Search

Parabens are preservatives widely used in consumer products including cosmetics and food. Whether low-dose paraben exposure may cause adverse health effects has been discussed controversially in recent years. Here we investigate the effect of prenatal paraben exposure on childhood overweight by combining epidemiological data from a mother–child cohort with experimental approaches. Mothers reporting the use of paraben-containing cosmetic products have elevated urinary paraben concentrations. For butyl paraben (BuP) a positive association is observed to overweight within the first eight years of life with a stronger trend in girls. Consistently, maternal BuP exposure of mice induces a higher food intake and weight gain in female offspring. The effect is accompanied by an epigenetic modification in the neuronal Pro-opiomelanocortin (POMC) enhancer 1 leading to a reduced hypothalamic POMC expression. Here we report that maternal paraben exposure may contribute to childhood overweight development by altered POMC-mediated neuronal appetite regulation.

Bisphenol A (BPA), which is used in a variety of consumer-related plastic products, was reported to cause adverse effects, including disruption of adipocyte differentiation, interference with obesity mechanisms, and impairment of insulin- and glucose homeostasis. Substitute compounds are increasingly emerging but are not sufficiently investigated. We aimed to investigate the mode of action of BPA and four of its substitutes during the differentiation of human preadipocytes to adipocytes and their molecular interaction with peroxisome proliferator-activated receptor γ (PPARγ), a pivotal regulator of adipogenesis. Binding and effective biological activation of PPARγ were investigated by surface plasmon resonance and reporter gene assay, respectively. Human preadipocytes were continuously exposed to BPA, BPS, BPB, BPF, BPAF, and the PPARγ-antagonist GW9662. After 12 days of differentiation, lipid production was quantified via Oil Red O staining, and global protein profiles were assessed using LC-MS/MS-based proteomics. All tested bisphenols bound to human PPARγ with similar efficacy as the natural ligand 15d-PGJ2 in vitro and provoked an antagonistic effect on PPARγ in the reporter gene assay at non-cytotoxic concentrations. During the differentiation of human preadipocytes, all bisphenols decreased lipid production. Global proteomics displayed a down-regulation of adipogenesis and metabolic pathways, similar to GW9662. Interestingly, pro-inflammatory pathways were up-regulated, MCP1 release was increased, and adiponectin decreased. pAKT/AKT ratios revealed significantly reduced insulin sensitivity by BPA, BPB, and BPS upon insulin stimulation. Thus, our results show that not only BPA but also its substitutes disrupt crucial metabolic functions and insulin signaling in adipocytes under low, environmentally relevant concentrations. This effect, mediated through inhibition of PPARγ, may promote hypertrophy of adipose tissue and increase the risk of developing metabolic syndrome, including insulin resistance.

The maternal inflammation status during pregnancy has been associated with metabolic imprinting and obesity development in the child. However, the influence of the maternal Th2 cytokines, interleukin-4 (IL4), IL5 and IL13, has not been studied so far. We investigated the relationship between maternal innate (IL6, IL8, IL10 and tumor necrosis factor-α (TNFa)) and adaptive (interferon-γ, IL4, IL5 and IL13) blood cytokine levels at 34 weeks of gestation and children’s overweight development until the age of 3 years in 407 children of the German longitudinal LINA (Lifestyle and Environmental Factors and their Influence on Newborns Allergy risk) cohort. Children’s body weight and height were measured during the annual clinical visits or acquired from questionnaires. Body mass index (BMI) Z-scores were calculated according to the WHO reference data to adjust for child’s age and gender. Cytokine secretion was stimulated with phytohemagglutinin or lipopolysaccharide and measured by cytometric bead assay. Furthermore, we assessed metabolic parameter in blood of 318 children at age 1 using the AbsoluteIDQ p180 Kit (Biocrates LIFE Science AG). Applying logistic regression models, we found that an increase of maternal IL4 and IL13 was associated with a decreased risk for overweight development in 1- and 2-year-old children. This effect was consistent up to the age of 3 years for IL13 and mainly concerns children without maternal history of atopy. Children’s acylcarnitine concentrations at 1 year were positively correlated with maternal IL13 levels and inversely associated with the BMI Z-score at age 1. We were able to show for the first time that the maternal Th2 status may be linked inversely to early childhood overweight development accompanied by an altered metabolic profile of the fetus. However, our data do not support a direct mediating role of acylcarnitines on maternal IL13-induced weight development.

Background Maternal perceived stress has been discussed to contribute to the development of childhood overweight. Our aim was to investigate the longitudinal relationship of early maternal perceived stress and BMI z-scores in preschool children (≤ five years). Methods A longitudinal analysis was conducted in 498 mother-child pairs of the German prospective birth cohort LINA with information on maternal perceived stress during pregnancy, one and two years after birth. BMI z-scores were based on annual measurements of children’s weight/height and calculated based on WHO reference data. General estimation equations were applied to evaluate the impact of maternal stress on children’s longitudinal BMI z-scores. Potential stressors contributing to the perceived stress of the mother were assessed by linear regression models. Using mediation analyses we evaluated the relationship between stressors, maternal perceived stress, and children’s BMI z-score development. Results Postnatal maternal stress during the first year after birth had a positive longitudinal relationship with children’s BMI z-scores up to the age of five years. Gender-stratified analyses revealed that only girls showed this positive association while boy’s BMI z-scores were unaffected by maternal stress. We identified three neighborhood strains and two socio-demographic factors, which contributed to the maternal perceived stress level. Stressors themselves did not directly affect girl’s BMI z-scores but rather mediated their effect through the perceived stress level. Conclusions While different stressors contribute to maternal stress, the perceived stress level - rather than the stressors themselves - is strongly positively associated with BMI z-score development in girls. Electronic supplementary material The online version of this article (10.1186/s12889-018-6110-5) contains supplementary material, which is available to authorized users.

Purpose. Enhanced eosinophil/basophil (Eo/B) progenitor cell levels are known to be associated with allergic inflammation and atopy risk. The aim of the present study was to investigate the influence of different indoor exposures on the recruitment and differentiation of Eo/B progenitors in mother-child pairs.Methods. In 68 mother-child pairs of the LINA study peripheral blood mononuclear cells were used to assess Eo/B colony forming units (CFUs). Information about disease outcomes and indoor exposures was obtained from questionnaires. Indoor concentrations of volatile organic compounds (VOCs) were measured by passive sampling.Results. Infant’s Eo/B CFUs were positively associated with exposure to tobacco smoke, disinfectants, or VOCs. In contrast, for maternal Eo/B CFUs, only a few associations were seen. Higher numbers of infant Eo/B CFUs were observed in children with wheezing symptoms within the second year of life.Conclusions. We demonstrate that infant’s hematopoietic cells seem to respond with more sensitivity to environmental exposure compared to maternal cells. At least in infants, an activation of these hematopoietic cells by environmental exposure could contribute to an enhanced risk for the development of respiratory outcomes.

Epigenetic mechanisms have emerged as links between prenatal environmental exposure and disease risk later in life. Here, we studied epigenetic changes associated with maternal smoking at base pair resolution by mapping DNA methylation, histone modifications, and transcription in expectant mothers and their newborn children. We found extensive global differential methylation and carefully evaluated these changes to separate environment associated from genotype‐related DNA methylation changes. Differential methylation is enriched in enhancer elements and targets in particular “commuting” enhancers having multiple, regulatory interactions with distal genes. Longitudinal whole‐genome bisulfite sequencing revealed that DNA methylation changes associated with maternal smoking persist over years of life. Particularly in children prenatal environmental exposure leads to chromatin transitions into a hyperactive state. Combined DNA methylation, histone modification, and gene expression analyses indicate that differential methylation in enhancer regions is more often functionally translated than methylation changes in promoters or non‐regulatory elements. Finally, we show that epigenetic deregulation of a commuting enhancer targeting c‐Jun N‐terminal kinase 2 (JNK2) is linked to impaired lung function in early childhood. ![][1] Genome‐wide epigenomic and transcriptomic data reveal that maternal smoking induces important changes in the methylome of mothers and their children that affect in particular enhancer regions. These changes are stably maintained for years in the epigenome of the child. Mol Syst Biol. (2016) 12: 861 [1]: /embed/graphic-1.gif

Vitamin D, formerly known as ‘the bone vitamin’, has become a subject of high interest in the last decade regarding its effects in different diseases such as cancer, diabetes, allergies or suscepti...

Redecoration of dwellings is a common behavior of expecting parents. Former studies gave evidence that early childhood exposure to volatile organic compounds (VOC) resulting from renovation activities may increase the risk for wheeze in infants. Objectives: The aim of the present study was to evaluate the impact of prenatal exposure on early wheeze and to identify sensitive time windows.Within the LINA birth cohort study data on renovation activities and respiratory outcomes were assessed via questionnaires during pregnancy and at children's age of one. At both timepoints, also indoor VOC concentrations were measured. The associations were studied by logistic regression analysis.Floor covering during pregnancy contributed to an increased risk for physician treated wheeze (adjusted odds ratio OR = 5.20, 95% confidence interval 1.8–15.2) during the first 12 months after birth in particular in children with an atopic predisposition. Thereby, wall-to-wall-carpets, PVC material, and laminate were the flooring materials which showed the strongest adverse associations. Floor covering was associated with enhanced concentrations of VOCs in the apartments. For the VOCs styrene, ethylbenzene, octane, 1-butanol, tridecane, and o-xylene, a significant association was found to the occurrence of wheezing symptoms. In contrast to pregnancy, exposure during the first 12 months after birth showed less detrimental associations. Only the association between wheezing and styrene as well as between wheezing and PVC flooring remained significant for exposure after birth.Redecoration during pregnancy, especially changing floor materials, increases the risk for respiratory diseases in early childhood and should therefore be avoided at least in families with a history of atopic diseases. Keywords: Childhood, Prenatal exposure, Wheezing, Volatile organic compounds, Redecoration

Rationale Cord blood eosinophil/basophil progenitor cells (Eo/B) of high risk infants have been shown to predict respiratory illnesses in infancy. Here we investigated this association in a population-based cohort. Furthermore, we analysed whether newborns Th1/Th2 balance and prenatal environmental exposure impact Eo/B recruitment. Methods In a sub-cohort of the LINA study cord blood mononuclear cells were used for methylcellulose assays to assess Eo/B differentiation. Questionnaires were recorded during pregnancy and annually thereafter. Volatile organic compounds were measured during pregnancy and cord blood cytokines after ex vivo stimulation. Results Cord blood IL-4 and IL-13 positively correlated with Eo/B. Tobacco smoke related benzene was also positively associated with Eo/B. Enhanced Eo/B numbers increased the risk for wheezing within the first 24 months. Conclusions The association between cord blood Eo/B and respiratory illnesses is not restricted to high-risk children. Prenatal environmental exposure and a Th2 milieu at birth contribute to Eo/B recruitment.

Summary Mutation is a fundamental process in tumorigenesis. However, the degree to which the rate of somatic mutation varies across the human genome and the mechanistic basis underlying this variation remain to be fully elucidated. Here, we performed a cross-cancer comparison of 402 whole genomes comprising a diverse set of childhood and adult tumors, including both solid and hematopoietic malignancies. Surprisingly, we found that the inactive X chromosome of many female cancer genomes accumulates on average twice and up to four times as many somatic mutations per megabase, as compared to the individual autosomes. Whole-genome sequencing of clonally expanded hematopoietic stem/progenitor cells (HSPCs) from healthy individuals and a premalignant myelodysplastic syndrome (MDS) sample revealed no X chromosome hypermutation. Our data suggest that hypermutation of the inactive X chromosome is an early and frequent feature of tumorigenesis resulting from DNA replication stress in aberrantly proliferating cells., Graphical Abstract, Highlights • X chromosome has up to 4× more mutations than the autosomes in female cancer genomes • Hypermutations only affect the inactive X chromosome • X hypermutation involves somatic point mutations and indels, but not germline mutations • No X hypermutation is found in clonal expansions of normal or premalignant cells, A comparison of 402 cancer genomes identifies a surprisingly high level of somatic mutations in the inactive X chromosome of female cancer genomes. As hypermutability of the inactive X was not observed in clonal hematopoietic progenitor or preleukemic samples, it is likely that it may be a contributing factor to tumorigenesis.