Prenatal exposure to multiple organochlorine compounds and childhood body mass index.

Background: Prenatal exposure to organochlorine compounds (OCs) has been associated with increased childhood body mass index (BMI); however, only a few studies have focused on longitudinal BMI trajectories, and none of them used multiple exposure mixture approaches. Aim: To determine the association between in-utero exposure to eight OCs and childhood BMI measures (BMI and BMI z-score) at 4 years and their yearly change across 4-12 years of age in 279 Rhea child-mother dyads. Methods: We applied three approaches: (1) linear mixed-effect regressions (LMR) to associate individual compounds with BMI measures; (2) Bayesian weighted quantile sum regressions (BWQSR) to provide an overall OC mixture association with BMI measures; and (3)Bayesian varying coefficient kernel machine regressions (BVCKMR) to model nonlinear and nonadditive associations. Results: In the LMR, yearly change of BMI measures was consistently associated with a quartile increase in hexachlorobenzene (HCB) (estimate [95% Confidence or Credible interval] BMI: 0.10 [0.06, 0.14]; BMI z-score: 0.02 [0.01, 0.04]). BWQSR results showed that a quartile increase in mixture concentrations was associated with yearly increase of BMI measures (BMI: 0.10 [0.01, 0.18]; BMI z-score: 0.03 [0.003, 0.06]). In the BVCKMR, a quartile increase in dichlorodiphenyldichloroethylene concentrations was associated with higher BMI measures at 4 years (BMI: 0.33 [0.24, 0.43]; BMI z-score: 0.19 [0.15, 0.24]); whereas a quartile increase in HCB and polychlorinated biphenyls (PCB)-118 levels was positively associated with BMI measures yearly change (BMI: HCB:0.10 [0.07, 0.13], PCB-118:0.08 [0.04, 012]; BMI z-score: HCB:0.03 [0.02, 0.05], PCB-118:0.02 [0.002,04]). BVCKMR suggested that PCBs had nonlinear relationships with BMI measures, and HCB interacted with other compounds. Conclusions: All analyses consistently demonstrated detrimental associations between prenatal OC exposures and childhood BMI measures.

Sex specific associations between in utero exposure to persistent organic pollutants and allergy-related outcomes in childhood: The Rhea Mother-Child Cohort (Crete, Greece).

Accumulating evidence suggests that in utero exposures can influence the development of the immune system. Few studies have investigated whether prenatal exposure to persistent organic pollutants (POPs) is associated with allergy-related phenotypes in childhood, nor explored sex differences. We examined the association between prenatal exposure to POPs and offspring allergic outcomes in early and mid-childhood. We included 682 mother-child pairs from the prospective birth cohort Rhea. We measured dichlorodiphenyldichloroethylene (DDE), hexachlorobenzene (HCB) and 6 polychlorinated biphenyl (PCB) congeners in maternal first trimester serum. Parents completed the questionnaires adapted from the International Study on Asthma and Allergy in Childhood (ISAAC) for allergy-related phenotypes when their children were 4 and 6 years old. We used Poisson regression models to estimate Risk Ratios. Prenatal HCB was associated with increased risk for rhinoconjunctivitis at 6 years (RR (95% CI): 2.5; (1.3, 4.8) for a doubling in the exposure). Among girls, prenatal DDE was associated with increased risk for current wheeze, current asthma and current rhinoconjunctivitis at 4 years (RR (95%CI): 1.4 (0.8, 2.6), 1.6 (1.1, 2.4) and 1.8 (1.0, 3.3) and p-interaction = 0.035, 0.027 and 0.059, respectively), with increased risk for current rhinoconjunctivitis at 6 years (RR (95%CI): 1.7 (0.7, 3.8) and p-interaction = 0.028) and total PCBs were associated with increased risk for current eczema at 4 years (RR (95%CI): 2.1 (1.1, 4.2) and p-interaction = 0.028). In boys, prenatal DDE was associated with decreased risk for current wheeze and current asthma at 4 years. Our findings suggest that even low levels of exposure to POPs prenatally may affect the development of childhood allergy-related outcomes in a sex and age-specific manner.

Two-year systematic investigation reveals alterations induced on chemical and bacteriome profile of PM2.5 by African dust incursions to the Mediterranean atmosphere.

PM2.5 atmospheric samples were regularly collected between January 2013 and March 2015 at a central location of Eastern Mediterranean (Island of Crete) during African dust events (DES) and periods of absence of such episodes as controls (CS). The elemental composition and microbiome DES and CS were thoroughly investigated. Fifty-six major and trace elements were determined by inductively coupled plasma-mass spectrometry. Relative mass abundances (RMA) of major crustal elements and lanthanoids were higher in DES than in CS. Conversely in CS, RMAs were higher for most anthropogenic transition metals. Lanthanum-to-other lanthanoids concentration ratios for DES approached the corresponding reference values for continental crust and several African dust source regions, while in CS they exceeded these values. USEPA's UNMIX receptor model, applied in all PM2.5 samples, established that African dust is the dominant contributing source (by 80%) followed by road dust/fuel oil emissions (17%) in the receptor area. Potential source contribution function (PSCF) identified dust hotspots in Tunisia, Libya and Egypt. The application of 16S rRNA gene amplicon sequencing revealed high variation of bacterial composition and diversity between DES and CS samples. Proteobacteria, Actinobacteria and Bacteroides were the most dominant in both DES and CS samples, representing ~88% of the total bacterial diversity. Cutibacterium, Tumebacillus and Sphingomonas dominated the CS samples, while Rhizobium and Brevundimonas were the most prevalent genera in DES. Mutual exclusion/co-occurrence network analysis indicated that Sphingomonas and Chryseobacterium exhibited the highest degrees of mutual exclusion in CS, while in DES the corresponding species were Brevundimonas, Delftia, Rubellimicrobium, Flavobacterium, Blastococcus, and Pseudarthrobacter. Some of these microorganisms are emerging global opportunistic pathogens and an increase in human exposure to them as a result of environmental changes, is inevitable.

Atmospheric particle-bound polycyclic aromatic hydrocarbons, n-alkanes, hopanes, steranes and trace metals: PM2.5 source identification, individual and cumulative multi-pathway lifetime cancer risk assessment in the urban environment.

The occurrence of atmospheric fine particles (PM2.5)-associated polycyclic aromatic hydrocarbons (PAHs), trace metals and organic molecular markers was investigated by conducting an intensive sampling campaign at the Eastern Mediterranean urban area of Nicosia (Cyprus). Sixty-two 24-hr PM2.5 samples were collected and analyzed for fifty parent and alkylated PAHs, twenty-five long chain n-alkanes, seventeen hopanes and twelve steranes used for source apportionment. The same number and kind of samples were analyzed to determine twenty-eight trace metals. Emphasis was given to investigate the air levels of the scarcely monitored although highly carcinogenic PAHs such as dibenzopyrenes, dibenzoanthracenes, 7H-benzo[c]fluorene and 5-methyl-chrysene, not included in the USEPA's sixteen PAH priority list (USEPA-16). UNMIX receptor model was applied to apportion the sources of atmospheric emissions of the determined organic compounds and trace metals and evaluate their daily contributions to the corresponding PM2.5 associated concentrations. For comparison purposes, principal component analysis with multiple linear regression (PCA/MLR) was also applied and its results are reported. The UNMIX receptor model, compared to PCA/MLR, offered a more precise source profile and more reliable daily mass source distributions by eliminating negative contributions. The individual and cumulative multi-pathway lifetime cancer risk (posed via inhalation, ingestion and dermal contact) by exposure to PM2.5-associated USEPA-16 listed and non-listed PAHs and selected airborne trace metals (As, Cd, Co, Ni, and Pb) were assessed. To estimate the contribution of each emission source to the total cancer risk, multiple linear regression analysis was performed, using as independent variables the daily source mass contributions and as dependent variables the respective cancer risk units. The estimated total cumulative cancer risk comprising all toxic PAHs, besides those included in the priority list, and metals was higher than the USEPA's threshold by a factor of eight, denoting a potential risk for long-term exposure of a population in the urban environment.

Study of the occurrence and multi-pathway health risk assessment of regulated and unregulated disinfection by-products in drinking and swimming pool waters of Mediterranean cities.

The occurrence of a wide variety of regulated (four trihalomethanes (THM(4)), five haloacetic acids (HAA(5))) and unregulated (haloacetonitriles (HANs), halogenated ketones, chloropicrin, carbon tetrachloride, and other haloacetic acids) disinfection by-products (DBPs) was studied, in two hundred twenty-six finished drinking water samples collected in Barcelona (Spain, between 2008 and 2009), Athens (Greece, 2009-2010), Heraklion (Greece, 2009-2010), Nicosia (Cyprus, 2012-2013), and Limassol (Cyprus, 2011). The samples were analyzed by using liquid-liquid extraction, gas chromatography coupled with an electron capture detector or negative chemical ionization mass spectrometry. In addition, fourteen swimming pool water samples (from Heraklion and Athens) were also investigated regarding their DBPs content. The studied DBPs were determined concurrently with pH, total organic carbon (TOC), and bromide. Spearman's statistical analysis has shown statistically significant (p < 0.001) weak correlations between TOC, THM(4), HANs and HAA(5) but a strong correlation between THM(4) and HANs. Principal component analysis (PCA) on THM(4), HANs and HAA(5) provided a clear differentiation between the examined drinking waters, on the basis of their DBPs content. In the drinking water of coastal cities, the brominated DBPs dominated over the chlorinated ones, due to the higher bromide concentrations occurring in the corresponding raw waters. Lifetime cancer risk and hazard quotient by exposure to four THMs, dichlorocetic acid and trichloroacetic acid in drinking water and indoor swimming pools through multiple pathways were estimated. Total cancer unit risks in drinking water for Nicosia, Barcelona, Limassol and Athens exceeded in most cases the US EPA's regulatory threshold (1.0E-06). The total lifetime cancer risk evaluated for the studied indoor swimming pools was above the US EPA's negligible level for male, female, and junior swimmers.

Trihalomethanes in Drinking Water and Bladder Cancer Burden in the European Union.

BACKGROUND: Trihalomethanes (THMs) are widespread disinfection by-products (DBPs) in drinking water, and long-term exposure has been consistently associated with increased bladder cancer risk. OBJECTIVE: We assessed THM levels in drinking water in the European Union as a marker of DBP exposure and estimated the attributable burden of bladder cancer. METHODS: We collected recent annual mean THM levels in municipal drinking water in 28 European countries (EU28) from routine monitoring records. We estimated a linear exposure-response function for average residential THM levels and bladder cancer by pooling data from studies included in the largest international pooled analysis published to date in order to estimate odds ratios (ORs) for bladder cancer associated with the mean THM level in each country (relative to no exposure), population-attributable fraction (PAF), and number of attributable bladder cancer cases in different scenarios using incidence rates and population from the Global Burden of Disease study of 2016. RESULTS: We obtained 2005-2018 THM data from EU26, covering 75% of the population. Data coverage and accuracy were heterogeneous among countries. The estimated population-weighted mean THM level was 11.7µg/L [standard deviation (SD) of 11.2]. The estimated bladder cancer PAF was 4.9% [95% confidence interval (CI): 2.5, 7.1] overall (range: 0-23%), accounting for 6,561 (95% CI: 3,389, 9,537) bladder cancer cases per year. Denmark and the Netherlands had the lowest PAF (0.0% each), while Cyprus (23.2%), Malta (17.9%), and Ireland (17.2%) had the highest among EU26. In the scenario where no country would exceed the current EU mean, 2,868 (95% CI: 1,522, 4,060; 43%) annual attributable bladder cancer cases could potentially be avoided. DISCUSSION: Efforts have been made to reduce THM levels in the European Union. However, assuming a causal association, current levels in certain countries still could lead to a considerable burden of bladder cancer that could potentially be avoided by optimizing water treatment, disinfection, and distribution practices, among other possible measures. https://doi.org/10.1289/EHP4495.

Source apportionment of organic pollutants in fine and coarse atmospheric particles in Doha, Qatar.

In this study, we investigated the sources of organic pollutants associated with fine (PM2.5) and coarse (PM2.5-10) atmospheric particulate matter in Doha, Qatar based on an eight-month sampling campaign conducted from May to December 2015. Multiple organic compound tracers including 36 PAH members, 25 n-alkane homologs, 17 hopanes, and 12 steranes were used for organic aerosols source apportionment. Source apportionment based on specific molecular markers, molecular diagnostic ratios/indices, and positive matrix factorization (PMF) modeling showed that similar sources are responsible for both fine- and coarse-particle organic pollutants. PMF analysis showed that biogenic aerosols, fugitive dust emissions, gasoline engine emissions, diesel engine emissions, and heavy oil combustion were the five main pollution sources of organic aerosols, which agreed well with the results from the diagnostic ratios analysis. The conditional bivariate probability functions (CPF) and potential source contribution function (PSCF) indicated that both regional (i.e., mixed biogenic/secondary particles and oil refinery/shipping emissions) and local sources contributed to airborne organic aerosol concentrations observed at the site, depending on the wind speed and direction. It appears that the relatively high levels of organic pollutants were contributed by local anthropogenic sources, such as fossil fuel combustion, vehicular emissions, and fugitive dust emissions. The high levels of local contributions indicated that there might be great opportunities for Qatar to considerably reduce emissions so that population exposures to carbonaceous aerosols and the public health risks associated with air pollution can be minimized. Implications: Multiple organic tracers and various source apportionment techniques have been used for convincing source apportionment. It was found that both long-range and local sources have a significant impact on atmospheric carbonaceous particles in the area, depending on the wind conditions. Relatively high levels of organic pollutants attributed to local anthropogenic sources indicate that there are great opportunities for Qatar to establish and implement more efficient pollution control measures and policies. Regional sources such as petroleum refineries and shipping-vessels emissions in the Gulf region should also be regulated and managed through regional cooperation to improve the air quality in the region.

Polyunsaturated fatty acid status at birth, childhood growth, and cardiometabolic risk: a pooled analysis of the MEFAB and RHEA cohorts.

BACKGROUND/OBJECTIVES: Polyunsaturated fatty acid (PUFA) status during pregnancy has been suggested to influence offspring obesity and cardiometabolic health. We assessed whether prenatal PUFA exposure is associated with rapid infant growth, childhood BMI, and cardiometabolic profile. SUBJECTS/METHODS: In the Dutch MEFAB (n = 266) and Greek RHEA (n = 263) cohorts, we measured n-3 and n-6 PUFA concentrations in cord blood phospholipids, which reflect fetal exposure in late pregnancy. We defined rapid infant growth from birth to 6 months of age as an increase in weight z-score >0.67. We analyzed body mass index (BMI) as continuous and in categories of overweight/obesity at 4 and 6 years. We computed a cardiometabolic risk score at 6-7 years as the sum of waist circumference, non-high-density lipoprotein cholesterol and blood pressure z-scores. Associations of PUFAs with child health outcomes were assessed using generalized linear models for binary outcomes and linear regression models for continuous ones after adjusting for important covariates, and for the pooled estimates, a cohort indicator. RESULTS: In pooled analyses, we found no association of PUFA levels with rapid infant growth, childhood BMI (ß per SD increase in the total n-3:n-6 PUFA ratio = -0.04 SD; 99% CI: -0.15, 0.06; P = 0.65 at 4 years, and -0.05 SD; 99% CI: -0.18, 0.08; P = 0.78 at 6 years), and overweight/obesity. We also found no associations for clustered cardiometabolic risk and its individual components. The results were similar across cohorts. CONCLUSIONS: Our findings suggest that PUFA concentrations at birth are not associated with later obesity development and cardiometabolic risk in childhood.

Significant metabolic improvement by a water extract of olives: animal and human evidence.

PURPOSE: Dyslipidemia and impaired glucose metabolism are the main health issues of growing prevalence and significant high healthcare cost, requiring novel prevention and/or therapeutic approaches. Epidemiological and animal studies revealed that olive oil is an important dietary constituent, inducing normolipidemia. However, no studies have specifically investigated the polyphenol-rich water extract of olives (OLWPE), generated during olive oil production. METHODS: In the present work, we initially examined the effect of OLPWE on animals' metabolic parameters. Rats fed with a high-fat diet were treated with three different doses of OLPWE for 4 months. Additionally, bioavailability was explored. Afterwards, OLWPE's metabolic effect was explored in humans. Healthy volunteers consumed microencapsulated OLWPE for 4 weeks, in a food matrix [one portion (30 g) of a meat product]. RESULTS: High-fat-fed rats developed a metabolic dysfunction, with increased LDL and insulin levels and decreased HDL; this syndrome was significantly impaired when treated with OLWPE. Treated rats had increased total plasma antioxidant capacity, while several phenolic compounds were detected in their blood. These findings were also verified in humans that consumed OLWPE, daily, for 4 weeks. Interestingly, in individuals with elements of cardio-metabolic risk, OLWPE consumption resulted in reduced glucose, insulin, total cholesterol, LDL and oxLDL levels. CONCLUSIONS: Our data clearly show that OLWPE can improve glucose and lipid profile, indicating its possible use in the design of functional food and/or therapeutic interventions.

Concentrations of aliphatic and polycyclic aromatic hydrocarbons in ambient PM2.5 and PM10 particulates in Doha, Qatar.

Organic carbon (OC), elemental carbon (EC), and 90 organic compounds (36 polycyclic aromatic hydrocarbons [PAHs], 25 n-alkane homologues, 17 hopanes, and 12 steranes) were concurrently quantified in atmospheric particulate matter of PM2.5 and PM10. The 24-hr PM samples were collected using Harvard Impactors at a suburban site in Doha, Qatar, from May to December 2015. The mass concentrations (mean ± standard deviation) of PM2.5 and PM10 were 40 ± 15 and 145 ± 70 µg m-3, respectively, exceeding the World Health Organization (WHO) air quality guidelines. Coarse particles comprised 70% of PM10. Total carbonaceous contents accounted for 14% of PM2.5 and 10% of PM10 particulate mass. The major fraction (90%) of EC was associated with the PM2.5. In contrast, 70% of OC content was found in the PM2.5-10 fraction. The secondary OC accounted for 60-68% of the total OC in both PM fractions, indicating photochemical conversions of organics are much active in the area due to higher air temperatures and solar radiations. Among the studied compounds, n-alkanes were the most abundant group, followed by PAHs, hopanes, and steranes. n-Alkanes from C25 to C35 prevailed with a predominance of odd carbon numbered congeners (C27-C31). High-molecular-weight PAHs (5-6 rings) also prevailed, within their class, with benzo[b + j]fluoranthene (Bb + jF) being the dominant member. PAHs were mainly (80%) associated with the PM2.5 fraction. Local vehicular and fugitive emissions were predominant during low-speed southeasterly winds from urban areas, while remote petrogenic/biogenic emissions were particularly significant under prevailing northwesterly wind conditions. Implications: An unprecedented study in Qatar established concentration profiles of EC, OC, and 90 organic compounds in PM2.5 and PM10. Multiple tracer organic compounds for each source can be used for convincing source apportionment. Particle concentrations exceeded WHO air quality guidelines for 82-96% of the time, revealing a severe problem of atmospheric PM in Doha. Dominance of EC and PAHs in fine particles signifies contributions from combustion sources. Dependence of pollutants concentrations on wind speed and direction suggests their significant temporal and spatial variability, indicating opportunities for improving the air quality by identifying sources of airborne contaminants.

Association of Early Life Exposure to Phthalates With Obesity and Cardiometabolic Traits in Childhood: Sex Specific Associations.

Few studies have investigated longitudinal associations between early life phthalate exposure and subsequent obesity and cardiovascular risks in children with inconsistent results. We aimed to evaluate the associations between phthalate exposure during gestation and childhood with offspring obesity and cardiometabolic risk factors in 500 mother-child pairs from the Rhea pregnancy cohort in Crete, Greece. Seven phthalate metabolites [monoethyl phthalate (MEP), mono-n-butyl phthalate (MnBP), mono-isobutyl phthalate (MiBP), monobenzyl phthalate (MBzP), mono(2-ethylhexyl) phthalate (MEHP), mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), and mono(2-ethyl-5-oxohexyl) phthalate (MEOHP)] were quantified in spot urine samples collected from mothers (1st trimester) and their children at 4 years of age. We calculated the molar sum of DEHP metabolites (MEHP, MEHHP, MEOHP). We measured child weight, height, waist circumference, skinfold thicknesses, blood pressure (BP), and lipids at 4 and 6 years and leptin, adiponectin, and C-reactive protein at 4 years. We used generalized estimating equations to examine associations at each age and tested for interaction by sex. Child exposure to phthalate metabolites was associated with lower BMI z-scores in boys and higher BMI z-scores in girls. Each 10-fold increase in ΣDEHP was associated with a change in waist circumference of -2.6 cm (95% CI: -4.72, -0.48) in boys vs. 2.14 cm (95% CI: -0.14, 4.43) in girls (p-sex interaction = 0.003) and a change in waist-to-height ratio of -0.01 (95% CI: -0.03, 0.01) in boys vs. 0.02 (95% CI: 0.01, 0.04) in girls (p-sex interaction = 0.006). Phthalate metabolite concentrations at age 4 were negatively associated with systolic and diastolic blood pressure. MEP was associated with lower systolic BP z-scores (adj. ß = -0.22; 95% CI: -0.36, -0.08) at 4 years. MnBP and MBzP were associated with lower diastolic BP z-scores (adj. ß = -0.13; 95%CI: -0.23, -0.04, and adj. ß = -0.11; 95% CI: -0.21, -0.01, respectively). A 10-fold increase in MiBP was associated with 4.4% higher total cholesterol levels (95% CI: 0.2, 8.7). Prenatal phthalate exposure was not consistently associated with child adiposity and cardiometabolic measures. Our findings suggest that early life phthalate exposure may affect child growth and adiposity in a sex-specific manner and depends on the timing of exposure.

The Urban Exposome during Pregnancy and Its Socioeconomic Determinants.

BACKGROUND: The urban exposome is the set of environmental factors that are experienced in the outdoor urban environment and that may influence child development. OBJECTIVE: The authors' goal was to describe the urban exposome among European pregnant women and understand its socioeconomic determinants. METHODS: Using geographic information systems, remote sensing and spatio-temporal modeling we estimated exposure during pregnancy to 28 environmental indicators in almost 30,000 women from six population-based birth cohorts, in nine urban areas from across Europe. Exposures included meteorological factors, air pollutants, traffic noise, traffic indicators, natural space, the built environment, public transport, facilities, and walkability. Socioeconomic position (SEP), assessed at both the area and individual level, was related to the exposome through an exposome-wide association study and principal component (PC) analysis. RESULTS: Mean±standard deviation (SD) NO2 levels ranged from 13.6±5.1 µg/m3 (in Heraklion, Crete) to 43.2±11 µg/m3 (in Sabadell, Spain), mean±SD walkability score ranged from 0.22±0.04 (Kaunas, Lithuania) to 0.32±0.07 (Valencia, Spain) and mean±SD Normalized Difference Vegetation Index ranged from 0.21±0.05 in Heraklion to 0.51±0.1 in Oslo, Norway. Four PCs explained more than half of variation in the urban exposome. There was considerable heterogeneity in social patterning of the urban exposome across cities. For example, high-SEP (based on family education) women lived in greener, less noisy, and less polluted areas in Bradford, UK (0.39 higher PC1 score, 95% confidence interval (CI): 0.31, 0.47), but the reverse was observed in Oslo (-0.57 PC1 score, 95% CI: -0.73, -0.41). For most cities, effects were stronger when SEP was assessed at the area level: In Bradford, women living in high SEP areas had a 1.34 higher average PC1 score (95% CI: 1.21, 1.48). CONCLUSIONS: The urban exposome showed considerable variability across Europe. Pregnant women of low SEP were exposed to higher levels of environmental hazards in some cities, but not others, which may contribute to inequities in child health and development. https://doi.org/10.1289/EHP2862.

Pre-diagnostic blood immune markers, incidence and progression of B-cell lymphoma and multiple myeloma: Univariate and functionally informed multivariate analyses.

Recent prospective studies have shown that dysregulation of the immune system may precede the development of B-cell lymphomas (BCL) in immunocompetent individuals. However, to date, the studies were restricted to a few immune markers, which were considered separately. Using a nested case-control study within two European prospective cohorts, we measured plasma levels of 28 immune markers in samples collected a median of 6 years before diagnosis (range 2.01-15.97) in 268 incident cases of BCL (including multiple myeloma [MM]) and matched controls. Linear mixed models and partial least square analyses were used to analyze the association between levels of immune marker and the incidence of BCL and its main histological subtypes and to investigate potential biomarkers predictive of the time to diagnosis. Linear mixed model analyses identified associations linking lower levels of fibroblast growth factor-2 (FGF-2 p = 7.2 × 10-4 ) and transforming growth factor alpha (TGF-α, p = 6.5 × 10-5 ) and BCL incidence. Analyses stratified by histological subtypes identified inverse associations for MM subtype including FGF-2 (p = 7.8 × 10-7 ), TGF-α (p = 4.08 × 10-5 ), fractalkine (p = 1.12 × 10-3 ), monocyte chemotactic protein-3 (p = 1.36 × 10-4 ), macrophage inflammatory protein 1-alpha (p = 4.6 × 10-4 ) and vascular endothelial growth factor (p = 4.23 × 10-5 ). Our results also provided marginal support for already reported associations between chemokines and diffuse large BCL (DLBCL) and cytokines and chronic lymphocytic leukemia (CLL). Case-only analyses showed that Granulocyte-macrophage colony stimulating factor levels were consistently higher closer to diagnosis, which provides further evidence of its role in tumor progression. In conclusion, our study suggests a role of growth-factors in the incidence of MM and of chemokine and cytokine regulation in DLBCL and CLL.

PUFA status at birth and allergy-related phenotypes in childhood: a pooled analysis of the Maastricht Essential Fatty Acid Birth (MEFAB) and RHEA birth cohorts.

Lower prenatal exposure to n-3 PUFA relative to n-6 PUFA has been hypothesised to influence allergy development, but evidence remains largely inconsistent. In the Dutch Maastricht Essential Fatty Acid Birth (MEFAB) (n 293) and Greek RHEA Mother-Child (n 213) cohorts, we investigated whether cord blood phospholipid PUFA concentrations are associated with symptoms of wheeze, asthma, rhinitis and eczema at the age of 6-7 years. Information on allergy-related phenotypes was collected using validated questionnaires. We estimated relative risks (RR) and 95 % CI for associations of PUFA with child outcomes using multivariable generalised linear regression models. In pooled analyses, higher concentration of the n-3 long-chain EPA and DHA and a higher total n-3:n-6 PUFA ratio were associated with lower risk of current wheeze (RR 0·61; 95 % CI 0·45, 0·82 per sd increase in EPA+DHA and 0·54; 95 % CI 0·39, 0·75 per unit increase in the n-3:n-6 ratio) and reduced asthma risk (RR 0·50; 95 % CI 0·31, 0·79 for EPA+DHA and 0·43; 95 % CI 0·26, 0·70 for the n-3:n-6 ratio). No associations were observed for other allergy-related phenotypes. The results were similar across cohorts. In conclusion, higher EPA and DHA concentrations and a higher n-3:n-6 fatty acid ratio at birth were associated with lower risk of child wheeze and asthma. Our findings suggest that dietary interventions resulting in a marked increase in the n-3:n-6 PUFA ratio, and mainly in n-3 long-chain PUFA intake in late gestation, may reduce the risk of asthma symptoms in mid-childhood.

Overcoming the plasticity of plant specialized metabolism for selective diterpene production in yeast.

Plants synthesize numerous specialized metabolites (also termed natural products) to mediate dynamic interactions with their surroundings. The complexity of plant specialized metabolism is the result of an inherent biosynthetic plasticity rooted in the substrate and product promiscuity of the enzymes involved. The pathway of carnosic acid-related diterpenes in rosemary and sage involves promiscuous cytochrome P450s whose combined activity results in a multitude of structurally related compounds. Some of these minor products, such as pisiferic acid and salviol, have established bioactivity, but their limited availability prevents further evaluation. Reconstructing carnosic acid biosynthesis in yeast achieved significant titers of the main compound but could not specifically yield the minor products. Specific production of pisiferic acid and salviol was achieved by restricting the promiscuity of a key enzyme, CYP76AH24, through a single-residue substitution (F112L). Coupled with additional metabolic engineering interventions, overall improvements of 24 and 14-fold for pisiferic acid and salviol, respectively, were obtained. These results provide an example of how synthetic biology can help navigating the complex landscape of plant natural product biosynthesis to achieve heterologous production of useful minor metabolites. In the context of plant adaptation, these findings also suggest a molecular basis for the rapid evolution of terpene biosynthetic pathways.

A glutathione-S-transferase (TuGSTd05) associated with acaricide resistance in Tetranychus urticae directly metabolizes the complex II inhibitor cyflumetofen.

Cyflumetofen is a recently introduced acaricide with a novel mode of action, acting as an inhibitor of complex II of mitochondrial electron transport chain. It is activated by hydrolysis and the resulting de-esterified metabolite is a much stronger inhibitor. Cyflumetofen represents a great addition for the control of mite species including Tetranychus urticae, a major agricultural pest, which has the ability to develop resistance to most classes of pesticides rapidly. A resistant strain (Tu008R) was recently described and synergism experiments pointed towards the involvement of GSTs. Here, we conducted genome-wide gene expression analysis, comparing Tu008R with its parental susceptible strain, and identified the delta GST TuGSTd05 as the prime resistance-conferring candidate. Docking analysis suggests that both cyflumetofen and its de-esterified metabolite are potential substrates for conjugation by TuGSTd05. Several amino acids were identified that might be involved in the interaction, with Y107 and N103 possibly having an important role. To further investigate interaction as well as the role of Y107 and N103 in vitro, we recombinantly expressed and kinetically characterized the wild type TuGSTd05, TuGSTd05 Y107F and TuGSTd05 N103L mutants. While cyflumetofen was not found to act as a strong inhibitor, the de-esterified metabolite showed strong affinity for TuGSTd05 (IC50 = 4 µM), which could serve as a mechanism of rapid detoxification. Y107 and N103 might contribute to this interaction. HPLC-MS analysis provided solid indications that TuGSTd05 catalyzes the conjugation of ionized glutathione (GS-) to cyflumetofen and/or its de-esterified metabolite and the resulting metabolite and possible site of attack were identified.

Development of West-European PM2.5 and NO2 land use regression models incorporating satellite-derived and chemical transport modelling data.

Satellite-derived (SAT) and chemical transport model (CTM) estimates of PM2.5 and NO2 are increasingly used in combination with Land Use Regression (LUR) models. We aimed to compare the contribution of SAT and CTM data to the performance of LUR PM2.5 and NO2 models for Europe. Four sets of models, all including local traffic and land use variables, were compared (LUR without SAT or CTM, with SAT only, with CTM only, and with both SAT and CTM). LUR models were developed using two monitoring data sets: PM2.5 and NO2 ground level measurements from the European Study of Cohorts for Air Pollution Effects (ESCAPE) and from the European AIRBASE network. LUR PM2.5 models including SAT and SAT+CTM explained ~60% of spatial variation in measured PM2.5 concentrations, substantially more than the LUR model without SAT and CTM (adjR2: 0.33-0.38). For NO2 CTM improved prediction modestly (adjR2: 0.58) compared to models without SAT and CTM (adjR2: 0.47-0.51). Both monitoring networks are capable of producing models explaining the spatial variance over a large study area. SAT and CTM estimates of PM2.5 and NO2 significantly improved the performance of high spatial resolution LUR models at the European scale for use in large epidemiological studies.

Association of early life exposure to bisphenol A with obesity and cardiometabolic traits in childhood.

BACKGROUND: Bisphenol A (BPA) is a chemical used extensively worldwide in the manufacture of plastic polymers. The environmental obesogen hypothesis suggests that early life exposure to endocrine disrupting chemicals such as BPA may increase the risk for wt gain later in childhood but few prospective epidemiological studies have investigated this relationship. OBJECTIVES: We examined the association of early life BPA exposure with offspring obesity and cardiometabolic risk factors in 500 mother-child pairs from the RHEA pregnancy cohort in Crete, Greece. METHODS: BPA concentrations were measured in spot urine samples collected at the 1st trimester of pregnancy) and from children at 2.5 and 4 years of age. We measured birth wt, body mass index (BMI) from 6 months to 4 years of age, waist circumference, skinfold thickness, blood pressure, serum lipids, C-reactive protein, and adipokines at 4 years of age. BMI growth trajectories from birth to 4 years were estimated by mixed effects models with fractional polynomials of age. Adjusted associations were obtained via multivariable regression analyses. RESULTS: The prevalence of overweight/obesity was 9% at 2, 13% at 3% and 17% at 4 years of age. Geometric mean BPA concentrations were 1.2µg/g creatinine±7.9 in 1st trimester, 5.1µg/g±13.3 in 2.5 years and 1.9µg/g±4.9 in 4 years. After confounder adjustment, each 10-fold increase in BPA at 4 years was associated with a higher BMI z-score (adj. ß=0.2; 95% CI: 0.01, 0.4), waist circumference (adj. ß=1.2; 95% CI: 0.1, 2.2) and sum of skinfold thickness (adj. ß=3.7mm; 95% CI: 0.7, 6.7) at 4 years. Prenatal BPA was negatively associated with BMI and adiposity measures in girls and positively in boys. We found no associations of early life exposure to BPA with other offspring cardiometabolic risk factors. CONCLUSIONS: Prenatal BPA exposure was not consistently associated with offspring growth and adiposity measures but higher early childhood BPA was associated with excess child adiposity.

Exposure of Preschool-Age Greek Children (RHEA Cohort) to Bisphenol A, Parabens, Phthalates, and Organophosphates.

Phthalate esters (PEs), bisphenol A (BPA), and parabens (PBs), which are used in numerous consumer products, are known for their endocrine disrupting properties. Organophosphate chemicals (OPs), which form the basis of the majority of pesticides, are known for their neurotoxic activity in humans. All of these chemicals are associated with health problems to which children are more susceptible. Once they enter the human body, PEs, BPA, PBs, and OPs are metabolized and/or conjugated and finally excreted via urine. Hence, human exposure to these substances is examined through a determination of the urinary concentrations of their metabolites. This study assessed the exposure of Greek preschool-age children to PEs, BPA, PBs, and OPs by investigating the urinary levels of seven PEs metabolites, six PBs, BPA, and six dialkyl phosphate metabolites in five-hundred samples collected from 4-year-old children, subjects of the "RHEA" mother-child cohort in Crete, Greece. Daily intake of endocrine disruptors, calculated for 4 year old children, was lower than the corresponding daily intake for 2.5 year old children, which were determined in an earlier study of the same cohort. In some cases the daily intake levels exceeded the U.S. Environmental Protection Agency Tolerable Daily Intake (TDI) values and the EFSA Reference Doses (RfD) (e.g., for di-2-ethyl-hexyl phthalate, 3.6% and 1% of the children exceeded RfD and TDi, respectively). Exposure was linked to three main sources: PEs-BPA to plastic, PBs-diethyl phthalate to personal hygiene products, and OPs to food.