health problems than in the general population, but the reasons for this are hard to untangle. Does poor mental health cause substance use, does substance abuse increase the risk of mental health problems, or are both affected by earlier life experiences? In order to try and untangle causality, methods such as Mendelian randomization can be used, where genetic predictors are used as proxies for confounded associations.

Sleep matters to those who care for young children. The duration and timing of sleep can have a profound effect on a young child’s everyday behaviour, learning and health and also has a significant impact on the routines and wellbeing of the adults who provide his or her care . Yet there is surprisingly little evidence regarding the developmental function of early sleep patterning to guide care practice. Current understanding of the processes underpinning the normative transition from multiple sleep wake cycles seen in infancy (polyphasic sleep) through to consolidation of sleep into a single night period (monophasic sleep) is limited. Age at cessation of napping occurs anywhere between age 1 and 5 years but we do not know whether this timing holds significance for long–term behavior, learning and health. Care practices almost certainly influence this timing but we do not understand in what way or to what effect. Understanding the developmental meaning of changing sleep patterns, the association of individual sleep patterns with variation in care environments and the pathway from these to long-term child outcomes are all necessary steps in identifying appropriate care. This knowledge will inform policy and practice in childcare settings where management of sleep is an issue of controversy and also inform parenting practice where early child sleep behaviours can have a major impact on family functiioning, parent wellbeing and child development

There is some evidence of a link between paracetamol use during pregnancy and detrimental effects on offspring cognition and behaviour including an increased risk for attention-deficit/hyperactivity and autism spectrum disorder symptoms. Several strategies have been used to test whether other behaviours or exposure related with maternal paracetamol use are confounding this association including partial adjustment by genetic and familial confounding. The use of other drugs during pregnancy and partner’s paracetamol use have previously been used as negative controls.
A large study combining results (meta-analysis) from several European birth-cohorts and accounting for the most relevant sources of confounding including child postnatal paracetamol use is needed to best inform public health advice. In this regard, given its severity and prevalence increase, there is special concern regarding the link between prenatal paracetamol exposure and child autism spectrum disorder symptoms. We plan to conduct this analysis in ALSPAC which will then be meta-analysed with the results from several other birth cohorts.

Emergency contraception (i.e. the morning after pill) is available directly from pharmacies as well as on prescription from a GP, in fact pharmacists currently provide around a third of all emergency contraception, without a prescription from a GP. It has been suggested that women who are in an abusive/violent relationship may be more likely to use emergency contraception, compared to those who are not, as their partner may persuade them to have unprotected sex or commit rape. A training programme has been developed to assist GPs and sexual health workers in identifying and supporting victims of domestic violence. Given that women may also visit their pharmacist for emergency contraception the question has been raised as to whether pharmacists would also benefit from this training programme. First, we need to find evidence to support the suggestion that women who experience domestic violence are more likely to use emergency contraception. This project using the ALSPAC resource will provide one set of evidence to help answer this question.

Depression is the leading cause of disability in the United States and represents a major public health burden. The proposed research focuses on epigenetic markers of depression because these are potential mechanisms by which environmental exposures during critical periods of development alter the expression of genes related to behaviors, affective states, and cognitions that increase vulnerability for depression. We aim to identify epigenetic correlates of depression symptom trajectories that are predicted to vary in terms of their severity and course across adolescence and to test whether these epigenetic differences partly explain emerging sex differences in the prevalence of depression in adolescence. Moving beyond a candidate gene, cross-sectional approach, we propose to prospectively examine the extent to which DNA methylation profiles at two sensitive points in development – birth and adolescence – are associated with trajectories of depression symptoms from early to late adolescence.