Serum persistent organic pollutants and diminished ovarian reserve: a single-exposure and mixture exposure approach from a French case-control study.

STUDY QUESTION: Are persistent organic pollutants (POPs) associated with a diminished ovarian reserve (DOR) in women of reproductive age? SUMMARY ANSWER: Amongst 17 POPs detected in over 20% of serum samples, only p,p'-DDE was significantly associated with an increased risk of DOR, and ß-hexachlorocyclohexane (ß-HCH) was significantly associated with a decreased risk of DOR whilst mixture analyses yielded non-significant associations and did not detect any interactions between POPs. WHAT IS KNOWN ALREADY: Animal studies have shown that several POPs can alter folliculogenesis and increase follicle depletion. However, only a few studies have been conducted in humans, with small sample sizes and inconsistent results. STUDY DESIGN, SIZE, DURATION: Our study included 138 cases and 151 controls from the AROPE case-control study. Study participants were women between 18 and 40 years of age recruited amongst couples consulting for infertility in four fertility centres in western France between 2016 and 2020. PARTICIPANTS/MATERIALS, SETTING, METHODS: Cases of DOR were defined as women with anti-Müllerian hormone (AMH) levels ≤1.1 ng/ml and/or antral follicle count (AFC) <7, and controls were women with AMH levels between 1.1 and 5 ng/ml and AFC ≥ 7, without genital malformations and with a menstrual cycle length between 26 and 35 days. A total of 43 POPs (including 15 organochlorine pesticides, 17 polychlorinated biphenyls, and 9 polybromodiphenylethers) were measured in the serum at inclusion into the study. We conducted logistic regression adjusted for potential confounders using a directed acyclic graph to study the effect of each POP on DOR as single exposures, and used Bayesian kernel machine regression (BKMR) to measure the mixture effect of POPs on DOR. MAIN RESULTS AND THE ROLE OF CHANCE: Of the 43 POPs, 17 were detected in over 20% of the serum samples. In the single-exposure multivariate logistic regressions, p,p'-DDE (median 165.0 IQR 161.0 ng/l in controls) as a continuous exposure was significantly associated with an increased risk of DOR (odds ratio (OR) 1.39, 95% CI 1.10-1.77) and non-significantly associated with an increased risk of DOR for the second and third terciles (OR 1.46, 95% CI 0.74-2.87, and OR 1.72, 95% CI 0.88-3.37, respectively). ß-HCH (median 24.2 IQR 21.5 ng/l in controls) was significantly associated with a decreased risk of DOR when ß-HCH was treated as a continuous exposure (OR 0.63, 95% CI 0.44-0.89) and for the third tercile of exposure (OR 0.43, 95% CI 0.21-0.84) and non-significantly associated with a decreased risk of DOR for the second tercile (OR 0.77, 95% CI 0.42-1.42). All sensitivity analyses confirmed our results. BKMR showed similar associations for single exposures but found no significant associations for the total mixture effect. In addition, the BKMR results did not suggest any interactions between POPs. LIMITATIONS, REASONS FOR CAUTION: Controls were recruited amongst infertile couples and thus may not be representative of all women of reproductive age. However, their POP concentrations were in the same range as in the general French population. WIDER IMPLICATIONS OF THE FINDINGS: This study is the first to examine the associations between serum POPs and DOR. The well-recognized anti-androgenic properties of p,p'-DDE and estrogenic properties of ß-HCH could explain these associations of opposite direction. If these results are replicated elsewhere, this could have an impact on fertility prevention messages and help in understanding the impact of POPs on the female reproductive system. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by the Fondation de France (grant numbers 2014-50537 and 00110196) and the French Biomedicine Agency (2016). None of the authors have any conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A.

The sensitization pattern differs according to rhinitis and asthma multimorbidity in adults: the EGEA study.

BACKGROUND: Mono- and polysensitization are different IgE-mediated allergic phenotypes in children. Allergic sensitization is associated with both allergic asthma and allergic rhinitis, however, associations between the sensitization pattern and particularly polysensitization with asthma and rhinitis remains poorly studied in adults. AIM: The aim of this study was to assess how the allergic sensitization pattern associates with asthma, rhinitis and their multimorbidity. METHODS: 1199 adults from the EGEA study, with extensive phenotypic characterization and all data available on skin prick tests to 10 allergens, total IgE and blood eosinophils were included. Using questionnaires only, participants were classified into 6 groups: asymptomatic (no asthma, no rhinitis), non-allergic rhinitis alone, allergic rhinitis alone, asthma alone, asthma+non-allergic rhinitis and asthma+allergic rhinitis. Mono- and polysensitization were defined by a positive skin prick test to one or more than one allergen respectively. RESULTS: Asymptomatic participants and those with non-allergic rhinitis alone were mostly non-sensitized (around 72%) while around 12% were polysensitized. Between 32% and 43% of participants with allergic rhinitis alone, asthma alone and asthma+non-allergic rhinitis were non-sensitized and between 37% and 46% of them were polysensitized. 65% of the participants with asthma+allergic rhinitis were polysensitized. The level of total IgE followed a similar trend to that of allergic sensitization. Eosinophils were increased in asthma, especially when associated with rhinitis. Nasal symptoms were more severe and eczema more common in participants with both asthma and allergic rhinitis than in the other groups. CONCLUSIONS: Allergic sensitization and particularly polysensitization rates widely differ according to asthma and rhinitis status. This study emphasized the importance of taking into account multimorbidity between asthma and rhinitis and showed that allergic sensitization is not a dichotomic variable.

MeDALL (Mechanisms of the Development of ALLergy): an integrated approach from phenotypes to systems medicine.

The origin of the epidemic of IgE-associated (allergic) diseases is unclear. MeDALL (Mechanisms of the Development of ALLergy), an FP7 European Union project (No. 264357), aims to generate novel knowledge on the mechanisms of initiation of allergy and to propose early diagnosis, prevention, and targets for therapy. A novel phenotype definition and an integrative translational approach are needed to understand how a network of molecular and environmental factors can lead to complex allergic diseases. A novel, stepwise, large-scale, and integrative approach will be led by a network of complementary experts in allergy, epidemiology, allergen biochemistry, immunology, molecular biology, epigenetics, functional genomics, bioinformatics, computational and systems biology. The following steps are proposed: (i) Identification of 'classical' and 'novel' phenotypes in existing birth cohorts; (ii) Building discovery of the relevant mechanisms in IgE-associated allergic diseases in existing longitudinal birth cohorts and Karelian children; (iii) Validation and redefinition of classical and novel phenotypes of IgE-associated allergic diseases; and (iv) Translational integration of systems biology outcomes into health care, including societal aspects. MeDALL will lead to: (i) A better understanding of allergic phenotypes, thus expanding current knowledge of the genomic and environmental determinants of allergic diseases in an integrative way; (ii) Novel diagnostic tools for the early diagnosis of allergy, targets for the development of novel treatment modalities, and prevention of allergic diseases; (iii) Improving the health of European citizens as well as increasing the competitiveness and boosting the innovative capacity of Europe, while addressing global health issues and ethical issues.

Association between modelled traffic-related air pollution and asthma score in the ECRHS.

The aim of our analysis was to study the association between air pollution and asthma among adults. For this goal, a previously developed "asthma score" was used. Persons aged 25-44 yrs were randomly selected (1991-1993) and followed up (2000-2002) within the European Community Respiratory Health Survey (ECRHS I and II, respectively). The asthma score was defined from 0 to 5, based on the positive answers to the following symptoms reported for the last 12 months: wheeze/breathlessness, chest tightness, dyspnoea at rest, dyspnoea after exercise and woken by dyspnoea. Participants' home addresses were linked to outdoor modelled NO2 estimates for 2001. Negative binomial regression was used to model the asthma score. The score from ECRHS II was positively associated with NO2 (ratio of the mean asthma score (RMS) 1.23, 95% CI 1.09-1.38, for an increase of 10 microg x m(-3)). After excluding participants with asthma and symptoms at baseline, the association remained (RMS 1.25, 95% CI 1.05-1.51), and was particularly high among those reporting a high score in ECRHS II. The latter probably reflects incident cases of asthma. Our results suggest that traffic-related pollution causes asthma symptoms and possibly asthma incidence in adults. The asthma score offers an alternative with which to investigate the course and aetiology of asthma in adults.

Total serum IgE levels are associated with ambient ozone concentration in asthmatic adults.

BACKGROUND: Effects of air pollution exposure on IgE-mediated response in asthmatics are poorly investigated. The aim was to examine the relationship between air pollution concentrations and total IgE levels in adult asthmatics. METHODS: The present study relates to the 369 asthmatic adults from the French Epidemiological study on Genetics and Environment of Asthma (EGEA), with availability of data on both total serum IgE measurements and air pollution concentrations. Geo-statistical models were performed on 4 x 4 km grids to assess individual outdoor air pollution exposure. Annual outdoor concentrations of ozone (O(3)), nitrogen dioxide (NO(2)), sulphur dioxide (SO(2)), and particulate matter smaller than 10 microm size (PM(10)), and concentrations of summer ozone were assigned to subject's home address. RESULTS: The geometric mean of total IgE was 161 IU/ml and the average of O(3) exposure was 44.9 +/- 9.5 microg/m(3). Ozone concentrations were positively related to total IgE levels and an increase of 10 microg/m(3) of O(3) resulted in an increase of 20.4% (95% CI = 3.0-40.7) in total IgE levels. Adjustment for age, gender, smoking habits and previous life in the countryside did not change the results, and an increase of 19.1% (2.4-38.6) in total IgE was observed with O(3). Negative associations observed between NO(2) and total IgE levels disappeared after including O(3) in the models. Neither SO(2) nor PM(10) were correlated with total IgE levels. CONCLUSIONS: Results suggest that O(3) or related ambient pollutants may up-regulate total IgE levels among asthmatic adults.

Interaction between smoking and the interleukin-6 gene affects systemic levels of inflammatory biomarkers.

BACKGROUND: Smoking is associated with a systemic inflammatory response. However, the role of genetic predisposition is not well known. We assessed whether circulatory acute phase reactants were associated with smoking and whether or not the association was modified by the major cytokine gene of the acute phase reaction, interleukin-6 (IL-6). METHODS: In total, 1,003 postmyocardial infarction patients were recruited in six European cities and six repeated clinical examinations performed. C-reactive protein (CRP), interleukin 6 (IL-6), and fibrinogen levels were assayed at 5,659 subject visits. Genotyping of single nucleotide polymorphisms was performed in the IL-6 gene. RESULTS: Cumulative smoking (pack-years) and time since smoking cessation were strongly associated with blood levels of all three inflammatory markers. Among subjects without any respiratory disorder, these associations remained statistically significant for CRP and IL-6. A polymorphism in the IL-6 gene (rs2069840) showed an interaction with smoking on CRP (p < .001) and IL-6 (p = .049) peripheral levels. CONCLUSIONS: These results indicate a potential role of the IL-6 gene in the inflammatory response associated with smoking and suggest rs2069840 polymorphism deserves attention.

Chronic bronchitis and urban air pollution in an international study.

OBJECTIVES: The chronic effects of urban air pollution are not well known. The authors' aim was to investigate the association between the prevalence and new onset of chronic bronchitis and urban air pollution. METHODS: Subjects from the general population randomly selected for the European Community Respiratory Health Survey (ECRHS I) during 1991-93 in 21 centres in 10 countries were followed up from the years 2000 to 2002 (n = 3232 males and 3592 females; average response rate = 65.3%). PM2.5 and elements, with the same equipment at centre level, and home outdoor NO2 in 1634 individuals were measured. Hierarchical models were used. RESULTS: The prevalence and new onset of chronic phlegm during follow up were 6.9% and 4.5%, respectively, 5.3% in males and 3.5% in females. Smoking, rhinitis, poor education, and low social class were associated with (prevalence and new onset of) chronic phlegm in both genders, and occupational exposures in males and traffic intensity (adjusted odds ratio for constant traffic, OR = 1.86; 95% CI 1.24 to 2.77) as well as home outdoor NO2 (OR > 50 microg/m3v < 20 microg3 = 2.71; 95% CI 1.03 to 7.16) among females. PM2.5 and S content at centre level did not show any association with prevalence or new onset of chronic phlegm. Similar results were obtained with chronic productive cough. CONCLUSION: Individual markers of traffic at household level such as reported intensity and outdoor NO2 were risk factors for chronic bronchitis among females.

[Genetic and environmental factors of asthma and allergy: Results of the EGEA study]. / Facteurs génétiques et environnementaux de l'asthme et de l'allergie: synthèse des résultats de l'étude EGEA.

INTRODUCTION AND METHODS: The EGEA study (epidemiological study on the genetics and environment of asthma, bronchial hyperresponsiveness and atopy), which combines a case-control and a family-based study of asthma case (n=2120 subjects) with three surveys over 20 years, aims to identify environmental and genetic factors associated with asthma and asthma-related phenotypes. We summarize the results of the phenotypic characterization and the investigation of environmental and genetic factors of asthma and asthma-related phenotypes obtained since 2007 in the EGEA study (42 articles). RESULTS: Both epidemiological and genetic results confirm the heterogeneity of asthma. These results strengthen the role of the age of disease onset, the allergic status and the level of disease activity in the identification of the different phenotypes of asthma. The deleterious role of active smoking, exposure to air pollution, occupational asthmogenic agents and cleaning products on the prevalence and/or activity of asthma has been confirmed. Accounting for gene-environment interactions allowed the identification of new genetic factors underlying asthma and asthma-related traits and better understanding of their mode of action. CONCLUSION: The EGEA study is contributing to the advances in respiratory research at the international level. The new phenotypic, environmental and biological data available in EGEA study will help characterizing the long-term evolution of asthma and the factors associated to this evolution.

Association between annoyance and individuals' values of nitrogen dioxide in a European setting.

INTRODUCTION: Annoyance caused by air pollution has been proposed as an indicator of exposure to air pollution. The aim of this study was to assess the geographical homogeneity of the relationship between annoyance and modelled home-based nitrogen dioxide (NO2) measurements. METHODS: The European Community Respiratory Health Survey II was conducted in 2000-1, in 25 European centres in 12 countries. This analysis included 4753 subjects (from 37 in Tartu, Estonia, to 532 in Antwerp, Belgium) who answered the annoyance question and with available outdoor residential NO2 (4399 modelled and 354 measured) including 20 cities from 10 countries. Annoyance as a result of air pollution was self-reported on an 11-point scale (0, no disturbance at all; 10, intolerable disturbance). Demographic and socioeconomic factors, smoking status and the presence of respiratory symptoms or disease were measured through a standard questionnaire. Negative binomial regression was used. RESULTS: The median NO2 concentration was 27 microg.m(-3) (from 10 in Umeå, Sweden, to 57 in Barcelona, Spain). The mean of annoyance was 2.5 (from 0.7 in Reykjavik, Iceland, to 4.4 in Huelva, Spain). NO2 was associated with annoyance (ratio of the mean score 1.26 per 10 microg.m(-3), 95% CI 1.19 to 1.34). The association between NO2 and annoyance was heterogeneous among cities (p for heterogeneity <0.001). CONCLUSIONS: Annoyance is associated with home outdoor air pollution but with a different strength by city. This indicates that annoyance is not a valid surrogate for air pollution exposure. Nevertheless, it may be a useful measure of perceived ambient air quality and could be considered a complementary tool for health surveillance.