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Metal exposure is associated with vascular endothelial inflammation, an early pathological phenotype of atherosclerotic cardiovascular events. However, the underlying mechanism linking exposure, metabolic changes, and outcomes remains unclear. We aimed to investigate the metabolic changes underlying the associations of chronic exposure to metal mixtures with vascular endothelial inflammation. We recruited 960 adults aged 20-75 years from residential areas surrounding rivers near abandoned lead-zinc mine and classified them into river area and non-river area exposure groups. Urine levels of 25 metals, Framingham risk score (FRS), and serum concentrations of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), as biomarkers of vascular endothelial inflammation, were assessed. A "meet-in-the-middle" approach was applied to identify causal intermediate metabolites and metabolic pathways linking metal exposure to vascular endothelial inflammation in representative metabolic samples from 64 participants. Compared to the non-river area exposure group, the river area exposure group had significantly greater urine concentrations of chromium, copper, cadmium, and lead; lower urine concentrations of selenium; elevated FRS; and increased concentrations of ICAM-1 and VCAM-1. In total, 38 differentially abundant metabolites were identified between the river area and non-river area exposure groups. Among them, 25 metabolites were significantly associated with FRS, 8 metabolites with ICAM-1 expression, and 10 metabolites with VCAM-1 expression. Furthermore, fructose, ornithine, alpha-ketoglutaric acid, urea, and cytidine monophosphate, are potential mediators of the relationship between metal exposure and vascular endothelial inflammation. Additionally, the metabolic changes underlying these effects included changes in arginine and proline metabolism, pyrimidine metabolism, starch and sucrose metabolism, galactose metabolism, arginine biosynthesis, and alanine, aspartate, and glutamate metabolism, suggesting the disturbance of amino acid metabolism, the tricarboxylic acid cycle, nucleotide metabolism, and glycolysis. Overall, our results reveal biomechanisms that may link chronic exposure to multiple metals with vascular endothelial inflammation and elevated cardiovascular risk.

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Studies on the dose effects of kidney impairment and metabolomes in co-exposure to polycyclic aromatic hydrocarbons (PAHs) and metals are limited. We aimed to identify overall associations and metabolic perturbations in 130 participants (53 petrochemical workers and 77 controls) exposed to a PAHs-metals mixture in Southern China. The urinary 7 hydroxylated PAHs and 15 metal(loid)s were determined, and serum creatinine, beta-2 microglobulin, and estimated glomerular filtration rate were health outcomes. The liquid chromatography-mass spectrometry-based method was applied to serum metabolomics. Generalized weighted quantile sum (gWQS) regressions were used to estimate the overall dose-response relationships, and pathway analysis, "meet-in-the-middle" approach, and mediation effect analyses were conducted to identify potential metabolites and biological mechanisms linking exposure with nephrotoxic effects. Our results indicated that renal function reduction was associated with a PAHs-metals mixture in a dose-dependent manner, and 1-hydroxynaphthalene and copper were the most predominant contributors among the two families of pollutants. Furthermore, the metabolic disruptions associated with the early onset of kidney impairment induced by the combination of PAHs and metals encompassed pathways such as phenylalanine-tyrosine-tryptophan biosynthesis, phenylalanine metabolism, and alpha-linolenic acid metabolism. In addition, the specifically identified metabolites demonstrated excellent potential as bridging biomarkers connecting the reduction in renal function with the mixture of PAHs and metals. These findings shed light on understanding the overall associations and metabolic mechanism of nephrotoxic effects of co-exposure to PAHs and metals.

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BACKGROUND: Exposure to persistent organic pollutants (POPs) has been related to the risk of endometriosis however the mechanisms remain unclear. The objective of the present study was to characterize the metabolic profiles underpinning the associations between POPs and endometriosis risk. METHODOLOGY: A hospital-based case-control study was conducted in France to recruit women with and without surgically confirmed deep endometriosis. Women's serum was analyzed using gas and liquid chromatography coupled to high-resolution mass spectrometry (HRMS) to measure the levels of polychlorinated biphenyls (PCBs), organochlorinated pesticides (OCPs) and per-/polyfluoroalkyl substances (PFAS). A comprehensive metabolomic profiling was conducted using targeted HRMS and 1H nuclear magnetic resonance (1H NMR) to cover polar and non-polar fractions. A "meet-in-the-middle" statistical framework was applied to identify the metabolites related to endometriosis and POP levels, using multivariate linear and logistic regressions adjusting for confounding variables. RESULTS: Fourteen PCBs, six OCPs and six PFAS were widely found in almost all serum samples. The pesticide trans-nonachlor was the POP most strongly and positively associated with deep endometriosis risk, with odds ratio (95 % confidence interval) of 2.42 (1.49; 4.12), followed by PCB180 and 167. Women with endometriosis exhibited a distinctive metabolic profile, with elevated serum levels of lactate, ketone bodies and multiple amino acids and lower levels of bile acids, phosphatidylcholines (PCs), cortisol and hippuric acid. The metabolite 2-hydroxybutyrate was simultaneously associated to endometriosis risk and exposure to trans-nonachlor. CONCLUSIONS: To the best of our knowledge, this is the first comprehensive metabolome-wide association study of endometriosis, integrating ultra-trace profiling of POPs. The results confirmed a metabolic alteration among women with deep endometriosis that could be also associated to the exposure to POPs. Further observational and experimental studies will be required to delineate the causal ordering of those associations and gain insight on the underlying mechanisms.

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Childhood obesity is an increasingly severe public health problem, with a prospective impact on health. We propose an exposome approach to identify actionable risk factors for this condition. Our assumption is that relationships between external exposures and outcomes such as rapid growth, overweight, or obesity in children can be better understood through a "meet-in-the-middle" model. This is based on a combination of external and internal exposome-based approaches, that is, the study of multiple exposures (in our case, dietary patterns) and molecular pathways (metabolomics and epigenetics). This may strengthen causal reasoning by identifying intermediate markers that are associated with both exposures and outcomes. Our biomarker-based studies in the STOP consortium suggest (in several ways, including mediation analysis) that branched-chain amino acids (BCAAs) could be mediators of the effect of dietary risk factors on childhood overweight/obesity. This is consistent with intervention and animal studies showing that higher intake of BCAAs has a positive impact on body composition, glycemia, and satiety. Concerning food, of particular concern is the trend of increasing intake of ultra-processed food (UPF), including among children. Several mechanisms have been proposed to explain the impact of UPF on obesity and overweight, including nutrient intake (particularly proteins), changes in appetite, or the role of additives. Research from the Avon Longitudinal Study of Parents and Children cohort has shown a relationship between UPF intake and trajectories in childhood adiposity, while UPF was related to lower blood levels of BCAAs. We suggest that an exposome-based approach can help strengthening causal reasoning and support policies. Intake of UPF in children should be restricted to prevent obesity.

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BACKGROUND: Effects of polybrominated diphenyl ethers (PBDEs) on neonatal birth outcomes vary across previous studies, and the related mechanism investigation remains poorly understood, especially at the metabolic level. OBJECTIVES: To evaluate the associations between prenatal PBDEs exposure and neonatal birth outcomes including gestational age, neonatal weight, birth length, head circumference (HC), Apgar score at 1 min (Apgar1) and 5 min, and further reveal the underlying metabolic disorders in a population-based birth cohort study. METHODS: Gas chromatography-triple quadrupole tandem mass spectrometry (GC-MS/MS) based targeted method and GC-MS based untargeted method were respectively conducted to obtain PBDE levels and metabolic profiles of 200 placental tissue samples from a typical e-waste recycling area (Guiyu) and reference area (Haojiang) in China. Spearman correlation and regression analyses were applied to assess the associations between the placental PBDE levels and birth outcomes. Metabolome-wide association studies and the meet-in-the-middle approach were employed to explore disruptions linking PBDE exposures and the corresponding adverse birth outcomes. RESULTS: Eight out of 27 PBDE congeners were detected in placenta with more than 50% frequency in at least one district and significantly higher in Guiyu than those in Haojiang. The lower HC and Apgar1 had significant associations with PBDE exposures after adjustment for potential confounders. A total of 66, 16 and 14 metabolites were significantly correlated with PBDE exposures, HC and Apgar1, respectively. 4 and 12 PBDE-related metabolites were significantly associated with the risks of decreasing neonatal HC and Apgar1. The disrupted metabolites were mainly involved in the pentose phosphate pathway, ascorbate metabolism, threonine metabolism, butanoate metabolism, lipid metabolism, and arginine biosynthesis. CONCLUSIONS: In this birth cohort, higher placental PBDE levels were significantly associated with the lower HC and Apgar1. The associations might be modified by multiple metabolic disturbances through increasing oxidative stress, mediating neurotoxicity, maternal gut microbiota dysbiosis and vasodilatation regulation.

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The biological mechanisms through which adherence to Mediterranean Diet (MD) protects against colon cancer (CC) are poorly understood. Evidence suggests that chronic inflammation may be implicated in the pathway. Both diet and CC are related to epigenetic regulation. We performed a nested case-control study on 161 pairs from the Italian component of the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, in which we looked for the methylation signals in DNA extracted from leucocytes associated with both CC and MD in 995 CpGs located in 48 inflammation genes. The DNA methylation signals detected in this analysis were validated in a subgroup of 47 case-control pairs and further replicated (where validated) in 95 new pairs by means of pyrosequencing. Among the CpG sites selected a-priori in inflammation-related genes, seven CpG sites were found to be associated with CC status and with MD, in line with its protective effect. Only two CpG sites (cg17968347-SERPINE1 and cg20674490-RUNX3) were validated using bisulphite pyrosequencing and, after replication, we found that DNA methylation of cg20674490-RUNX3 may be a potential molecular mediator explaining the protective effect of MD on CC onset. The use of a 'meet-in-the-middle' approach to identify the overlap between exposure and predictive markers of disease is innovative in studies on the relationship between diet and cancer, in which exposure assessment is difficult and the mechanisms through which the nutrients exert their protective effect is largely unknown.

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BACKGROUND: Cancer is believed to arise through the perturbation of pathways and the order of pathway perturbation events can enhance understanding and evaluation of carcinogenicity. This order has not been examined so far, and this study aimed to fill this gap by attempting to gather evidence on the potential temporal sequence of events in carcinogenesis. DESIGN: The methodology followed was to discuss first the temporal sequence of hallmarks of cancer from the point of view of pathological specimens of cancer (essentially branched mutations) and then to consider the hallmarks of cancer that one well-known carcinogen, benzo(a)pyrene, can modify. RESULTS: Even though the sequential order of driving genetic alterations can vary between and within tumours, the main cancer pathways affected are almost ubiquitous and follow a generally common sequence: resisting cell death, insensitivity to antigrowth signals, sustained proliferation, deregulated energetics, replicative immortality and activation of invasion and metastasis. The first 3 hallmarks can be regarded as almost simultaneous while angiogenesis and avoiding immune destruction are perhaps the only hallmarks with a varying position in the above sequence. CONCLUSIONS: Our review of hallmarks of cancer and their temporal sequence, based on mutational spectra in biopsies from different cancer sites, allowed us to propose a hypothetical temporal sequence of the hallmarks. This sequence can add molecular support to the evaluation of an agent as a carcinogen as it can be used as a conceptual framework for organising and evaluating the strength of existing evidence.

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