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BACKGROUND: Overweight and obesity impose a considerable individual and social burden, and the urban environments might encompass factors that contribute to obesity. Nevertheless, there is a scarcity of research that takes into account the simultaneous interaction of multiple environmental factors. OBJECTIVES: Our objective was to perform an exposome-wide association study of body mass index (BMI) in a multicohort setting of 15 studies. METHODS: Studies were affiliated with the Dutch Geoscience and Health Cohort Consortium (GECCO), had different population sizes (688-141,825), and covered the entire Netherlands. Ten studies contained general population samples, others focused on specific populations including people with diabetes or impaired hearing. BMI was calculated from self-reported or measured height and weight. Associations with 69 residential neighborhood environmental factors (air pollution, noise, temperature, neighborhood socioeconomic and demographic factors, food environment, drivability, and walkability) were explored. Random forest (RF) regression addressed potential nonlinear and nonadditive associations. In the absence of formal methods for multimodel inference for RF, a rank aggregation-based meta-analytic strategy was used to summarize the results across the studies. RESULTS: Six exposures were associated with BMI: five indicating neighborhood economic or social environments (average home values, percentage of high-income residents, average income, livability score, share of single residents) and one indicating the physical activity environment (walkability in 5-km buffer area). Living in high-income neighborhoods and neighborhoods with higher livability scores was associated with lower BMI. Nonlinear associations were observed with neighborhood home values in all studies. Lower neighborhood home values were associated with higher BMI scores but only for values up to [euro]300,000. The directions of associations were less consistent for walkability and share of single residents. DISCUSSION: Rank aggregation made it possible to flexibly combine the results from various studies, although between-study heterogeneity could not be estimated quantitatively based on RF models. Neighborhood social, economic, and physical environments had the strongest associations with BMI. https://doi.org/10.1289/EHP13393, Introduction Overweight and obesity impose a considerable individual and social burden, with global rates that have nearly tripled since 1975. (1) This striking rise could be attributed to changes in [...]

The severity of COVID-19 is linked to an imbalanced immune response. The dysregulated metabolism of small molecules and bioactive lipids has also been associated with disease severity. To promote understanding of the disease biochemistry and provide targets for intervention, we applied a range of LC-MS platforms to analyze over 100 plasma samples from patients with varying COVID-19 severity and with detailed clinical information on inflammatory responses (>30 immune markers). This is the third publication in a series, and it reports the results of comprehensive lipidome profiling using targeted LC-MS/MS. We identified 1076 lipid features across 25 subclasses, including glycerophospholipids, sterols, glycerolipids, and sphingolipids, among which 531 lipid features were dramatically changed in the plasma of intensive care unit (ICU) patients compared to patients in the ward. Patients in the ICU showed 1.3–57-fold increases in ceramides, (lyso-)glycerophospholipids, diglycerides, triglycerides, and plasmagen phosphoethanolamines, and 1.3–2-fold lower levels of a cyclic lysophosphatidic acid, sphingosine-1-phosphates, sphingomyelins, arachidonic acid-containing phospholipids, lactosylceramide, and cholesterol esters compared to patients in the ward. Specifically, phosphatidylinositols (PIs) showed strong fatty acid saturation-dependent behavior, with saturated fatty acid (SFA)- and monosaturated fatty acid (MUFA)-derived PI decreasing and polystaturated (PUFA)-derived PI increasing. We also found ~4000 significant Spearman correlations between lipids and multiple clinical markers of immune response with |R| ≥ 0.35 and FDR corrected Q < 0.05. Except for lysophosphatidic acid, lysophospholipids were positively associated with the CD4 fraction of T cells, and the cytokines IL-8 and IL-18. In contrast, sphingosine-1-phosphates were negatively correlated with innate immune markers such as CRP and IL-6. Further indications of metabolic changes in moderate COVID-19 disease were demonstrated in recovering ward patients compared to those at the start of hospitalization, where 99 lipid species were altered (6 increased by 30–62%; 93 decreased by 1.3–2.8-fold). Overall, these findings support and expand on early reports that dysregulated lipid metabolism is involved in COVID-19.

Background: Impairment of the hematopoietic system is one of the primary adverse health effects from exposure to benzene. We previously have shown that exposure to benzene at low levels (

Background: Multiple epidemiological studies have shown that exposure to single pesticide active ingredients or chemical groups is associated with adverse neurobehavioral outcomes in farmers. In agriculture, exposure to multiple pesticide active ingredients is the rule, rather than exception. Therefore, occupational studies on neurobehavioral effects of pesticides should account for potential co-exposure confounding. Methods: We conducted a cross-sectional study of 288 Ugandan smallholder farmers between September and December 2017. We collected data on self-reported use of pesticide products during the 12 months prior to survey and estimated yearly exposure-intensity scores for 14 pesticide active ingredients using a semi-quantitative exposure algorithm. We administered 11 neurobehavioral tests to assess five neurobehavioral domains. We implemented a Bayesian Model-Averaging (BMA) approach to examine the association between exposure to multiple pesticides and neurobehavioral outcomes, while accounting for multiple testing. We applied two levels of inference to determine (1) which neurobehavioral outcomes were associated with overall pesticide exposure (marginal inclusion probability (MIP) for covariate-only models 0.5). Results: Seventy-two percent of farmers reported use of pesticide products that contained at least one of 14 active ingredients, while the applicators used in median three different active ingredients (interquartile range (IQR) 4) in the 12 months prior to the study. The most widely used active ingredients were glyphosate (79%), cypermethrin (60%), and mancozeb (55%). We found that overall pesticide exposure was associated with impaired visual memory (Benton Visual Retention Test (BVRT)), language (semantic verbal fluency test), perceptual-motor function (Finger tapping test), and complex attention problems (Trail making A test and digit symbol test). However, when we looked at the associations for individual active ingredients, we only observed a positive association between glyphosate exposure and impaired visual memory (-0.103 [95% Bayesian Credible Interval (BCI)] [-0.24, 0] units in BVRT scores per interquartile range (IQR) increase in annual exposure to glyphosate, relative to a median [IQR] of 6 [3] units in BVRT across the entire study population). Conclusions: We found that overall pesticide exposure was associated with several neurobehavioral outcome variables. However, when we examined individual pesticide active ingredients, we observed predominantly null associations, except for a positive association between glyphosate exposure and impaired visual memory. Additional epidemiologic studies are needed to evaluate glyphosate’s neurotoxicity, while accounting for co-pollutant confounding.

COVID-19 is characterised by a dysregulated immune response, that involves signalling lipids acting as mediators of the inflammatory process along the innate and adaptive phases. To promote understanding of the disease biochemistry and provide targets for intervention, we applied a range of LC-MS platforms to analyse over 100 plasma samples from patients with varying COVID-19 severity and with detailed clinical information on inflammatory responses (>30 immune markers). The second publication in a series reports the results of quantitative LC-MS/MS profiling of 63 small lipids including oxylipins, free fatty acids, and endocannabinoids. Compared to samples taken from ward patients, intensive care unit (ICU) patients had 2–4-fold lower levels of arachidonic acid (AA) and its cyclooxygenase-derived prostanoids, as well as lipoxygenase derivatives, exhibiting negative correlations with inflammation markers. The same derivatives showed 2–5-fold increases in recovering ward patients, in paired comparison to early hospitalisation. In contrast, ICU patients showed elevated levels of oxylipins derived from poly-unsaturated fatty acids (PUFA) by non-enzymatic peroxidation or activity of soluble epoxide hydrolase (sEH), and these oxylipins positively correlated with markers of macrophage activation. The deficiency in AA enzymatic products and the lack of elevated intermediates of pro-resolving mediating lipids may result from the preference of alternative metabolic conversions rather than diminished stores of PUFA precursors. Supporting this, ICU patients showed 2-to-11-fold higher levels of linoleic acid (LA) and the corresponding fatty acyl glycerols of AA and LA, all strongly correlated with multiple markers of excessive immune response. Our results suggest that the altered oxylipin metabolism disrupts the expected shift from innate immune response to resolution of inflammation.

The COVID-19 pandemic raised a need to characterise the biochemical response to SARS-CoV-2 infection and find biological markers to identify therapeutic targets. In support of these aims, we applied a range of LC-MS platforms to analyse over 100 plasma samples from patients with varying COVID-19 severity and with detailed clinical information on inflammatory responses (>30 immune markers). The first publication in a series reports the results of quantitative LC-MS/MS profiling of 56 amino acids and derivatives. A comparison between samples taken from ICU and ward patients revealed a notable increase in ten post-translationally modified amino acids that correlated with markers indicative of an excessive immune response: TNF-alpha, neutrophils, markers for macrophage, and leukocyte activation. Severe patients also had increased kynurenine, positively correlated with CRP and cytokines that induce its production. ICU and ward patients with high IL-6 showed decreased levels of 22 immune-supporting and anti-oxidative amino acids and derivatives (e.g., glutathione, GABA). These negatively correlated with CRP and IL-6 and positively correlated with markers indicative of adaptive immune activation. Including corresponding alterations in convalescing ward patients, the overall metabolic picture of severe COVID-19 reflected enhanced metabolic demands to maintain cell proliferation and redox balance, alongside increased inflammation and oxidative stress.

Background: The genotoxicity of benzene has been investigated in dozens of biomonitoring studies, mainly by studying (classical) chromosomal aberrations (CAs) or micronuclei (MN) as markers of DNA damage. Both have been shown to be predictive of future cancer risk in cohort studies and could, therefore, potentially be used for risk assessment of genotoxicity-mediated cancers. Objectives: We sought to estimate an exposure-response curve (ERC) and quantify between-study heterogeneity using all available quantitative evidence on the cytogenetic effects of benzene exposure on CAs and MN respectively. Methods: We carried out a systematic literature review and summarized all available data of sufficient quality using meta-analyses. We assessed the heterogeneity in slope estimates between studies and conducted additional sensitivity analyses to assess how various study characteristics impacted the estimated ERC. Results: Sixteen CA (1,356 individuals) and 13 MN studies (2,097 individuals) were found to be eligible for inclusion in a meta-analysis. Studies where benzene was the primary genotoxic exposure and that had adequate assessment of both exposure and outcomes were used for the primary analysis. Estimated slope estimates were an increase of 0.27% CA [(95% CI: 0.08%, 0.47%); based on the results from 4 studies] and 0.27% MN [(95% CI: -0.23%, 0.76%); based on the results from 7 studies] per parts-per-million benzene exposure. We observed considerable between-study heterogeneity for both end points ([I.sup.2] > 90%). Discussion: Our study provides a systematic, transparent, and quantitative summary of the literature describing the strong association between benzene exposure and accepted markers of genotoxicity in humans. The derived consensus slope can be used as a best estimate of the quantitative relationship between real-life benzene exposure and genetic damage in future risk assessment. We also quantitate the large between-study heterogeneity that exists in this literature, a factor which is crucial for the interpretation of single-study or consensus slopes. https://doi.org/10.1289/EHP6404, Introduction Benzene is a well-known environmental contaminant that was classified as a human carcinogen (IARC Group 1) in 1974 (IARC 1974), which was recently reconfirmed (IARC 2018). Benzene and its [...]

Background: Lung cancer rates among never-smoking women in Xuanwei and Fuyuan in China are among the highest in the world and have been attributed to the domestic use of smoky (bituminous) coal for heating and cooking. However, the key components of coal that drive lung cancer risk have not been identified. Objectives: We aimed to investigate the relationship between lifelong exposure to the constituents of smoky coal (and other fuel types) and lung cancer. Methods: Using a population-based case-control study of lung cancer among 1,015 never-smoking female cases and 485 controls, we examined the association between exposure to 43 household air pollutants and lung cancer. Pollutant predictions were derived from a comprehensive exposure assessment study, which included methylated polycyclic aromatic hydrocarbons (PAHs), which have never been directly evaluated in an epidemiological study of any cancer. Hierarchical clustering and penalized regression were applied in order to address high colinearity in exposure variables. Results: The strongest association with lung cancer was for a cluster of 25 PAHs [odds ratio (OR): 2.21; 95% confidence interval (CI): 1.67, 2.87 per 1 standard deviation (SD) change], within which 5-methylchrysene (5-MC), a mutagenic and carcinogenic PAH, had the highest individual observed OR (5.42; 95% CI: 0.94, 27.5). A positive association with nitrogen dioxide (N[O.sub.2]) was also observed (OR: 2.06; 95% CI: 1.19, 3.49). By contrast, neither benzo(a)pyrene (BaP) nor fine particulate matter with aerodynamic diameter [less than or equal to] 2.5 [micro]m (P[M.sub.2.5]) were associated with lung cancer in the multipollutant models. Conclusions: To our knowledge, this is the first study to comprehensively evaluate the association between lung cancer and household air pollution (HAP) constituents estimated over the entire life course. Given the global ubiquity of coal use domestically for indoor cooking and heating and commercially for electric power generation, our study suggests that more extensive monitoring of coal combustion products, including methylated PAHs, may be warranted to more accurately assess health risks and develop prevention strategies from this exposure. https://doi.org/10.1289/EHP4913, Introduction The incidence of lung cancer among female never smokers in Asia is among the highest in the world (Couraud et al. 2012; Epplein et al. 2005; Pelosof et al. [...]