Healthy lifestyle change and all-cause and cancer mortality in the European Prospective Investigation into Cancer and Nutrition cohort.

BACKGROUND: Healthy lifestyles are inversely associated with the risk of noncommunicable diseases, which are leading causes of death. However, few studies have used longitudinal data to assess the impact of changing lifestyle behaviours on all-cause and cancer mortality. METHODS: Within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, lifestyle profiles of 308,497 cancer-free adults (71% female) aged 35-70 years at recruitment across nine countries were assessed with baseline and follow-up questionnaires administered on average of 7 years apart. A healthy lifestyle index (HLI), assessed at two time points, combined information on smoking status, alcohol intake, body mass index, and physical activity, and ranged from 0 to 16 units. A change score was calculated as the difference between HLI at baseline and follow-up. Associations between HLI change and all-cause and cancer mortality were modelled with Cox regression, and the impact of changing HLI on accelerating mortality rate was estimated by rate advancement periods (RAP, in years). RESULTS: After the follow-up questionnaire, participants were followed for an average of 9.9 years, with 21,696 deaths (8407 cancer deaths) documented. Compared to participants whose HLIs remained stable (within one unit), improving HLI by more than one unit was inversely associated with all-cause and cancer mortality (hazard ratio [HR]: 0.84; 95% confidence interval [CI]: 0.81, 0.88; and HR: 0.87; 95% CI: 0.82, 0.92; respectively), while worsening HLI by more than one unit was associated with an increase in mortality (all-cause mortality HR: 1.26; 95% CI: 1.20, 1.33; cancer mortality HR: 1.19; 95% CI: 1.09, 1.29). Participants who worsened HLI by more than one advanced their risk of death by 1.62 (1.44, 1.96) years, while participants who improved HLI by the same amount delayed their risk of death by 1.19 (0.65, 2.32) years, compared to those with stable HLI. CONCLUSIONS: Making healthier lifestyle changes during adulthood was inversely associated with all-cause and cancer mortality and delayed risk of death. Conversely, making unhealthier lifestyle changes was positively associated with mortality and an accelerated risk of death.

Lifestyle changes in middle age and risk of cancer: evidence from the European Prospective Investigation into Cancer and Nutrition.

In this study, we aimed to provide novel evidence on the impact of changing lifestyle habits on cancer risk. In the EPIC cohort, 295,865 middle-aged participants returned a lifestyle questionnaire at baseline and during follow-up. At both timepoints, we calculated a healthy lifestyle index (HLI) score based on cigarette smoking, alcohol consumption, body mass index and physical activity. HLI ranged from 0 (most unfavourable) to 16 (most favourable). We estimated the association between HLI change and risk of lifestyle-related cancers-including cancer of the breast, lung, colorectum, stomach, liver, cervix, oesophagus, bladder, and others-using Cox regression models. We reported hazard ratios (HR) with 95% confidence intervals (CI). Median time between the two questionnaires was 5.7 years, median age at follow-up questionnaire was 59 years. After the follow-up questionnaire, we observed 14,933 lifestyle-related cancers over a median follow-up of 7.8 years. Each unit increase in the HLI score was associated with 4% lower risk of lifestyle-related cancers (HR 0.96; 95%CI 0.95-0.97). Among participants in the top HLI third at baseline (HLI > 11), those in the bottom third at follow-up (HLI ≤ 9) had 21% higher risk of lifestyle-related cancers (HR 1.21; 95%CI 1.07-1.37) than those remaining in the top third. Among participants in the bottom HLI third at baseline, those in the top third at follow-up had 25% lower risk of lifestyle-related cancers (HR 0.75; 95%CI 0.65-0.86) than those remaining in the bottom third. These results indicate that lifestyle changes in middle age may have a significant impact on cancer risk.

A comprehensive multiplatform metabolomic analysis reveals alterations of 2-hydroxybutyric acid among women with deep endometriosis related to the pesticide trans-nonachlor.

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.

On the use of the healthy lifestyle index to investigate specific disease outcomes.

The healthy lifestyle index (HLI), defined as the unweighted sum of individual lifestyle components, was used to investigate the combined role of lifestyle factors on health-related outcomes. We introduced weighted outcome-specific versions of the HLI, where individual lifestyle components were weighted according to their associations with disease outcomes. Within the European Prospective Investigation into Cancer and Nutrition (EPIC), we examined the association between the standard and the outcome-specific HLIs and the risk of T2D, CVD, cancer, and all-cause premature mortality. Estimates of the hazard ratios (HRs), the Harrell's C-index and the population attributable fractions (PAFs) were compared. For T2D, the HR for 1-SD increase of the standard and T2D-specific HLI were 0.66 (95% CI: 0.64, 0.67) and 0.43 (0.42, 0.44), respectively, and the C-index were 0.63 (0.62, 0.64) and 0.72 (0.72, 0.73). Similar, yet less pronounced differences in HR and C-index were observed for standard and outcome-specific estimates for cancer, CVD and all-cause mortality. PAF estimates for mortality before age 80 were 57% (55%, 58%) and 33% (32%, 34%) for standard and mortality-specific HLI, respectively. The use of outcome-specific HLI could improve the assessment of the role of lifestyle factors on disease outcomes, thus enhancing the definition of public health recommendations.

Associations between persistent organic pollutants and endometriosis: A multiblock approach integrating metabolic and cytokine profiling.

Humans are exposed daily to complex mixtures of chemical pollutants through their environment and diet, some of which have the potential to disrupt the bodies' natural endocrine functions and contribute to reproductive diseases like endometriosis. Increasing epidemiological and experimental evidence supports the association between endometriosis and certain persistent organic pollutants (POPs) like dioxins; however, little is known about the underlying linking mechanisms. The main objective of this study is to proof the methodological applicability and discovery potential of integrating ultra-trace mass spectrometry (MS) profiling of POP biomarkers and endogenous biomarker profiling (MS metabolomics and cytokines) in a case-control study for the etiological research of endometriosis. The approach is applied in a pilot clinical-based study conducted in France where women with and without surgically confirmed endometriosis were recruited. Serum samples were analysed with high-resolution MS for about 30 polychlorinated biphenyls (PCBs), organochlorinated pesticides and perfluoroalkyl substances (PFAS). About 600 serum metabolites and lipids were identified with targeted metabolomics using tandem MS with the Biocrates MxP® Quant 500 Kit. A panel of 4 pro-inflammatory cytokines were analysed using ELISA-based 4-PLEX analyser. Statistical analysis included a battery of variable selection approaches, multivariate logistic regression for single-chemical associations, Bayesian kernel machine regressions (BKMR) to identify mixture effects of POPs and a multiblock approach to identify shared biomarker signatures among high risk clusters. The results showed the positive associations between some POPs and endometriosis risk, including the pesticide trans-nonachlor Odds Ratio (95% Confidence Interval) 3.38 (2.06-5.98), p < 0.0001 and PCB 114 OR (95% CI) 1.83 (1.17-2.93), p = 0.009. The BKMR approach showed a tendency of a positive cumulative effect of the mixture, however trans-nonachlor exhibited significant associations within the mixture and interacted with other PCBs, strengthening the effects at highest concentrations. Finally, the multiblock analysis, relating the various blocks of data, revealed a latent cluster of women with higher risk of endometrioma presenting higher concentrations of trans-nonachlor, PCB 114 and dioxin-like toxic equivalents from PCBs, together with an increased inflammatory profile (i.e. elevated interleukin-8 and monocyte chemoattractant protein-1). It was also highlighted a specific metabolic pattern characterized by dysregulation of bile acid homeostasis and lipase activity. Further research will be required with larger sample size to confirm these findings and gain insight on the underlying mechanisms between POPs and endometriosis.

Associations between Exposure to Organochlorine Chemicals and Endometriosis: A Systematic Review of Experimental Studies and Integration of Epidemiological Evidence.

BACKGROUND: Growing epidemiological evidence suggests that organochlorine chemicals (OCCs), including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), may play a role in the pathogenesis of endometriosis. OBJECTIVES: We aimed to systematically review the experimental evidence (in vivo and in vitro) on the associations between exposure to OCCs and endometriosis-related end points. METHODS: A systematic review protocol was developed following the National Toxicology Program /Office of Health Assessment and Translation (NTP/OHAT) framework and managed within a web-based interface. In vivo studies designed to evaluate the impact of OCCs on the onset or progression of endometriosis and proliferation of induced endometriotic lesions were eligible. Eligible in vitro studies included single-cell and co-culture models to evaluate the proliferation, migration, and/or invasion of endometrial cells. We applied the search strings to PubMed, Web of Science, and Scopus®. A final search was performed on 24 June 2020. Assessment of risk of bias and the level of evidence and integration of preevaluated epidemiological evidence was conducted using NTP/OHAT framework Results: Out of 812 total studies, 39 met the predetermined eligibility criteria (15 in vivo, 23 in vitro, and 1 both). Most studies (n=27) tested TCDD and other dioxin-like chemicals. In vivo evidence supported TCDD's promotion of endometriosis onset and lesion growth. In vitro evidence supported TCDD's promotion of cell migration and invasion, but there was insufficient evidence for cell proliferation. In vitro evidence further supported the roles of the aryl hydrocarbon receptor and matrix metalloproteinases in mediating steroidogenic disruption and inflammatory responses. Estrogen interactions were found across studies and end points. CONCLUSION: Based on the integration of a high level of animal evidence with a moderate level of epidemiological evidence, we concluded that TCDD was a known hazard for endometriosis in humans and the conclusion is supported by mechanistic in vitro evidence. Nonetheless, there is need for further research to fill in our gaps in understanding of the relationship between OCCs and their mixtures and endometriosis, beyond the prototypical TCDD. https://doi.org/10.1289/EHP8421.

Associations between persistent organic pollutants and endometriosis: A multipollutant assessment using machine learning algorithms.

Endometriosis is a gynaecological disease characterised by the presence of endometriotic tissue outside of the uterus impacting a significant fraction of women of childbearing age. Evidence from epidemiological studies suggests a relationship between risk of endometriosis and exposure to some organochlorine persistent organic pollutants (POPs). However, these chemicals are numerous and occur in complex and highly correlated mixtures, and to date, most studies have not accounted for this simultaneous exposure. Linear and logistic regression models are constrained to adjusting for multiple exposures when variables are highly intercorrelated, resulting in unstable coefficients and arbitrary findings. Advanced machine learning models, of emerging use in epidemiology, today appear as a promising option to address these limitations. In this study, different machine learning techniques were compared on a dataset from a case-control study conducted in France to explore associations between mixtures of POPs and deep endometriosis. The battery of models encompassed regularised logistic regression, artificial neural network, support vector machine, adaptive boosting, and partial least-squares discriminant analysis with some additional sparsity constraints. These techniques were applied to identify the biomarkers of internal exposure in adipose tissue most associated with endometriosis and to compare model classification performance. The five tested models revealed a consistent selection of most associated POPs with deep endometriosis, including octachlorodibenzofuran, cis-heptachlor epoxide, polychlorinated biphenyl 77 or trans-nonachlor, among others. The high classification performance of all five models confirmed that machine learning may be a promising complementary approach in modelling highly correlated exposure biomarkers and their associations with health outcomes. Regularised logistic regression provided a good compromise between the interpretability of traditional statistical approaches and the classification capacity of machine learning approaches. Applying a battery of complementary algorithms may be a strategic approach to decipher complex exposome-health associations when the underlying structure is unknown.

Associations between exposure to organochlorine chemicals and endometriosis in experimental studies: A systematic review protocol.

BACKGROUND: Endometriosis is a hormone-dependent gynaecological disease characterised by the presence and growth of endometrial tissues outside of the uterus. There is growing experimental evidence that suggests environmental endocrine disrupting chemicals, specifically organochlorine chemicals (OCCs), may play a role in the pathogenesis of endometriosis, but to date, there are no studies attempting to gather and synthesise the published literature systematically. OBJECTIVES: The main objective of this SR is to evaluate the associations between the exposure to OCCs and endometriosis in experimental models (in vivo and in vitro). METHODS: The SR framework has been developed following the guidelines established in National Toxicology Program/ Office of Health Assessment and Translation (NTP/OHAT) Handbook for Conducting a Literature-Based Health Assessment, which provides a standardised methodology to implement the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to environmental health assessments. The review process will be managed and documented through HAWC, an open-source content management system, to guarantee transparency. ELIGIBILITY CRITERIA: Only experimental studies, in vivo, ex vivo or in vitro, exploring associations between controlled exposures to OCCs and endometriosis and related outcomes will be included. Eligible studies will include peer reviewed articles of any publication date which are sources of primary data. Only studies published in English will be considered. INFORMATION SOURCES: We will apply the search strings to the scientific literature databases NCBI PubMed, Web of Science and SCOPUS. Manual searches will be performed through the list of references of included articles. DATA EXTRACTION AND SYNTHESIS OR RESULTS: Data will be extracted according to a pre-defined set of forms and synthesised in a narrative report. Given sufficient commensurate data, a meta-analysis may also be performed. RISK OF BIAS: A quality assessment will be performed for in vivo and in vitro studies using the NTP/OHAT Risk of Bias Rating Tool for Human and Animal Studies. LEVEL OF EVIDENCE RATING: Following a comprehensive assessment of the quality of evidence for both in vivo and in vitro studies, a confidence rating will be assigned to the body of literature and subsequently translated into a rating on the level of evidence (high, moderate, low, or inadequate) regarding the research question. Systematic review registration: PROSPERO CRD42018102618.

Human epidemiological evidence about the associations between exposure to organochlorine chemicals and endometriosis: Systematic review and meta-analysis.

BACKGROUND: Endometriosis is a gynaecological disease characterized by the presence of ectopic endometrial tissue that affects women during their reproductive years, having a strong impact on their lives, fertility and healthcare costs. The aetiology remains largely unknown, but current evidence suggests that it is multi-causal and oestrogen-dependent. Many epidemiologic studies have explored associations between organochlorine chemicals (OCCs) and endometriosis, but the findings are inconsistent. OBJECTIVES: A systematic review (SR) and meta-analysis were conducted to gather and synthesize all the available evidence from human epidemiological studies about the associations between OCCs and endometriosis. DATA SOURCES: The searches were conducted in PubMed and Web of Science in June 2016 with a final follow-up in August 2018. STUDY ELIGIBILITY CRITERIA: Only human epidemiological studies were considered, independent of participant age, body mass index or life-stage. Studies reporting individual measures of exposure to OCCs were included, considering but not limited to polychlorinated dibenzodioxins and dibenzofurans (PCDD/Fs), polychlorinated biphenyls (PCBs), or organochlorine pesticides (OCPs). The primary health outcome was presence of endometriosis, including all sub-types. Eligibility criteria excluded articles not written in English, conference papers, reviews and studies with overlapping information. STUDY APPRAISAL AND SYNTHESIS METHODS: A SR protocol pre-registered at PROSPERO was applied in duplicate to gather and extract all eligible original papers from PUBMED and Web of Science databases. Odds ratios were pooled using the inverse variance method for random effects meta-analysis for each group of OCCs. Risk of bias was assessed using the National Toxicology Program/Office of Health Assessment and Translation (NTP/OHAT) Risk of Bias Rating Tool for Human and Animal Studies adapted to the review question. The confidence in the body of evidence and related level of evidence was measured by using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) based NTP/OHAT framework. The results were structured and presented in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. RESULTS: Of the 51 studies retained for the full-text screening, 17 provided effect sizes and metrics sufficient for pooling estimates through meta-analysis. The overall odds ratios and 95% confidence intervals were 1.65 (1.14; 2.39) for dioxins (n = 10), 1.70 (1.20; 2.39) for PCBs (n = 9), and 1.23 (1.13; 1.36) for OCPs (n = 5). Despite being statistically significant, these estimates should be considered with caution given the notable heterogeneity and small estimated effect size. Misclassification of exposure, due to varying laboratory detection rate capabilities, and disease status, due to varying definitions of endometriosis, were identified as major sources of uncertainty. LIMITATIONS, CONCLUSIONS, AND IMPLICATIONS OF KEY FINDINGS: The level of evidence was considered to be "moderate" with "serious" risk of bias according the NTP/OHAT criteria, supporting the need for further well-designed epidemiological research to fill lingering data gaps. Given the complexity of endometriosis and lack of known biomarkers suitable for population-based research, carefully designed observational studies play an important role in better understanding the aetiology of endometriosis, as will evolving mixture modeling approaches capable of handling various environmental chemical exposures. Attention to critical windows of exposure will shed further light on the possible developmental origin of endometriosis. Considering the high economic and societal cost associated with endometriosis, further research on this field is urged. SYSTEMATIC REVIEW REGISTRATION NUMBER: CRD42018080956.