Éditeur(s) : HAL CCSD Taylor & Francis
Résumé : International audience
Humans may be exposed via their environment to multiple chemicals as a consequence of human activities and use of synthetic products. Little knowledge is routinely generated on the hazards of these chemical mixtures. The metabolomic approach is widely used to identify metabolic pathways modified by diseases, drugs, or exposures to toxicants. This review, based on the state of the art of the current applications of metabolomics in environmental health, attempts to determine whether metabolomics might constitute an original approach to the study of associations between multiple, low-dose environmental exposures in humans. Studying the biochemical consequences of complex environmental exposures is a challenge demanding the development of careful experimental and epidemiological designs, in order to take into account possible confounders associated with the high level of interindividual variability induced by different lifestyles. The choices of populations studied, sampling and storage procedures, statistical tools used, and system biology need to be considered. Suggestions for improved experimental and epidemiological designs are described. Evidence indicates that metabolomics may be a powerful tool in environmental health in the identification of both complex exposure biomarkers directly in human populations and modified metabolic pathways, in an attempt to improve understanding the underlying environmental causes of diseases. Nevertheless, the validity of biomarkers and relevancy of animal-to-human extrapolation remain key challenges that need to be properly explored.
ISSN: 1093-7404

hal-00976116
https://hal-univ-rennes1.archives-ouvertes.fr/hal-00976116
https://hal-univ-rennes1.archives-ouvertes.fr/hal-00976116/document
https://hal-univ-rennes1.archives-ouvertes.fr/hal-00976116/file/Potential_input_from_metabolomics_accepted.pdf
DOI : 10.1080/10937404.2013.860318

Éditeur(s) : HAL CCSD National Institute of Environmental Health Sciences
Résumé : International audience
BACKGROUND: Women of reproductive age can be exposed to endocrine-disrupting chemicals (EDCs) at work, and exposure to EDCs in pregnancy may affect fetal growth. OBJECTIVES: We assessed whether maternal occupational exposure to EDCs during pregnancy as classified by application of a job exposure matrix was associated with birth weight, term low birth weight (LBW), length of gestation, and preterm delivery. METHODS: Using individual participant data from 133,957 mother-child pairs in 13 European cohorts spanning births from 1994 through 2011, we linked maternal job titles with exposure to 10 EDC groups as assessed through a job exposure matrix. For each group, we combined the two levels of exposure categories (possible and probable) and compared birth outcomes with the unexposed group (exposure unlikely). We performed meta-analyses of cohort-specific estimates. RESULTS: Eleven percent of pregnant women were classified as exposed to EDCs at work during pregnancy, based on job title. Classification of exposure to one or more EDC group was associated with an increased risk of term LBW [odds ratio (OR) = 1.25; 95% CI: 1.04, 1.49], as were most specific EDC groups; this association was consistent across cohorts. Further, the risk increased with increasing number of EDC groups (OR = 2.11; 95% CI: 1.10, 4.06 for exposure to four or more EDC groups). There were few associations (p < 0.05) with the other outcomes; women holding job titles classified as exposed to bisphenol A or brominated flame retardants were at higher risk for longer length of gestation. CONCLUSION: Results from our large population-based birth cohort design indicate that employment during pregnancy in occupations classified as possibly or probably exposed to EDCs was associated with an increased risk of term LBW.
ISSN: 0091-6765

hal-01405823
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01405823
DOI : 10.1289/EHP208
PUBMED : 27152464

Éditeur(s) : HAL CCSD National Institute of Environmental Health Sciences
Résumé : International audience
Background: Glycol ethers (GE) are widely used organic solvents. Despite the potential neurotoxicity of several families of organic solvents, little is known about the impact of GE on the neurodevelopment of infants and children. Objectives: We investigated the relation between urinary concentrations of GE metabolites in pregnant women and neurocognitive abilities in their 6-year-old children in the PELAGIE mother-child cohort. Methods: Five GE metabolites were measured in first morning void urine samples of 204 French pregnant women in early pregnancy (<19 weeks of gestation). Psychologists assessed the neurocognitive abilities of their 6-year-old children with the Wechsler Intelligence Scale for Children IV (WISC) and the Developmental Neuropsychological Assessment (NEPSY). We analyzed the results with linear (WISC) and Poisson regression models (NEPSY), adjusted for potential confounders, including child's stimulation at home. Results: GE metabolites were detected in 90-100% of maternal urine samples. The WISC Verbal Comprehension score was significantly lower for children with the highest tertile of urinary phenoxyacetic acid (PhAA) [beta (third vs. first tertile)=-6.53; 95% CI: -11.44, -1.62]. Similarly, the NEPSY Design Copying subtest score was lower in those with the highest tertile of urinary ethoxyacetic acid (EAA) [beta (third vs. first tertile)=-0.11; 95% CI: -0.21, 0.00]. The other GE metabolites we studied were not significantly associated with WISC or NEPSY scores. Conclusions: Prenatal urine concentrations of two GE metabolites were associated with lower WISC Verbal Comprehension Index scores and NEPSY Design Copying subscale scores, respectively, at age 6 years. PhAA is the primary metabolite of 2-phenoxyethanol (EGPhE), which is commonly found in cosmetics, and precursors of EAA are frequently used in cleaning agents. Additional research is needed to confirm our findings and further explore potential effects of prenatal GE exposures on neurocognitive performance in children.
ISSN: 0091-6765

hal-01519256
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01519256
DOI : 10.1289/EHP39
PUBMED : 27740510

Éditeur(s) : HAL CCSD American Society of Clinical Oncology
Résumé : International audience
PURPOSE: Determining whether environmental estrogens are associated with the risk of prostate cancer may have important implications for our general understanding of this disease. The estrogenic insecticide chlordecone was used extensively in the French West Indies, contaminating the population for more than 30 years. We analyzed the relationship between exposure to chlordecone and the risk of prostate cancer. PATIENTS AND METHODS: We investigated 623 men with prostate cancer and 671 controls. Exposure was analyzed according to case-control status, using either current plasma concentration or a cumulative exposure index based on years of exposure. We genotyped two single-nucleotide polymorphisms (rs3829125 and rs17134592) in the gene encoding chlordecone reductase. RESULTS: We found a significant increase in the risk of prostate cancer with increasing plasma chlordecone concentration (odds ratio [OR], 1.77; 95% CI, 1.21 to 2.58 for the highest tertile of values above the limit of detection [LD]; P trend = .002) and for cumulative exposure index (OR, 1.73; 95% CI, 1.04 to 2.88 for the highest quartile; P trend = .004). Stronger associations were observed among those with a positive family history of prostate cancer and among those who had lived in a Western country. The rs3829125 and rs17134592 allele variants were in complete linkage disequilibrium and were found at low frequency (0.04). Among subjects with plasma chlordecone concentrations above the LD, carriers of the allele variants had a higher risk of prostate cancer (OR, 5.23; 95% CI, 0.82 to 33.32). CONCLUSION: These findings support the hypothesis that exposure to environmental estrogens increases the risk of prostate cancer.
ISSN: 0732-183X

inserm-00518099
http://www.hal.inserm.fr/inserm-00518099
DOI : 10.1200/JCO.2009.27.2153
PUBMED : 20566993

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
Pyrethroid insecticides are widely used in agriculture and in homes. Despite the neurotoxicity of these insecticides at high doses, few studies have examined whether lower-level exposures could adversely affect children's neurodevelopment. The PELAGIE cohort included 3421 pregnant women from Brittany, France between 2002 and 2006. When their children reached their sixth birthday, 428 mothers from the cohort were randomly selected, successfully contacted and found eligible. A total of 287 (67%) mothers agreed to participate with their children in the neuropsychological follow-up. Two cognitive domains were assessed by the Wechsler Intelligence Scale for Children: verbal comprehension and working memory. Five pyrethroid and two organophosphate insecticide metabolites were measured in maternal and child first-void urine samples collected between 6 and 19 gestational weeks and at 6 years of age, respectively. Linear regression models were used to estimate associations between cognitive scores and urinary pyrethroid metabolite concentrations, adjusting for organophosphate metabolite concentrations and potential confounders. Maternal prenatal pyrethroid metabolite concentrations were not consistently associated with any children's cognitive scores. By contrast, childhood 3-PBA and cis-DBCA concentrations were both negatively associated with verbal comprehension scores (P-trend = 0.04 and P-trend < 0.01, respectively) and with working memory scores (P-trend = 0.05 and P-trend < 0.01, respectively). No associations were observed for the three other childhood pyrethroid metabolite concentrations (4-F-3-PBA, cis-DCCA, and trans-DCCA). Low-level childhood exposures to deltamethrin (as cis-DBCA is its principal and selective metabolite), in particular, and to pyrethroid insecticides, in general (as reflected in levels of the 3-PBA metabolite) may negatively affect neurocognitive development by 6 years of age. Whatever their etiology, these cognitive deficits may be of importance educationally, because cognitive impairments in children interfere with learning and social development. Potential causes that can be prevented are of paramount public health importance
ISSN: 0160-4120

hal-01162374
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01162374
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01162374/document
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01162374/file/Pyrethroid%20insecticide%20exposure.pdf
DOI : 10.1016/j.envint.2015.05.009

Éditeur(s) : HAL CCSD National Institute of Environmental Health Sciences
Résumé : International audience
BACKGROUND: Glycol ethers are present in a wide range of occupational and domestic products. Animal studies have suggested that some of them may affect ovarian function. OBJECTIVE: To study the relation between women's exposure to glycol ethers and time to pregnancy. METHODS: Urine from randomly selected women in the PELAGIE mother-child cohort who had samples collected before 19 weeks of gestation was tested to measure eight glycol ether metabolites by chromatography coupled to mass spectrometry. Time to pregnancy was collected at the beginning of the pregnancy by asking women how many months they took to conceive. Associations between metabolite levels and time to pregnancy were estimated in 519 women with complete data using discrete-time Cox proportional hazards models to adjust for potential confounders. RESULTS: Glycol ether metabolites were detected in 6% (for ethoxyacetic acid) to 93% (for phenoxyacetic and butoxyacetic acids) of urine samples. Phenoxyacetic acid was the only metabolite with a statistically significant association with longer time to pregnancy (fecundability OR 0.82; 95% CI: 0.63, 1.06 for the second and third quartile combined; fecundability OR 0.70; 95% CI: 0.52, 0.95 for a fourth-quartile (≥1.38 mg/L) vs. first-quartile concentration (<0.14 mg/L)). This association remained stable after multiple sensitivity analyses. CONCLUSION: Phenoxyacetic acid, which was present in most of the urine samples tested in our study, was associated with increased time to pregnancy. This metabolite and its main parent compound, 2-phenoxyethanol, are plausible causes of decreased fecundability, but may also be surrogates for potential co-exposures frequently present in cosmetics.
ISSN: 0091-6765

hal-00866023
https://hal-univ-rennes1.archives-ouvertes.fr/hal-00866023
https://hal-univ-rennes1.archives-ouvertes.fr/hal-00866023/document
https://hal-univ-rennes1.archives-ouvertes.fr/hal-00866023/file/Urinary_Glycol_Ether-accepted.pdf
DOI : 10.1289/ehp.1206103

Éditeur(s) : HAL CCSD Springer Verlag
Résumé : International audience
: Human exposure to xenobiotics is usually estimated by indirect methods. Biological monitoring has emerged during the last decade to improve assessment of exposure. However, biomonitoring is still an analytical challenge, because the amounts of sample available are often very small yet analysis must be as thorough and sensitive as possible. The purpose of this work was to develop an untargeted "exposomics" approach by using ultra-high-performance liquid chromatography coupled to high-resolution mass spectrometry (UHPLC-HRMS), which was applied to the characterization of pesticide metabolites in urine from pregnant women from a French epidemiological cohort. An upgradable list of pesticides commonly used on different crops, with their metabolites (more than 400 substances) was produced. Raw MS data were then processed to extract signals from these substances. Metabolites were identified by tandem mass spectrometry; putative identifications were validated by comparison with standards and metabolites generated by experiments on animals. Finally, signals of identified compounds were statistically analyzed by use of multivariate methods. This enabled discrimination of exposure groups, defined by indirect methods, on the basis of four metabolites from two fungicides (azoxystrobin, fenpropimorph) used in cereal production. This original approach applied to pesticide exposure can be extended to a variety of contaminant families for upstream evaluation of exposure from food and the environment.
ISSN: 1618-2642

hal-00875889
https://hal.archives-ouvertes.fr/hal-00875889
DOI : 10.1007/s00216-013-7136-2
PUBMED : 23892877

Éditeur(s) : HAL CCSD Oxford University Press (OUP)
Résumé : International audience
Adverse pregnancy outcomes entail a large health burden for the mother and offspring; a part of it might be avoided by better understanding the role of environmental factors in their etiology. Our aims were to review the assessment tools to characterize fecundity troubles and pregnancy-related outcomes in human populations and their sensitivity to environmental factors. For each outcome, we reviewed the possible study designs, main sources of bias, and their suggested cures. In terms of study design, for most pregnancy outcomes, cohorts with recruitment early during or even before pregnancy allow efficient characterization of pregnancy-related events, time-varying confounders, and in utero exposures that may impact birth outcomes and child health. Studies on congenital anomalies require specific designs, assessment of anomalies in medical pregnancy terminations, and, for congenital anomalies diagnosed postnatally, follow-up during several months after birth. Statistical analyses should take into account environmental exposures during the relevant time windows; survival models are an appropriate approach for fecundity, fetal loss, and gestational duration/preterm delivery. Analysis of gestational duration could distinguish pregnancies according to delivery induction (and possibly pregnancy-related conditions). In conclusion, careful design and analysis are required to better characterize environmental effects on human reproduction.
ISSN: 0193-936X

hal-01002724
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01002724
DOI : 10.1093/epirev/mxt011
PUBMED : 24363355

Éditeur(s) : HAL CCSD
Résumé : National audience
Epidemiological researches in the field of DOHaD are in favor of a role of early environment, including chemical (pesticides), physical (air pollution), nutritional or psychosocial environment, on child and adult health. Disentangling the different factors of environment that may affect health, especially over time, and identifying critical periods of exposure remains a major challenge. The biological mechanisms involved remain elusive in human beings. Nevertheless, it seems that whatever the nature of the exposure, epigenetic mechanisms are currently discussed to explain how the environment may alter biological systems over time.
Les résultats épidémiologiques dans le domaine de la DOHaD (developmental origins of health and disease) sont en faveur d’un rôle de l’environnement précoce sur la santé immédiate mais aussi future, qu’il s’agisse de l’environnement physique, chimique, nutritionnel ou encore psychosocial. Faire la part des différents facteurs de l’environnement susceptibles de modifier la santé, notamment sur le long terme, et des périodes critiques d’exposition reste un enjeu majeur. De même, les multiples mécanismes biologiques impliqués restent encore, pour une grande part, à identifier chez l’homme. Il semble néanmoins que, quelle que soit la nature de l’exposition considérée, des mécanismes épigénétiques sont actuellement évoqués pour expliquer comment l’environnement est susceptible de modifier des systèmes biologiques sur le long terme.
Médecine Sciences: M/S

hal-01274219
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01274219
DOI : 10.1051/medsci/20163201005
PUBMED : 26850603

Éditeur(s) : HAL CCSD John Libbey Eurotext
ISSN: 1635-0421

hal-00688468
https://hal.archives-ouvertes.fr/hal-00688468
DOI : 10.1684/ers.2007.0121

Éditeur(s) : HAL CCSD
Résumé : International audience
BACKGROUND: Worrying trends regarding human reproductive endpoints (e.g. semen quality, reproductive cancers) have been reported and there is growing circumstantial evidence for a possible causal link between these trends and exposure to endocrine disrupting chemicals (EDCs). However, there is a striking lack of human data to fill the current knowledge gaps. To answer the crucial questions raised on human reproductive health, there is an urgent need for a reproductive surveillance system to be shared across countries. METHODS: A multidisciplinary network named HUman Reproductive health and Global ENvironment Network (HURGENT) was created aiming at designing a European monitoring system for reproductive health indicators. Collaborative work allowed setting up the available knowledge to design such a system. Furthermore we conducted an overview of 23 potential indicators, based upon a weight of evidence (WoE) approach according to their potential relation with EDC exposure. RESULTS: The framework and purposes of the surveillance system are settled as well as the approach to select suitable reproductive indicators. The indicators found with the highest scores according to the WoE approach are prostate and breast cancer incidence, sex ratio, endometriosis and uterine fibroid incidence, indicators related to the testicular dysgenesis syndrome, precocious puberty incidence and reproductive hormone levels. CONCLUSION: Not only sentinel health endpoints, but also diseases with high burdens in public health are highlighted as prior indicators in the context of EDC exposure. Our work can serve as a basis to construct, as soon as possible, the first multi-country reproductive monitoring system
European Journal of Public Health

hal-01197348
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01197348
DOI : 10.1093/eurpub/ckv153
PUBMED : 26330492

Éditeur(s) : HAL CCSD
Résumé : International audience
Obesity is currently an increasing public health problem. The intra-uterine environment plays a critical role in foetal development. The objective of this study is to investigate the association of obesity with modifications in the metabolic profiles of pregnant women, and their new-borns. Based on the PELAGIE cohort (Brittany, France), a sample of 321 pregnant women was divided into three groups according to their body mass index (BMI) (normal, over-weight and obese). Nuclear magnetic resonance-based metabolomics analyses were performed on maternal urine and cord-blood samples. Partial least squares regression-discriminant analysis (PLS-DA), polytomous and logistic regressions were used to differentiate the metabolic profiles of the three BMI groups after adjusting for potential confounders. Specific profiles were observed for the overweight and obese women (BMI > 25) compared to the normal-weight women: they had a decrease in urinary hippurate excretion associated with a decrease in phenylalanine and an increase in creatinine. We also showed an increase in the urinary excretion of lactate, citrate, acetate, creatine, and lysine only in obese women (BMI > 30) compared to the normal-weight women. The PLS-DA modelling did not reveal any significant difference between the cord-blood metabolic profiles of newborns according to maternal BMI—although infants born of obese women had a higher birth weight and a lower Apgar score. Our results confirmed the potential link between obesity and gut microbiota disruption (changes in urinary acids), as well as energy and amino-acid metabolism but did not reveal any disruption among newborns.
Metabolomics

Droits : info:eu-repo/semantics/OpenAccess
hal-01195742
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01195742
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01195742/document
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01195742/file/Impact%20of%20maternal%20obesity_accepted.pdf
DOI : 10.1007/s11306-015-0836-1

Éditeur(s) : HAL CCSD Oxford University Press (OUP)
Résumé : International audience
Although prenatal exposure to water disinfection by-products does not appear to affect the duration of gestation, its impact on fetal growth remains an open question. The authors studied the associations between prenatal exposure to disinfection by-products and fetal growth restriction (FGR) and preterm birth in the PELAGIE cohort, a French birth cohort comprising 3,421 pregnant women recruited between 2002 and 2006. Exposure was assessed by estimating levels of trihalomethanes (THMs) in tap water during pregnancy and maternal water use and by measuring maternal urinary levels of trichloroacetic acid (TCAA) during early pregnancy in a nested case-control design that compared 174 FGR cases, 114 preterm births, and 399 controls. Higher uptake of THMs (especially brominated THMs) was associated with a higher risk of FGR. Women with TCAA detected in their urine (>0.01 mg/L) had a higher risk of FGR than those with TCAA levels below the detection limit (adjusted odds ratio = 1.8, 95% confidence interval: 0.9, 3.7) and had an odds ratio for preterm birth below 1 (adjusted odds ratio = 0.8, 95% confidence interval: 0.3, 2.6). Results from this prospective study, the first to use a biomarker of disinfection by-product exposure, suggest that prenatal exposure affects fetal growth, but the causal agent or agents remain to be identified.
ISSN: 0002-9262

hal-00682627
https://hal.archives-ouvertes.fr/hal-00682627
DOI : 10.1093/aje/kwr419
PUBMED : 22156019