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Environmental exposures during early life play a critical role in life-course health, yet the molecular phenotypes underlying environmental effects on health are poorly understood. In the Human Early Life Exposome (HELIX) project, a multi-centre cohort of 1301 mother-child pairs, we associate individual exposomes consisting of >100 chemical, outdoor, social and lifestyle exposures assessed in pregnancy and childhood, with multi-omics profiles (methylome, transcriptome, proteins and metabolites) in childhood. We identify 1170 associations, 249 in pregnancy and 921 in childhood, which reveal potential biological responses and sources of exposure. Pregnancy exposures, including maternal smoking, cadmium and molybdenum, are predominantly associated with child DNA methylation changes. In contrast, childhood exposures are associated with features across all omics layers, most frequently the serum metabolome, revealing signatures for diet, toxic chemical compounds, essential trace elements, and weather conditions, among others. Our comprehensive and unique resource of all associations (https://helixomics.isglobal.org/) will serve to guide future investigation into the biological imprints of the early life exposome. Environmental exposures in early life can have lasting health effects, but the molecular mechanisms are not well understood. Here, the authors discover >1000 associations between exposure factors and child multi-omics profiles, revealing signatures for diet, toxic chemical compounds, essential trace elements, and weather conditions. [ABSTRACT FROM AUTHOR]

The potential etiological role of early acetaminophen exposure on Autism Spectrum Conditions (ASC) and Attention-Deficit/Hyperactivity Disorder (ADHD) is inconclusive. We aimed to study this association in a collaborative study of six European population-based birth/child cohorts. A total of 73,881 mother–child pairs were included in the study. Prenatal and postnatal (up to 18 months) acetaminophen exposure was assessed through maternal questionnaires or interviews. ASC and ADHD symptoms were assessed at 4–12 years of age using validated instruments. Children were classified as having borderline/clinical symptoms using recommended cutoffs for each instrument. Hospital diagnoses were also available in one cohort. Analyses were adjusted for child and maternal characteristics along with indications for acetaminophen use. Adjusted cohort-specific effect estimates were combined using random-effects meta-analysis. The proportion of children having borderline/clinical symptoms ranged between 0.9 and 12.9% for ASC and between 1.2 and 12.2% for ADHD. Results indicated that children prenatally exposed to acetaminophen were 19% and 21% more likely to subsequently have borderline or clinical ASC (OR = 1.19, 95% CI 1.07–1.33) and ADHD symptoms (OR = 1.21, 95% CI 1.07–1.36) compared to non-exposed children. Boys and girls showed higher odds for ASC and ADHD symptoms after prenatal exposure, though these associations were slightly stronger among boys. Postnatal exposure to acetaminophen was not associated with ASC or ADHD symptoms. These results replicate previous work and support providing clear information to pregnant women and their partners about potential long-term risks of acetaminophen use. [ABSTRACT FROM AUTHOR]

There are several prognostic multigene-based tests for managing breast cancer (BC), but limited data comparing them in the same cohort. We compared the prognostic performance of the EndoPredict (EP) test (standardized for pathology laboratory) with the research-based PAM50 non-standardized qRT-PCR assay in node-positive estrogen receptor-positive (ER+) and HER2-negative (HER2−) BC patients receiving adjuvant chemotherapy followed by endocrine therapy (ET) in the GEICAM/9906 trial. EP and PAM50 risk of recurrence (ROR) scores [based on subtype (ROR-S) and on subtype and proliferation (ROR-P)] were compared in 536 ER+/HER2− patients. Scores combined with clinical information were evaluated: ROR-T (ROR-S, tumor size), ROR-PT (ROR-P, tumor size), and EPclin (EP, tumor size, nodal status). Patients were assigned to risk-categories according to prespecified cutoffs. Distant metastasis-free survival (MFS) was analyzed by Kaplan-Meier. ROR-S, ROR-P, and EP scores identified a low-risk group with a relative better outcome (10-year MFS: ROR-S 87 %; ROR-P 89 %; EP 93 %). There was no significant difference between tests. Predictors including clinical information showed superior prognostic performance compared to molecular scores alone (10-year MFS, low-risk group: ROR-T 88 %; ROR-PT 92 %; EPclin 100 %). The EPclin-based risk stratification achieved a significantly improved prediction of MFS compared to ROR-T, but not ROR-PT. All signatures added prognostic information to common clinical parameters. EPclin provided independent prognostic information beyond ROR-T and ROR-PT. ROR and EP can reliably predict risk of distant metastasis in node-positive ER+/HER2− BC patients treated with chemotherapy and ET. Addition of clinical parameters into risk scores improves their prognostic ability. [ABSTRACT FROM AUTHOR]

Seafood consumption provides a significant amount of arsenic, although in its organic, nontoxic forms. Mediterranean populations may incorporate high levels of this metalloid as a consequence of seafood consumption. In the present study, the significance of this input among pregnant women from a Mediterranean city (Sabadell, Catalonia, Spain) is assessed. Total urinary arsenic was analyzed in 489 pairs of urine samples, corresponding to the 12th and 32th weeks of pregnancy. Association of arsenic content with seafood and other dietary items were studied. Geometric mean concentrations were 34 and 37 μg/g creatinine during the first and third trimesters, respectively. The observed concentrations were similar to those reported in studies from other Mediterranean countries. The differences between both periods were not statistically significant. The only dietary factor significantly and positively associated with total urinary arsenic in both series of samples was seafood, particularly lean fish. Moreover, lean fish consumption during both periods was found to be the main determinant for differences in levels of arsenic between the first and third trimesters, which confirms the association between high levels of total urinary arsenic and seafood consumption. [ABSTRACT FROM AUTHOR]

Prenatal exposure to trace metals, whether they are essential, non-essential, or toxic, must be assessed for their potential health effects in the offspring. Herein is reported an approach to this end which involved collection of urine samples during the first and third trimesters of pregnancy from 489 mothers from Sabadell (Catalonia, Spain), a highly industrialized town. These samples were analyzed for cobalt (Co), nickel (Ni), copper (Cu), zinc (Zn), selenium (Se), arsenic (As), molybdenum (Mo), cadmium (Cd), antimonium (Sb), cesium (Cs), thallium (Tl), and lead (Pb). An acid digestion method was developed and validated for inductively coupled plasma quadruple mass spectrometry (Q-ICP-MS) analysis of these 12 metals. The median concentrations of metals ranged from 0.13 to 290 μg/g creatinine, the highest levels were found for Zn and the lowest for Th. The mean concentrations of most metals except As, Ni, Th, and Pb showed statistically significant differences between both trimesters. The concentrations of Mo, Se, Cd, Cs, and Sb were higher in the first than in the third trimester, whereas the opposite was found for Co, Cu, and Zn. The concentrations of all metals in both sampling periods showed statistically significant correlations ( p < 0.01 for Mo and Cu, p < 0.001 for the others). The significant correlations of metal urine concentrations in the first and third trimesters of pregnancy suggest that the observed differences between both periods are related to physiological changes. Accordingly, the measured urine concentrations during either the first or third trimesters can be used as estimates of exposure during pregnancy and can serve as markers for prenatal intake of these metals in the studied cohort. [ABSTRACT FROM AUTHOR]

Socioeconomic disadvantage can be harmful for mother's health and can influence child's health long term. The aim of this study is to analyse social inequalities between pregnant women from four INMA ( INfancia y Medio Ambiente) cohorts. The analysis included 2,607 pregnant women recruited between 2004 and 2008 from four INMA cohorts. Data on maternal characteristics were collected through two questionnaires completed in the first and third trimester of pregnancy. The relationship between socioeconomic status (SES) and maternal health, dietary intake, lifestyle habits and self-care related variables was modelled using logistic regression analysis. 33.5 % of women had a university level of education and 47 % had high occupational class. Women with higher SES reported healthier habits, fewer complications during pregnancy, better weight gain control and attended more prenatal appointments than women with lower SES. The risk of sedentary behaviour and passive smoking was higher among women with a lower level of education (OR = 1.7, 95 % CI 1.3-2.2 and OR = 1.6, 95 % CI 1.2-2.3, respectively) and with less skilled occupations (OR = 1.7, 95 % CI 1.4-2.0 and OR = 1.2, 95 % CI 1.0-1.5, respectively). Although both SES indicators-occupation and education-act as social determinants of diet, occupation was a more powerful determinant than education. For other lifestyle and self-caring variables, education was a more powerful predictor than occupation. Social inequalities were observed in health, habits and self-care during pregnancy. Proper care during pregnancy requires the control of common clinical variables and the knowledge of socioeconomic conditions of the pregnant women. [ABSTRACT FROM AUTHOR]

To identify a group of patients who might benefit from the addition of weekly paclitaxel to conventional anthracycline-containing chemotherapy as adjuvant therapy of node-positive operable breast cancer. The predictive value of PAM50 subtypes and the 11-gene proliferation score contained within the PAM50 assay were evaluated in 820 patients from the GEICAM/9906 randomized phase III trial comparing adjuvant FEC to FEC followed by weekly paclitaxel (FEC-P). Multivariable Cox regression analyses of the secondary endpoint of overall survival (OS) were performed to determine the significance of the interaction between treatment and the (1) PAM50 subtypes, (2) PAM50 proliferation score, and (3) clinical and pathological variables. Similar OS analyses were performed in 222 patients treated with weekly paclitaxel versus paclitaxel every 3 weeks in the CALGB/9342 and 9840 metastatic clinical trials. In GEICAM/9906, with a median follow up of 8.7 years, OS of the FEC-P arm was significantly superior compared to the FEC arm (unadjusted HR = 0.693, p = 0.013). A benefit from paclitaxel was only observed in the group of patients with a low PAM50 proliferation score (unadjusted HR = 0.23, p < 0.001; and interaction test, p = 0.006). No significant interactions between treatment and the PAM50 subtypes or the various clinical-pathological variables, including Ki-67 and histologic grade, were identified. Finally, similar OS results were obtained in the CALGB data set, although the interaction test did not reach statistical significance ( p = 0.109). The PAM50 proliferation score identifies a subset of patients with a low proliferation status that may derive a larger benefit from weekly paclitaxel. [ABSTRACT FROM AUTHOR]

The application of metabolic phenotyping in clinical and epidemiological studies is limited by a poor understanding of inter-individual, intra-individual and temporal variability in metabolic phenotypes. Using 1H NMR spectroscopy we characterised short-term variability in urinary metabolites measured from 20 children aged 8-9 years old. Daily spot morning, night-time and pooled (50:50 morning and night-time) urine samples across six days (18 samples per child) were analysed, and 44 metabolites quantified. Intraclass correlation coefficients (ICC) and mixed effect models were applied to assess the reproducibility and biological variance of metabolic phenotypes. Excellent analytical reproducibility and precision was demonstrated for the 1H NMR spectroscopic platform (median CV 7.2%). Pooled samples captured the best inter-individual variability with an ICC of 0.40 (median). Trimethylamine, N-acetyl neuraminic acid, 3-hydroxyisobutyrate, 3-hydroxybutyrate/3-aminoisobutyrate, tyrosine, valine and 3-hydroxyisovalerate exhibited the highest stability with over 50% of variance specific to the child. The pooled sample was shown to capture the most inter-individual variance in the metabolic phenotype, which is of importance for molecular epidemiology study design. A substantial proportion of the variation in the urinary metabolome of children is specific to the individual, underlining the potential of such data to inform clinical and exposome studies conducted early in life. [ABSTRACT FROM AUTHOR]