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Breast cancer (BC) is one of the most common causes of cancer in the world and the second leading cause of cancer deaths among women. Mortality is associated mainly with the development of metastases. Identification of the mechanisms involved in metastasis formation is, therefore, a major public health issue. Among the proposed risk factors, chemical environment and pollution are increasingly suggested to have an effect on the signaling pathways involved in metastatic tumor cells emergence and progression. The purpose of this article is to summarize current knowledge about the role of environmental chemicals in breast cancer progression, metastasis formation and resistance to chemotherapy. Through a scoping review, we highlight the effects of a wide variety of environmental toxicants, including persistent organic pollutants and endocrine disruptors, on invasion mechanisms and metastatic processes in BC. We identified the epithelial-to-mesenchymal transition and cancer-stemness (the stem cell-like phenotype in tumors), two mechanisms suspected of playing key roles in the development of metastases and linked to chemoresistance, as potential targets of contaminants. We discuss then the recently described pro-migratory and pro-invasive Ah receptor signaling pathway and conclude that his role in BC progression is still controversial. In conclusion, although several pertinent pathways for the effects of xenobiotics have been identified, the mechanisms of actions for multiple other molecules remain to be established. The integral role of xenobiotics in the exposome in BC needs to be further explored through additional relevant epidemiological studies that can be extended to molecular mechanisms.

Objective: To assess the associations between exposure to food additive emulsifiers and risk of cardiovascular disease (CVD).Design: Prospective cohort study.Setting: French NutriNet-Santé study, 2009-21.Participants: 95 442 adults (>18 years) without prevalent CVD who completed at least three 24 hour dietary records during the first two years of follow-up.Main outcome measures: Associations between intake of food additive emulsifiers (continuous (mg/day)) and risk of CVD, coronary heart disease, and cerebrovascular disease characterised using multivariable proportional hazard Cox models to compute hazard ratios for each additional standard deviation (SD) of emulsifier intake, along with 95% confidence intervals.Results: Mean age was 43.1 (SD 14.5) years, and 79.0% (n=75 390) of participants were women. During follow-up (median 7.4 years), 1995 incident CVD, 1044 coronary heart disease, and 974 cerebrovascular disease events were diagnosed. Higher intake of celluloses (E460-E468) was found to be positively associated with higher risks of CVD (hazard ratio for an increase of 1 standard deviation 1.05, 95% confidence interval 1.02 to 1.09, P=0.003) and coronary heart disease (1.07, 1.02 to 1.12, P=0.004). Specifically, higher cellulose E460 intake was linked to higher risks of CVD (1.05, 1.01 to 1.09, P=0.007) and coronary heart disease (1.07, 1.02 to 1.12, P=0.005), and higher intake of carboxymethylcellulose (E466) was associated with higher risks of CVD (1.03, 1.01 to 1.05, P=0.004) and coronary heart disease (1.04, 1.02 to 1.06, P=0.001). Additionally, higher intakes of monoglycerides and diglycerides of fatty acids (E471 and E472) were associated with higher risks of all outcomes. Among these emulsifiers, lactic ester of monoglycerides and diglycerides of fatty acids (E472b) was associated with higher risks of CVD (1.06, 1.02 to 1.10, P=0.002) and cerebrovascular disease (1.11, 1.06 to 1.16, P<0.001), and citric acid ester of monoglycerides and diglycerides of fatty acids (E472c) was associated with higher risks of CVD (1.04, 1.02 to 1.07, P=0.004) and coronary heart disease (1.06, 1.03 to 1.09, P<0.001). High intake of trisodium phosphate (E339) was associated with an increased risk of coronary heart disease (1.06, 1.00 to 1.12, P=0.03). Sensitivity analyses showed consistent associations.Conclusion: This study found positive associations between risk of CVD and intake of five individual and two groups of food additive emulsifiers widely used in industrial foods.

Background: Emulsifiers are widely used food additives in industrially processed foods to improve texture and enhance shelf-life. Experimental research suggests deleterious effects of emulsifiers on the intestinal microbiota and the metabolome, leading to chronic inflammation and increasing susceptibility to carcinogenesis. However, human epidemiological evidence investigating their association with cancer is nonexistent. This study aimed to assess associations between food additive emulsifiers and cancer risk in a large population-based prospective cohort.Methods and findings This study included 92,000 adults of the French NutriNet-Santé cohort without prevalent cancer at enrolment (44.5 y [SD: 14.5], 78.8% female, 2009 to 2021). They were followed for an average of 6.7 years [SD: 2.2]. Food additive emulsifier intakes were estimated for participants who provided at least 3 repeated 24-h dietary records linked to comprehensive, brand-specific food composition databases on food additives. Multivariable Cox regressions were conducted to estimate associations between emulsifiers and cancer incidence. Overall, 2,604 incident cancer cases were diagnosed during follow-up (including 750 breast, 322 prostate, and 207 colorectal cancers). Higher intakes of mono- and diglycerides of fatty acids (FAs) (E471) were associated with higher risks of overall cancer (HR high vs. low category = 1.15; 95% CI [1.04, 1.27], p-trend = 0.01), breast cancer (HR = 1.24; 95% CI [1.03, 1.51], p-trend = 0.04), and prostate cancer (HR = 1.46; 95% CI [1.09, 1.97], p-trend = 0.02). In addition, associations with breast cancer risk were observed for higher intakes of total carrageenans (E407 and E407a) (HR = 1.32; 95% CI [1.09, 1.60], p-trend = 0.009) and carrageenan (E407) (HR = 1.28; 95% CI [1.06, 1.56], p-trend = 0.01). No association was detected between any of the emulsifiers and colorectal cancer risk. Several associations with other emulsifiers were observed but were not robust throughout sensitivity analyses. Main limitations include possible exposure measurement errors in emulsifiers intake and potential residual confounding linked to the observational design.Conclusions In this large prospective cohort, we observed associations between higher intakes of carrageenans and mono- and diglycerides of fatty acids with overall, breast and prostate cancer risk. These results need replication in other populations. They provide new epidemiological evidence on the role of emulsifiers in cancer risk. Trial registration ClinicalTrials.gov NCT03335644 .

Food additives (e.g. artificial sweeteners, emulsifiers, dyes, etc.) are ingested by billions of individuals daily. Some concerning results, mainly derived from animal and/or cell-based experimental studies, have recently emerged suggesting potential detrimental effects of several widely consumed additives. Profiles of additive exposure as well as the potential long-term impact of multiple exposure on human health are poorly documented. This work aimed to estimate the usual intake of food additives among participants of the French NutriNet-Santé cohort and to identify and describe profiles of exposure (single substances and mixtures). Overall, 106,489 adults from the French NutriNet-Santé cohort study (2009-ongoing) were included. Consumption of 90 main food additives was evaluated using repeated 24 h dietary records including information on brands of commercial products. Qualitative information (as presence/absence) of each additive in food products was determined using 3 large-scale composition databases (OQALI, Open Food Facts, GNPD), accounting for the date of consumption of the product. Quantitative ingested doses were estimated using a combination of laboratory assays on food matrixes (n = 2677) and data from EFSA and JECFA. Exposure was estimated in mg per kg of body weight per day. Profiles of exposure to food additive mixtures were extracted using Non-negative Matrix Factorization (NMF) followed by k-means clustering as well as Graphical Lasso. Sociodemographic and dietary comparison of clusters of participants was performed by Chi-square tests or linear regressions. Data were weighted according to the national census. Forty-eight additives were consumed by more than 10% of the participants, with modified starches and citric acid consumed by more than 90%. The top 50 also included several food additives for which potential adverse health effects have been suggested by recent experimental studies: lecithins (86.6% consumers), mono- and diglycerides of fatty acids (78.1%), carrageenan (77.5%), sodium nitrite (73.9%), di-, tri- and polyphosphates (70.1%), potassium sorbate (65.8%), potassium metabisulphite (44.8%), acesulfame K (34.0%), cochineal (33.9%), potassium nitrate (31.6%), sulfite ammonia caramel (28.8%), bixin (19.5%), monosodium glutamate (15.1%) and sucralose (13.5%). We identified and described five clusters of participants more specifically exposed to five distinct additive mixtures and one additional cluster gathering participants with overall low additive exposure. Food additives, including several for which health concerns are currently debated, were widely consumed in this population-based study. Furthermore, main mixtures of additives were identified. Their health impact and potential cocktail effects should be explored in future epidemiological and experimental studies.

Resveratrol (RES), a polyphenol found in natural foods, displays anti-oxidant, anti-inflammatory and anti-proliferative properties potentially beneficial in cancers, in particular in the prevention of tumor growth. However, the rapid metabolism of resveratrol strongly limits its bioavailability. The molecular mechanisms sustaining the potential biological activity of low doses of resveratrol has not been extensively studied and, thus, needs better characterization. Here, we show that resveratrol (10 µM, 48 hr) induces both a cell growth arrest and a metabolic reprogramming in colon cancer cells. Resveratrol modifies the lipidomic profile, increases oxidative capacities and decreases glycolysis, in association with a decreased pentose phosphate activity and an increased ATP production. Resveratrol targets the pyruvate dehydrogenase (PDH) complex, a key mitochondrial gatekeeper of energy metabolism, leading to an enhanced PDH activity. Calcium chelation, as well as the blockade of the mitochondrial calcium uniport, prevents the resveratrol-induced augmentation in oxidative capacities and the increased PDH activity suggesting that calcium might play a role in the metabolic shift. We further demonstrate that the inhibition of the CamKKB or the downstream AMPK pathway partly abolished the resveratrol-induced increase of glucose oxidation. This suggests that resveratrol might improve the oxidative capacities of cancer cells through the CamKKB/AMPK pathway.

Deciphering the relationship between molecules, olfactory receptors (ORs) and corresponding odors remains a challenging task. It requires a comprehensive identification of ORs responding to a given odorant. With the recent advances in artificial intelligence and the growing research in decoding the human olfactory perception from chemical features of odorant molecules, the applications of advanced machine learning have been revived. In this study, Convolutional Neural Network (CNN) and Graphical Convolutional Network (GCN) models have been developed on odorant moleculesodors and odorant molecules-olfactory receptors using a large set of 5955 molecules, 160 odors and 106 olfactory receptors. The performance of such models is promising with a Precision/Recall Area Under Curve of 0.66 for the odorant-odor and 0.91 for the odorant-olfactory receptor GCN models respectively. Furthermore, based on the correspondence of odors and ORs associated for a set of 389 compounds, an odor-olfactory receptor pairwise score was computed for each odor-OR combination allowing to suggest a combinatorial relationship between olfactory receptors and odors. Overall, this analysis demonstrate that artificial intelligence may pave the way in the identification of the smell perception and the full repertoire of receptors for a given odorant molecule.

BACKGROUND: Prenatal exposure to persistent organic pollutants (POPs) may contribute to the development of childhood obesity and metabolic disor-ders. However, little is known about whether the maternal nutritional status during pregnancy can modulate these associations.OBJECTIVES: The main objective was to characterize the joint associations and interactions between prenatal levels of POPs and nutrients on child-hood obesity.METHODS: We used data from to the Spanish INfancia y Medio Ambiente-Environment and Childhood (INMA) birth cohort, on POPs and nutritional biomarkers measured in maternal blood collected at the first trimester of pregnancy and child anthropometric measurements at 7 years of age. Six organochlorine compounds (OCs) [dichlorodiphenyldichloroethylene, hexachlorobenzene (HCB), 0-hexachlorocyclohexane (0-HCH) and polychlori-nated biphenyls 138, 153, 180] and four per-and polyfluoroalkyl substances (PFAS) were measured. Nutrients included vitamins (D, B12, and folate), polyunsaturated fatty acids (PUFAs), and dietary carotenoids. Two POPs-nutrients mixtures data sets were established: a) OCs, PFAS, vitamins, and carotenoids (n = 660), and b) OCs, PUFAs, and vitamins (n = 558). Joint associations of mixtures on obesity were characterized using Bayesian kernel machine regression (BKMR). Relative importance of biomarkers and two-way interactions were identified using gradient boosting machine, hierarchi-cal group lasso regularization, and BKMR. Interactions were further characterized using multivariate regression models in the multiplicative and addi-tive scale. RESULTS: Forty percent of children had overweight or obesity. We observed a positive overall joint association of both POPs-nutrients mixtures on overweight/obesity risk, with HCB and vitamin B12 the biomarkers contributing the most. Recurrent interactions were found between HCB and vita-min B12 across screening models. Relative risk for a natural log increase of HCB was 1.31 (95% CI: 1.11, 1.54, pInteraction = 0:02) in the tertile 2 of vitamin B12 and in the additive scale a relative excess risk due to interaction of 0.11 (95% CI: 0.02, 0.20) was found. Interaction between perfluorooc-tane sulfonate and 0-cryptoxanthin suggested a protective effect of the antioxidant on overweight/obesity risk.CONCLUSION: These results support that maternal nutritional status may modulate the effect of prenatal exposure to POPs on childhood overweight/ obesity. These findings may help to develop a biological hypothesis for future toxicological studies and to better interpret inconsistent findings in epi-demiological studies. https://doi.org/10.1289/EHP11258

This study aims to highlight the relationships between the structure of smell compounds and their odors. For this purpose, heterogeneous data sources were screened, and 6038 odorant compounds and their known associated odors (162 odor notes) were compiled, each individual molecule being represented with a set of 1024 structural fingerprint. Several dimensional reduction techniques (PCA, MDS, t-SNE and UMAP) with two clustering methods (k-means and agglomerative hierarchical clustering AHC) were assessed based on the calculated fingerprints. The combination of UMAP with k-means and AHC methods allowed to obtain a good representativeness of odors by clusters, as well as the best visualization of the proximity of odorants on the basis of their molecular structures. The presence or absence of molecular substructures has been calculated on odorant in order to link chemical groups to odors. The results of this analysis bring out some associations for both the odor notes and the chemical structures of the molecules such as “woody” and “spicy” notes with allylic and bicyclic structures, “balsamic” notes with unsaturated rings, both “sulfurous” and “citrus” with aldehydes, alcohols, carboxylic acids, amines and sulfur compounds, and “oily”, “fatty” and “fruity” characterized by esters and with long carbon chains. Overall, the use of UMAP associated to clustering is a promising method to suggest hypotheses on the odorant structure-odor relationships.

The adverse outcome pathway (AOP) has been conceptualized in 2010 as an analytical construct to describe a sequential chain of causal links between key events, from a molecular initiating event leading to an adverse outcome (AO), considering several levels of biological organization. An AOP aims to identify and organize available knowledge about toxic effects of chemicals and drugs, either in ecotoxicology or toxicology, and it can be helpful in both basic and applied research and serve as a decision-making tool in support of regulatory risk assessment. The AOP concept has evolved since its introduction, and recent research in toxicology, based on integrative systems biology and artificial intelligence, gave it a new dimension. This innovative in silico strategy can help to decipher mechanisms of action and AOP and offers new perspectives in AOP development. However, to date, this strategy has not yet been applied to ecotoxicology. In this context, the main objective of this short article is to discuss the relevance and feasibility of transferring this strategy to ecotoxicology. One of the challenges to be discussed is the level of organisation that is relevant to address for the AO (population/community). This strategy also offers many advantages that could be fruitful in ecotoxicology and overcome the lack of time, such as the rapid identification of data available at a time t, or the identification of “data gaps”. Finally, this article proposes a step forward with suggested priority topics in ecotoxicology that could benefit from this strategy.

To assess the efficacy of horticultural therapy (HT) on anterior cingulate cortex (ACC) activity and the changes in rumination and catastrophizing scores in individuals with chronic low back pain (LBP). We conducted a randomized, controlled, cross-over, 3-week pilot study (ClinicalTrials.gov Identifier: NCT04656158). The departments of physical medicine and rehabilitation (hospital grounds and occupational therapy room) and imaging research were involved. The participants were adults with non-specific chronic LBP. All participants underwent two 90-min HT sessions and two 90-min handiwork sessions per week. The activity sequence order was randomized, and the activities were separated by a wash-out period of 1 week. Each participant underwent 3 brain MRIs: before, after the first, and after the second activity. The primary outcome was the change in ACC perfusion in ml/100g/min using arterial spin labeling MRI. The secondary outcomes were the changes in self-reported rumination and catastrophizing scores after each activity compared to baseline. Sixteen participants were included: 14 women (87.5%), LBP intensity (numeric rating scale) mean (SD) 45.1 (27.2)/100, specific activity limitation (Roland Morris disability questionnaire) 9.3 (4.1)/24. Change in ACC perfusion from baseline was -0.1 (10.7), 95% CI [-5.6, 5.8] ml (blood)/100g (tissue)/min after handiwork and -0.1 (8.7), [-4.7, 4.6] after HT and did not differ between the 2 activities (p = 0.91). Change in rumination [-0.5 (4.4) after handiwork and -0.3 (2.8) after HT] and catastrophizing scores [-2 (2.8) after handiwork and -1.4 (2.3) after HT] did not differ between activities (p = 0.99 and 0.22, respectively). Limited exposure to the interventions and the sample profile (moderate levels of pain) may explain our results. Our results highlight the need for future studies using the most appropriate outcomes to determine the exact effects of nature experiences in people with chronic musculoskeletal disease.