Systematic investigation of organochlorine pesticides and polychlorinated biphenyls blood levels in Greek children from the Rhea birth cohort suggests historical exposure to DDT and through diet to DDE

Data availability: Data will be made available on request.Supplementary data are available online at: https://www.sciencedirect.com/science/article/pii/S0160412024002721#s0090:~:text=Appendix%20A.-,Supplementary%20data,-Data%20availability .The blood levels of organochlorine pesticides (OCPs) and polychlorinated biphenyls (PCBs) have been thoroughly investigated in Greek children from the Rhea birth cohort study. This investigation aimed to assess exposure levels, explore their possible relationship with children's age and sex, and indicate potential sources of exposure. Exposure patterns and common sources of PCBs and OCPs were analyzed using bivariate and multivariate statistics. A total of 947 blood samples from study participants were analyzed for OCP and PCB exposure, with 375 samples collected at 4 years old, 239 at 6.5 years old, and 333 at 11 years old. Elevated levels of DDE were observed in 6.5-year-old children compared to corresponding levels in other European countries. Higher levels of DDE were found in 4-year-old children, with the lowest concentrations in the 11-year-old group. The DDT/DDE ratio was consistently less than 1 among all the examined subjects. These results indicate exposure to DDT and DDE both in utero and through breastfeeding and dietary intake. For the entire cohort population, the highest concentration was determined for PCB 28, followed by PCBs 138, 153, and 180. The sum of the six indicator PCBs implied low exposure levels for the majority of the cohort population. Spearman correlations revealed strong associations between PCBs and OCPs, while principal component analysis identified two different groupings of exposure. DDE exhibited a correlation with a series of PCBs (153, 156, 163, 180), indicating a combined OCP-PCB source, and an anticorrelation with others (52, 28, 101), implying a separate and competing source.Hellenic Ministry of Health and the General Secretariat for Research and Innovation

Maternal mild thyroid dysfunction and offspring cognitive and motor development from infancy to childhood: the Rhea mother-child cohort study in Crete, Greece

BACKGROUND: Maternal thyroid hormones’ supply is crucial for fetal neurodevelopment; however, the role of maternal mild thyroid dysfunction is not clear. We aimed to assess the association of maternal mild thyroid dysfunction with child neuropsychological development from infancy to early childhood. METHODS: We included 757 mother-child pairs from the prospective “Rhea” cohort on Crete, Greece. Maternal thyroid functioning was assessed by quantitative analysis of serum thyroid stimulating hormone (TSH), free thyroxine (fT4), thyroid peroxidase antibodies (TPO-Abs), and thyroglobulin antibodies (Tg-Abs) at early gestation (mean=14 weeks). Neuropsychological assessment was based on Bayley Scales of Infant Development (18 months of age), McCarthy Scales of Children’s Abilities (4 years of age), Raven’s Coloured Progressive Matrices, Trail Making Test, and Finger Tapping Test (6 years of age). RESULTS: In multivariate adjusted linear regression analyses maternal hypothyroxinemia was associated with decreased verbal scores at 4 years and reduced motor speed at 6 years of age. Maternal thyroid autoimmunity was associated with decreased child perceptual and motor ability at 4 years of age. Four trajectories of longitudinal non-verbal cognitive development were identified and children exposed to maternal thyroid autoimmunity had increased risk for belonging to an adverse trajectory (“Low”: adjusted-RRR = 2.7 95%CI: [1.4, 5.2], “High-decreasing”: adjusted-RRR = 2.2 95%CI: [1.2, 4.0], “Low-increasing”: adjusted-RRR = 1.8 95%CI: [1.0, 3.2]). CONCLUSION: Maternal hypothyroxinemia is associated with reduced offspring verbal and motor ability. Maternal thyroid autoimmunity is associated with decreased offspring perceptual performance and motor ability and increased risk for adverse non-verbal cognitive development from infancy to childhood

The longitudinal association of eating behaviour and ADHD symptoms in school age children: a follow-up study in the RHEA cohort

BACKGROUND: Previous evidence suggests a link between ADHD symptoms and disordered eating behaviours, however the direction of the causal association remains unclear. Building on our previous research, we aimed to examine the longitudinal association between eating behaviours at 4 years, ADHD symptoms at 6 years of age, and the role of body mass index (BMI). METHODS: We included children from the RHEA mother-child cohort in Greece, followed up at 4 and 6 years (n=926). Parents completed the Children’s Eating Behaviour Questionnaire (CEBQ) to assess children’s eating behaviour at 4 years and the ADHD Test (ADHDT) and Child Behaviour Checklist for ages 6–18 (CBCL/6–18) to evaluate ADHD symptoms at 4 and 6 years respectively, as well as measures of BMI. Longitudinal Structural Equation Modeling (SEM) was carried out to evaluate the associations of all variables between 4 and 6 years. RESULTS: Food responsiveness at 4 years was positively associated with hyperactivity at age 6, whereas emotional overeating was negatively associated with hyperactivity. There was no evidence of an association between eating behaviours of preschoolers and BMI at 6 years, or BMI at 4 years and later ADHD symptoms and vice versa. CONCLUSIONS: Findings suggest that food responsiveness is an early marker of ADHD symptoms at 6 years of age. In contrast to our hypothesis there was no significant association between ADHD at age 4 and BMI at age 6

Cord Leptin is Associated with Neuropsychomotor Development in Childhood

Objective: Leptin is critical for central nervous system development and maturation. This study aimed to evaluate the potential regulatory role of cord leptin in the neuropsychomotor development of children ages 18 months to 6 years. Methods: This study included 424 children from a prospective mother-child cohort (Rhea Study; Crete, Greece) with available cord leptin levels and data on neurodevelopmental outcomes at 18 months (Bayley Scales of Infant and Toddler Development, Third Edition), 4 years (McCarthy Scales of Children's Abilities), and 6 years (Raven's Coloured Progressive Matrices and Trail Making Test). Multivariable linear regression models were used to explore the associations. Results: Each 10-ng/mL increase in the cord leptin level was associated with increased scores on the gross motor scale at 18 months (β coefficient: 3.8; 95% CI: 0.0-7.5), with decreased scores in the general cognitive performance (β coefficient: −3.0; 95% CI: −5.5 to −0.4), perceptual performance (β coefficient: −3.4; 95% CI: −6.0 to −9.9), working memory (β coefficient: −3.1; 95% CI: −5.7 to −0.4), executive function (β coefficient −3.1; 95% CI: −5.7 to −0.5), and functions of the posterior cortex (β coefficient: −2.7; 95% CI: −5.2 to −0.1) scales at 4 years, and with a 3.7-unit decrease in the Raven's Coloured Progressive Matrices score at 6 years (β coefficient: −3.7; 95% CI: −6.9 to −0.5). Conclusions: Increased cord leptin levels are associated with enhanced gross motor development at 18 months but decreased cognitive performance in early and middle childhood. © 2019 The Obesity Societ

Unraveling the Serum Metabolomic Profile of Post-partum Depression

Post-partum depression (PPD) is a severe psychiatric disorder affecting similar to 15% of young mothers. Early life stressful conditions in periconceptual, fetal and early infant periods or exposure to maternal psychiatric disorders, have been linked to adverse childhood outcomes interfering with physiological, cognitive and emotional development. The molecular mechanisms of PPD are not yet fully understood. Unraveling the molecular underpinnings of PPD will allow timely detection and establishment of effective therapeutic approaches. To investigate the underlying molecular correlates of PPD in peripheral material, we compared the serum metabolomes of an in detail characterized group of mothers suffering from PPD and a control group of mothers, all from Heraklion, Crete in Greece. Serum samples were analyzed by a mass spectrometry platform for targeted metabolomics, based on selected reaction monitoring (SRM), which measures the levels of up to 300 metabolites. In the PPD group, we observed increased levels of glutathione-disulfide, adenylosuccinate, and ATP, which associate with oxidative stress, nucleotide biosynthesis and energy production pathways. We also followed up the metabolomic findings in a validation cohort of PPD mothers and controls. To the very best of our knowledge, this is the first metabolomic serum analysis in PPD. Our data show that molecular changes related to PPD are detectable in peripheral material, thus paving the way for additional studies in order to shed light on the molecular correlates of PPD

Polyunsaturated fatty acid levels at birth and child-to-adult growth: Results from the MEFAB cohort

BACKGROUND: Prenatal exposure to polyunsaturated fatty acids (PUFAs) may influence childhood growth. However, available evidence mostly derived from short-term studies is inconsistent. OBJECTIVE: To assess whether fetal PUFA exposure is associated with height and body mass index (BMI), a common measure of adiposity, from 6 months to 23 years of age. METHODS: In the MEFAB cohort, we assessed cord blood phospholipid n-3 and n-6 PUFA levels, reflecting fetal exposure in late pregnancy. For 250 (45.2% females) participants, we collected a total of 1770 (n= 802 for females) repeated growth measurements from infancy to young adulthood. We examined sex-specific associations of PUFAs with height and BMI at different developmental ages (infant: 6 months; toddler: 2 years; pre-schooler: 4 years; school-aged child: 7 years; adolescent: 12 years; and young adult: 23 years) using fractional polynomial mixed models adjusted for important covariates. RESULTS: Higher n-3 PUFA levels were associated with higher infant length in males (β= 0.44cm [95% CI: 0.07, 0.82] per SD increase), whereas, for females, higher n-6 PUFA concentrations were associated with lower length in infancy (β= -0.69cm [95% CI: -1.08, -0.30] per SD increase). A higher ratio of n-3 to n-6 PUFAs was associated with higher infant length in both sexes (β= 0.40cm [95% CI: 0.01, 0.78] and 0.42cm [95% CI: 0.05, 0.79] per unit increase for males and females, respectively). These associations were not detectable later in childhood and young adulthood. No associations with BMI were found at any time point examined. CONCLUSIONS: Our findings suggest a small sex-specific influence of PUFA status at birth on length in infancy, but this does not persist in later life up to young adulthood. PUFA status at birth does not seem to affect BMI from infancy till young adulthood

In utero exposure to mercury is associated with increased susceptibility to liver injury and inflammation in childhood

Nonalcoholic fatty liver disease (NAFLD) is the most prevalent cause of liver disease in children. Mercury (Hg), a ubiquitous toxic metal, has been proposed as an environmental factor contributing to toxicant‐associated fatty liver disease. We investigated the effect of prenatal exposure to Hg on childhood liver injury by combining epidemiological results from a multicenter mother‐child cohort with complementary in vitro experiments on monocyte cells that are known to play a key role in liver immune homeostasis and NAFLD. We used data from 872 mothers and their children (median age, 8.1 years; interquartile range [IQR], 6.5‐8.7) from the European Human Early‐Life Exposome (HELIX) cohort. We measured Hg concentration in maternal blood during pregnancy (median, 2.0 μg/L; IQR, 1.1‐3.6). We also assessed serum levels of alanine aminotransferase (ALT), a common screening tool for pediatric NAFLD, and plasma concentrations of inflammation‐related cytokines in children. We found that prenatal Hg exposure was associated with a phenotype in children that was characterized by elevated ALT (≥22.1 U/L for females and ≥25.8 U/L for males) and increased concentrations of circulating interleukin (IL)‐1β, IL‐6, IL‐8, and tumor necrosis factor α (TNF‐α). Consistently, inflammatory monocytes exposed in vitro to a physiologically relevant dose of Hg demonstrated significant up‐regulation of genes encoding these four cytokines and increased concentrations of IL‐8 and TNF‐α in the supernatants. Conclusion: These findings suggest that developmental exposure to Hg can contribute to inflammation and increased NAFLD risk in early life

Urinary metabolic biomarkers of diet quality in European children are associated with metabolic health

Urinary metabolic profiling is a promising powerful tool to reflect dietary intake and can help understand metabolic alterations in response to diet quality. Here, we used 1H NMR spectroscopy in a multicountry study in European children (1147 children from 6 different cohorts) and identified a common panel of 4 urinary metabolites (hippurate, N-methylnicotinic acid, urea, and sucrose) that was predictive of Mediterranean diet adherence (KIDMED) and ultra-processed food consumption and also had higher capacity in discriminating children's diet quality than that of established sociodemographic determinants. Further, we showed that the identified metabolite panel also reflected the associations of these diet quality indicators with C-peptide, a stable and accurate marker of insulin resistance and future risk of metabolic disease. This methodology enables objective assessment of dietary patterns in European child populations, complementary to traditional questionary methods, and can be used in future studies to evaluate diet quality. Moreover, this knowledge can provide mechanistic evidence of common biological pathways that characterize healthy and unhealthy dietary patterns, and diet-related molecular alterations that could associate to metabolic disease.The HELIX project has received funding from the European Community’s Seventh Framework Programme (FP7/2007–2013) under grant agreement no. 308,333. The STOP project (http://www.stopchildobesity.eu/) received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement no. 774,548. The STOP Consortium is coordinated by Imperial College London and includes 24 organizations across Europe, the United States, and New Zealand. The content of this publication reflects only the views of the authors, and the European Commission is not liable for any use that may be made of the information it contains. INMA data collections were supported by grants from the Instituto de Salud Carlos III, CIBERESP, and the Generalitat de Catalunya-CIRIT. KANC was funded by the grant of the Lithuanian Agency for Science Innovation and Technology (6-04-2014_31 V-66). For a full list of funding that supported the EDEN cohort, refer to: Heude B et al. Cohort Profile: The EDEN mother–child cohort on the prenatal and early postnatal determinants of child health and development. Int J Epidemiol. 2016 Apr;45(2):353–63. The Norwegian Mother, Father and Child Cohort Study (MoBa) is supported by the Norwegian Ministry of Health and Care Services and the Ministry of Education and Research. The Rhea project was financially supported by European projects, and the Greek Ministry of Health (Program of Prevention of Obesity and Neurodevelopmental Disorders in Preschool Children, in Heraklion district, Crete, Greece: 2011–2014; 'Rhea Plus': Primary Prevention Program of Environmental Risk Factors for Reproductive Health, and Child Health: 2012–2015). Born in Bradford received funding from the Wellcome Trust (101597). Professor Wright and McEachan receive funding from the National Institute for Health Research Applied Research Collaboration for Yorkshire and Humber. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. Dr. Maribel Casas received funding from Instituto de Salud Carlos III (Ministry of Economy and Competitiveness) (MS16/00128). Dr. Leda Chatzi was supported by NIH/NIEHS R01 ES029944, R01ES030691, R01ES030364, R21 ES029681, R21 ES028903, and P30 ES007048-23. Dr. David Conti was supported by P01CA196569, R01CA140561, R01 ES016813, R01 ES029944, R01ES030691, and R01ES030364. Dr. Nikos Stratakis was supported by NIH/NIEHS R21 ES029681 and P30 ES007048-23, and NIH/NIDDK P30 DK048522-24. Dr. Hector Keun and Dr. Alexandros Siskos were also supported by the European Union’s Horizon 2020 research and innovation programme under grant agreement no. 874,583 ('ATHLETE'). Dr. Eleni Papadopoulou was supported by the Research Council of Norway, under the MILJØFORSK program (project no. 268465). Dr. Fernanda Rauber was supported by the Fundação de Amparo à Pesquisa do Estado de São Paulo 2016/14302-7 and 2018/19820-1. The CRG/UPF Proteomics Unit is part of the Spanish Infrastructure for Omics Technologies (ICTS OmicsTech) and it is a member of the ProteoRed PRB3 consortium which is supported by grant PT17/0019 of the PE I + D + i 2013–2016 from the Instituto de Salud Carlos III (ISCIII) and ERDF. ISGlobal acknowledges support from the Spanish Ministry of Science, Innovation and Universities, 'Centro de Excelencia Severo Ochoa 2013–2017', SEV-2012–0208, and 'Secretaria d’Universitats i Recerca del Departament d’Economia i Coneixement de la Generalitat de Catalunya' (2017SGR595)