Éditeur(s) : HAL CCSD American Society for Biochemistry and Molecular Biology
Résumé : International audience
2-Amino-9H-pyrido[2,3-b]indole (AαC) is a carcinogenic heterocyclic aromatic amine (HAA) that arises in tobacco smoke. UDP-glucuronosyltransferases (UGTs) are important enzymes that detoxicate many procarcinogens, including HAAs. UGTs compete with P450 enzymes, which bioactivate HAAs by N-hydroxylation of the exocyclic amine group; the resultant N-hydroxy-HAA metabolites form covalent adducts with DNA. We have characterized the UGT-catalyzed metabolic products of AαC and the genotoxic metabolite 2-hydroxyamino-9H-pyrido[2,3- b]indole (HONH-AαC) formed with human liver microsomes, recombinant human UGT isoforms, and human hepatocytes. The structures of the metabolites were elucidated by 1H NMR and mass spectrometry. AαC and HONH-AαC underwent glucuronidation by UGTs to form, respectively, N 2-(β- D-glucosidurony1)-2-amino-9H-pyrido[2,3-b]indole (AαC-N 2-Gl) and N 2-(β-D-glucosidurony1)-2-hydroxyamino-9H-pyrido[2,3-b] indole (AαC-HON 2-Gl). HONH-AαC also underwent glucuronidation to form a novel O-linked glucuronide conjugate, O-(β-D-glucosidurony1)-2-hydroxyamino-9H-pyrido[2,3-b]indole (AαC-HN 2-O-Gl). AαC-HN 2-O-Gl is a biologically reactive metabolite and binds to calf thymus DNA (pH 5.0 or 7.0) to form the N-(deoxyguanosin-8-yl)-AαC adduct at 20-50-fold higher levels than the adduct levels formed with HONH-AαC. Major UGT isoforms were examined for their capacity to metabolize AαC and HONH-AαC. UGT1A4 was the most catalytically efficient enzyme (V max/K m) at forming AαC-N 2-Gl (0.67 μl*min -1*mg of protein -1), and UGT1A9 was most catalytically efficient at forming AαC-HN-O-Gl (77.1 μl*min -1*mg of protein -1), whereas UGT1A1 was most efficient at forming AαC-HON 2-Gl (5.0 μl*min -1*mg of protein -1). Human hepatocytes produced AαC-N 2-Gl and AαC-HN 2-O-Gl in abundant quantities, but AαC-HON 2-Gl was a minor product. Thus, UGTs, usually important enzymes in the detoxication of many procarcinogens, serve as a mechanism of bioactivation of HONH-AαC. © 2012 by The American Society for Biochemistry and Molecular Biology, Inc.
ISSN: 0021-9258

hal-00696860
https://hal-anses.archives-ouvertes.fr/hal-00696860
DOI : 10.1074/jbc.M111.320093
PUBMED : 22393056

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 BioMed Central
Résumé : International audience
Background: Overweight in Guadeloupe is a public health matter affecting children and adults. In the present study we evaluated the metabolic profile, including serum ghrelin, leptin and adiponectin levels, in normal weight, overweight and obese school children and we analyzed the potential changes in anthropometric and metabolic risk factors after a 1-year lifestyle intervention program. Methods: Parameters were assessed at baseline and at 1 year. Three groups (G) were defined according the International Obesity Task Force reference values, G1: normal weight / G2: overweight / G3: obese. The lifestyle intervention included dietary counseling, regular physical activity and family support. Results: A total of 120 children (G1: n = 44, G2: n = 39, G3: n = 37), aged 11– 15 years and 59 % girls were enrolled. Obese children showed significant lower HDL-C, adiponectin and ghrelin concentrations, higher triglycerides, fasting blood glucose, insulin and leptin levels and also higher frequencies of abdominal obesity (G1: 2.3 %, G2: 28.2 %, G3: 73 %) and insulin resistance (GI: 39 %, G2: 72 %, G3: 89 %) than the other groups. In the overall sample, the linear regressions exploring the associations of ghrelin, adiponectin and leptin with age, gender, BMI z-score, HOMA-IR and tanner stage as independent variables showed strong associations of leptin levels with weight status and insulin resistance at baseline. The models accounted for 58 % of variability in leptin levels compared with 26 and 15 % for adiponectin and ghrelin levels respectively. In 83 children who completed the program, significant decreases in BMI z-score in overweight and obese children were noted. Leptin levels decreased significantly only in the obese group whereas adiponectin concentrations increased significantly in the three groups, In obese children, a significant correlation was found between changes in BMI Z-score, and changes in leptin levels (r = 0.39; P = 0.049) but not with changes in adiponectin levels. Conclusions: Abdominal obesity and insulin resistance were highly prevalent in obese children highlighting their risk of metabolic complications in adulthood. A 1-year long lifestyle intervention was associated with improvement in BMI z-score and metabolic parameters.
ISSN: 1743-7075

Droits : http://creativecommons.org/licenses/by/
hal-01231394
http://hal.upmc.fr/hal-01231394
http://hal.upmc.fr/hal-01231394/document
http://hal.upmc.fr/hal-01231394/file/art_10.1186_s12986-015-0039-9.pdf
DOI : 10.1186/s12986-015-0039-9

Éditeur(s) : HAL CCSD ACSM
Résumé : International audience
The aim of this study was to examine the effects of the cycle-run and run-cycle successions of the triathlon and duathlon, respectively, on respiratory muscle strength and endurance. Methods: Respiratory muscle strength was assessed by measuring maximal inspiratory (P1max) and expiratory {PEmax) pressures. Respiratory muscle endurance was assessed by measuring the time limit (Tlim). Twelve triathleles participated in a three-trial protocol. The first trial consisted of an incremental cycle test to assess the maximal oxygen uptake (VO2max) of triathletes. Trial 2 consisted of 20 min of cycling followed by 20 min of running (C-R), and trial 3 consisted of 20 min of running followed by 20 min of cycling (R-C). Trials 2 and 3 were performed at the same metabolic intensity (% VO2max). P1max and P1max were measured before and 10 min after C-R and R-C, and I min after the post-C-R and post-R-C Tlim measurements (P1max l'). Tlim was measured I d before and 30 min after C-R and R-C. Results: The results showed a significant decrease in P1max after C-R (126.7 ± 4.3 cmH2O, P < 0.05) and R-C (123.7 ± 4.9 cmH2O, P < 0.05) compared with the baseline values (130 ± 3.8 and 129.6 ± 4.3 cmH2O, respectively). P1max 1' showed a significantly greater decrease after R-C versus C-R(111.2 ± 5.5 cmH2O vs 121.2 ± 3.9 cmH2O,respectively, P < 0.001). Tlim after C-R (3.3 ± 0.3 min) decreased significantly compared with baseline values (4.19 ± 0.3min and 4.02 ± 0.3 min, respectively). However, the Tlim decrease after R-C was significantly greater than after C-R (P < 0.001). Conclusion: We concluded that respiratory muscle strength and endurance were less decreased after the cycle-run succession and that cycling induced a greater decrease in respiratory muscle endurance than running.
Medicine & Science in Sports & exercise

hal-00720796
https://hal.univ-antilles.fr/hal-00720796

Éditeur(s) : Actes de colloques. Ifremer Brest [ACTES COLLOQ. IFREMER.]. 1986
Résumé : Bacterial density of the coelenteric fluid (CF) of some anthozoan species was determined in situ and under laboratory conditions. In all species examined bacterial density of the CF was higher in the gastral cavity than in ambient ranging from 10 super(5) up to 5 x 10 super(6) cells. ml super(-1). Incubation experiments with the CF indicate that a bacterial population within the coelenteron is efficiently controlled by the CF, favoring bacterial growth if bacterial densities are low in the CF and showing clearance activity at high bacterial densities. Feeding of pre-starved anthozoans caused a rapid response of coelenteric rod-shaped bacteria. Evidence is presented that coelenteric bacteria are digested periodically although they contribute 1% to the respiratory carbon losses of the antozoans tested. Therefore, it is more likely that the coelenteric bacterial population provide other substances which cannot be synthesized by the host.
La densité des bactéries du fluide gastrique de différents anthozoaires a été déterminée in situ et au laboratoire. Pour toutes les espèces étudiées, la densité des bactéries dans le fluide gastrique était plus élevée que dans l'eau ambiante et comprise entre 105et 106 cellules m"1. Des expériences d'incubation du fluide gastrique montrent que la population bactérienne est contrôlée efficacement par ce fluide gastrique, favorisant la croissance de bactéries lorsque la densité est faible mais révélant des activités de digestion lorsque la densité est élevée. En nourrissant des anthozoaires mis àjeun plusieurs jours, on provoque une réaction rapide des bactéries déforme bacillaire. Certaines observations montrent que les bactéries gastriques se développent et sont digérées par cycle dans le coelenteron. Néanmoins, la contribution en carbone de ces dernières, comparée aux pertes d'énergie par Sa respiration, représenterait moins de i ','-£. li est probable que cette population bactérienne fournisse des substances qui ne peuvent être synthétisées par i'hôte.

Droits : info:eu-repo/semantics/openAccess
http://archimer.ifremer.fr/doc/1984/acte-989.pdf
http://archimer.ifremer.fr/doc/00000/989/

Éditeur(s) : Actes de colloques Ifremer, Tahiti, French Polynesia, 20 Feb - 4 Mar 1989, n°9, chap. 68, pp.751-755
Résumé : If warmwater finfish protein requirements as level in diet is low, absolute intake per day is similar to those of coldwater species. But relation of this requirement with specific growth rate differs for strictly warmwater fishes as Tilapias. Analysis of partition between protein and non-protein energy retention shows that these species with Clarias make a better use of non-protein energy provided and consequently improve their protein retention. Better carbohydrate digestibility and metabolism are propounded as part of the explanation.

Droits : info:eu-repo/semantics/openAccess
http://archimer.ifremer.fr/doc/1989/acte-1424.pdf
http://archimer.ifremer.fr/doc/00000/1424/

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 Elsevier
Résumé : International audience
The mangrove swamp environment constitutes a sulphide rich habitat harbouring some thioautotrophic organisms. The ciliate Zoothamnium niveum and the nematode Eubostrichus dianae, both known to live associated with bacterial sulphide-oxidizing ectosymbionts, were analysed as positive controls by Raman microspectrometry. The detection of the 3 Raman bands characteristic of elemental sulphur (S8) allows us to define a positive model of sulphide-oxidizing symbiotic invertebrates and by extrapolation, of thioautotrophic organisms. A fast screening using this tool was carried out on eukaryotic organisms such as hydrozoan, nematodes, annelids, copepods, and ciliate (Pseudovorticella sp.) and on free-living filamentous bacteria found on decomposing leaves in order to detect thioautotrophic organisms. The Raman microspectrometry permits us: (i) to reveal thioautotrophic metabolism of free-living bacteria (Beggiatoa sp.) and even for Archaea and (ii) to detect sulphide-oxidizing endosymbiotic and ectosymbiotic bacteria associated with the Bivalve Lucina pectinata and Pseudovorticella sp., respectively. Raman microspectrometry represents a fast, easy and non destructive technique which can be used on living organisms without constraints of sample size. The Raman analysis can also be completed by ultrastructural analysis (SEM, TEM) on the same sample.
ISSN: 0141-1136

hal-00715329
https://hal.univ-antilles.fr/hal-00715329
DOI : 10.1016/j.marenvres.2010.02.001

Éditeur(s) : Springer
Résumé : The French Atlantic coast contains large highly productive intertidal mudflats that are colonised by juveniles of numerous flatfish species, including the common sole (Solea solea, L.). These ecosystems are also heavily exploited by the shellfish farming industry. Intensive bivalve culture is associated with substantial biodeposition (1-6 t-dw ha(-1) day(-1)), which directly or indirectly contributes to increase exopolysaccharide (EPS) concentrations at the interface between water column and seabed. EPS are long-chain molecules organised into colloids, which influence rheological properties of water, particularly viscosity. Increased water viscosity had consequences for ventilatory activity of juvenile flatfish, whereby the minimal pressure required to ventilate the medium increases directly with EPS concentration. Moreover, the critical EPS concentration ([EPS](crit)) at which water was no longer able to flow through the branchial basket ranged from almost nil to over 30 mg l(-1), depending on species and size. [EPS](crit) was lower in small individuals and individuals from species with high metabolic rates (turbot and plaice). These differences may depend upon gill and bucco-branchial cavity morphometrics. The ventilatory workload of sole increased with viscosity to a maximum at 2 mg EPS l(-1). Viscosity might, therefore, be a limiting factor for flatfish post larvae, which colonise the intertidal mudflats, depending upon their size and species. EPS concentrations in the field can reach 15 mg l(-1). A selective effect is conceivable but remains to be estimated in the field.
Marine Biology (0025-3162) (Springer), 2007-09 , Vol. 152 , N. 4 , P. 803-814

Droits : 2007 Springer
http://archimer.ifremer.fr/doc/2007/publication-2801.pdf
DOI:10.1007/s00227-007-0731-z
http://archimer.ifremer.fr/doc/00000/2801/

Éditeur(s) : HAL CCSD Public Library of Science
Résumé : International audience
BACKGROUND: Estrogens are thought to play a critical role in prostate carcinogenesis. It has been suggested that polymorphisms of genes encoding enzymes involved in estrogen metabolism are risk factors for prostate cancer. However, few studies have been performed on populations of African ancestry, which are known to have a high risk of prostate cancer. OBJECTIVE: We investigated whether functional polymorphisms of CYP17, CYP19, CYP1B1, COMT and UGT1A1 affected the risk of prostate cancer in two different populations of African ancestry. METHODS: In Guadeloupe (French West Indies), we compared 498 prostate cancer patients and 565 control subjects. In Kinshasa (Democratic Republic of Congo), 162 prostate cancer patients were compared with 144 controls. Gene polymorphisms were determined by the SNaPshot technique or short tandem repeat PCR analysis. Logistic regression was used to estimate adjusted odds ratios (OR) and 95% confidence intervals (CI). RESULTS: The AA genotype and the A allele of rs4680 (COMT) appeared to be inversely associated with the risk of prostate cancer in adjusted models for both Afro-Caribbean and native African men. For the A allele, a significant inverse association was observed among cases with low-grade Gleason scores and localized clinical stage, in both populations. CONCLUSIONS: These preliminary results support the hypothesis that polymorphisms of genes encoding enzymes involved in estrogen metabolism may modulate the risk of prostate cancer in populations of African ancestry
ISSN: 1932-6203

hal-01305477
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01305477
DOI : 10.1371/journal.pone.0153609
PUBMED : 27074016

Éditeur(s) : HAL CCSD Cambridge University Press
Résumé : International audience
The liver is the most important link between the circadian system and metabolism. As a food-entrainable oscillator, the hepatic clock needs to be entrained by food-related signals. The objective of the present study was to investigate the possible role of ghrelin (an orexigenic peptide mainly synthesized in the gastrointestinal tract) as an endogenous synchronizer of the liver oscillator in teleosts. To achieve this aim, we first examined the presence of ghrelin receptors in the liver of goldfish. Then, the ghrelin regulation of clock gene expression in the goldfish liver was studied. Finally, the possible involvement of the phospholipase C/ protein kinase C (PLC/ PKC) and adenylate cyclase/protein kinase A (AC/PKA) intracellular signalling pathways was investigated. Ghrelin receptor transcripts, ghs-r1a, are present in the majority of goldfish hepatic cells. Ghrelin induced the mRNA expression of the positive (gbmal1a, gclock1a) and negative (gper genes) elements of the main loop of the molecular clock machinery, as well as grev-erba (auxiliary loop) in cultured liver. These effects were blocked, at least in part, by a ghrelin antagonist. Incubation of liver with a PLC inhibitor (U73122), a PKC activator (phorbol 12-myristate 13-acetate) and a PKC inhibitor (chelerythrine chloride) demonstrated that the PLC/ PKC pathway mediates such ghrelin actions. Experiments with an AC activator (forskolin) and a PKA inhibitor (H89) showed that grev-erba regulation could be due to activation of PKA. Taken together, the present results show for the first time in vertebrates a direct action of ghrelin on hepatic clock genes and support a role for this hormone as a temporal messenger in the entrainment of liver circadian functions.
Journal of Experimental Biology

hal-01519254
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01519254
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01519254/document
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01519254/file/Ghrelin%20induces%20clock%20gene%20expression.pdf
DOI : 10.1242/jeb.144253

Éditeur(s) : HAL CCSD
Résumé : International audience
High-mass-resolution imaging mass spectrometry promises to localize hundreds of metabolites in tissues, cell cultures, and agar plates with cellular resolution, but it is hampered by the lack of bioinformatics tools for automated metabolite identification. We report pySM, a framework for false discovery rate (FDR)-controlled metabolite annotation at the level of the molecular sum formula, for high-mass-resolution imaging mass spectrometry (https://github.com/alexandrovteam/pySM). We introduce a metabolite-signal match score and a target-decoy FDR estimate for spatial metabolomics. © 2017 Nature America, Inc., part of Springer Nature. All rights reserved.
Nature Methods

hal-01467553
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01467553
DOI : 10.1038/nmeth.4072
PUBMED : 27842059

Éditeur(s) : HAL CCSD Nature Publishing Group
Résumé : International audience
Most tumors undergo metabolic reprogramming towards glycolysis, the so-called Warburg effect, to support growth and survival. Overexpression of IF1, the physiological inhibitor of the F0F1ATPase, has been related to this phenomenon and appears to be a relevant marker in cancer. Environmental contributions to cancer development are now widely accepted but little is known about the underlying intracellular mechanisms. Among the environmental pollutants humans are commonly exposed to, benzo[a]pyrene (B[a]P), the prototype molecule of polycyclic aromatic hydrocarbons (PAHs), is a well-known human carcinogen. Besides apoptotic signals, B[a]P can also induce survival signals in liver cells, both likely involved in cancer promotion. Our previous works showed that B[a]P elicited a Warburg-like effect, thus favoring cell survival. The present study aimed at further elucidating the molecular mechanisms involved in the B[a]P-induced metabolic reprogramming, by testing the possible involvement of IF1. We presently demonstrate, both in vitro and in vivo, that PAHs, especially B[a]P, strongly increase IF1 expression. Such an increase, which might rely on β2-adrenergic receptor activation, notably participates to the B[a]P-induced glycolytic shift and cell survival in liver cells. By identifying IF1 as a target of PAHs, this study provides new insights about how environmental factors may contribute to related carcinogenesis.
ISSN: 2045-2322

hal-01518808
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01518808
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01518808/document
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01518808/file/Hardonni%C3%A8re%20et%20al%202017.pdf
DOI : 10.1038/s41598-017-00269-7

Éditeur(s) : HAL CCSD
Résumé : International audience
Background: We examined the association between exposure during pregnancy to trihalomethanes, the most common water disinfection by-products, and birth outcomes in a European cohort study (Health Impacts of Long-Term Exposure to Disinfection By-Products in Drinking Water). We took into account exposure through different water uses, measures of water toxicity, and genetic susceptibility. Methods: We enrolled 14,005 mothers (2002-2010) and their children from France, Greece, Lithuania, Spain, and the UK. Information on lifestyle- and water-related activities was recorded. We ascertained residential concentrations of trihalomethanes through regulatory records and ad hoc sampling campaigns and estimated route-specific trihalomethane uptake by trimester and for whole pregnancy. We examined single nucleotide polymorphisms and copy number variants in disinfection by-product metabolizing genes in nested case-control studies. Results: Average levels of trihalomethanes ranged from around 10 μg/L to above the regulatory limits in the EU of 100 μg/L between centers. There was no association between birth weight and total trihalomethane exposure during pregnancy (β = 2.2 g in birth weight per 10 μg/L of trihalomethane, 95% confidence interval = 3.3, 7.6). Birth weight was not associated with exposure through different routes or with specific trihalomethane species. Exposure to trihalomethanes was not associated with low birth weight (odds ratio [OR] per 10 μg/L = 1.02, 95% confidence interval = 0.95, 1.10), small-for-gestational age (OR = 0.99, 0.94, 1.03) and preterm births (OR = 0.98, 0.9, 1.05). We found no gene-environment interactions for mother or child polymorphisms in relation to preterm birth or small-for-gestational age. Conclusions: In this large European study, we found no association between birth outcomes and trihalomethane exposures during pregnancy in the total population or in potentially genetically susceptible subgroups. © 2016 Wolters Kluwer Health, Inc.
Epidemiology

hal-01392115
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01392115
DOI : 10.1097/EDE.0000000000000544
PUBMED : 27468006

Éditeur(s) : HAL CCSD
Résumé : Benzophenone derivatives (BPs) are used as UV filters in many different products. These lipophilic compounds were recently described as ubiquitous contaminant of different compartiments of aquatic systems, including fish. In this study, we evaluated estrogenic activity of ten BPs in a model fish species, the zebrafish (Danio rerio), by combining newly developed in vitro and in vivo models. In vitro, three specific zebrafish reporter gene models expressing zebrafish estrogen receptors (ZfERs) in zebrafish hepatic cell line (ZFL) were used.Estrogenic activity of BPs was quantify in vivo by using a newly developed transgenic zebrafish line that expresses green fluorescent protein (GFP) under the control of the cyp19a1b promoter. The cyp19a1b gene codes for the brain aromatase B that is under the control of estrogens. Vitellogenin (Vtg), a marker of estrogenic compound, was used to assess the potential estrogenic effect of certain BPs in male fish. Five of 10 BPs induced an estrogenic activity on the three models: BP2, THB, BP1, 4BP, while BP and 234 BP were non active. We noted diffrence in BPs ranking depending on the zfER subtypes suggesting ?/? receptor selectivity by certain BPs. By quantifying GFP expression in live zebrafish, we confirm the estrogenic activity of some BP, i.e., BP1, THB, 4BP and 44'BP, as shown by their ability to induce GFP in a concentration-dependent manner. However, the ranking of BPs as a function of their estrogenic activity assay is different between models. For instance, 4BP was the most estrogenic compound in vivo but not in vitro. Differences were also noticed regarding the estrogenic activity of BP2. In vitro, BP2 has strong activity but had no effect on GFP in cyp19a1b-GFP embryo. However, BP2 induced strongly Vtg in male. The lack of estrogenic activity of BP2 in embryo may be related to difference of biodisponibility and/or metabolisation of this compound between embryo and adult fish. Our approach allows to characterize the estrogenic potency of emerging pollutants, using innovative in vitro and in vivo assays within a unique model fish species. The differences observed between assays deserve further studies to characterize the behavior of compounds in the different biological models in term of biodisponibility and metabolism.
1. European Conference on the Replacement, Reduction and Refinement of Animal Experiments in Ecotoxicology
Dübendorf, Switzerland

ineris-00971019
https://hal-ineris.archives-ouvertes.fr/ineris-00971019
INERIS : EN-2012-243

Éditeur(s) : HAL CCSD American Chemical Society
Résumé : International audience
2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), a carcinogenic heterocyclic aromatic amine formed in cooked meats, is metabolically activated to electrophilic intermediates that form covalent adducts with DNA and protein. We previously identified an adduct of PhIP formed at the Cys34 residue of human serum albumin following reaction of albumin with the genotoxic metabolite 2-hydroxyamino-1-methyl-6-phenylimidazo[4,5-b]pyridine (HONH-PhIP). The major adducted peptide recovered from a tryptic/chymotryptic digest was identified as the missed-cleavage peptide LQQC*[SO2PhIP]PFEDHVK, a [cysteine-S-yl-PhIP]-S-dioxide linked adduct. In this investigation, we have characterized the albumin adduction products of N-sulfooxy-2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (N-sulfooxy-PhIP), which is thought to be a major genotoxic metabolite of PhIP formed in vivo. Targeted and data-dependent scanning methods showed that N-sulfooxy-PhIP adducted to the Cys34 of albumin in human plasma to form LQQC*[SO2PhIP]PFEDHVK at levels that were 8-10-fold greater than the adduct levels formed with N-(acetyloxy)-2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (N-acetoxy-PhIP) or HONH-PhIP. We also discovered that N-sulfooxy-PhIP forms an adduct at the sole tryptophan (Trp214) residue of albumin in the sequence AW*[PhIP]AVAR. However, stable adducts of PhIP with albumin were not detected in human hepatocytes. Instead, PhIP and 2-amino-1-methyl-6-(5-hydroxy)phenylimidazo[4,5-b]pyridine (5-HO-PhIP), a solvolysis product of the proposed nitrenium ion of PhIP, were recovered during the proteolysis, suggesting a labile sulfenamide linkage had formed between an N-oxidized intermediate of PhIP and Cys34 of albumin. A stable adduct was formed at the Tyr411 residue of albumin in hepatocytes and identified as a deaminated product of PhIP, Y*[desaminoPhIP]TK, where the 4-HO-tyrosine group bound to the C-2 imidazole atom of PhIP.
ISSN: 0893-228X

hal-01146777
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01146777
DOI : 10.1021/acs.chemrestox.5b00075
PUBMED : 25815793

Éditeur(s) : Public Library Science
Résumé : Biological invasions rank amongst the most deleterious components of global change inducing alterations from genes to ecosystems. The genetic characteristics of introduced pools of individuals greatly influence the capacity of introduced species to establish and expand. The recently demonstrated heritability of microbial communities associated to individual genotypes of primary producers makes them a potentially essential element of the evolution and adaptability of their hosts. Here, we characterized the bacterial communities associated to native and non-native populations of the marine green macroalga Caulerpa racemosa through pyrosequencing, and explored their potential role on the strikingly invasive trajectory of their host in the Mediterranean. The similarity of endophytic bacterial communities from the native Australian range and several Mediterranean locations confirmed the origin of invasion and revealed distinct communities associated to a second Mediterranean variety of C. racemosa long reported in the Mediterranean. Comparative analysis of these two groups demonstrated the stability of the composition of bacterial communities through the successive steps of introduction and invasion and suggested the vertical transmission of some major bacterial OTUs. Indirect inferences on the taxonomic identity and associated metabolism of bacterial lineages showed a striking consistency with sediment upheaval conditions associated to the expansion of their invasive host and to the decline of native species. These results demonstrate that bacterial communities can be an effective tracer of the origin of invasion and support their potential role in their eukaryotic host's adaptation to new environments. They put forward the critical need to consider the 'meta-organism' encompassing both the host and associated micro-organisms, to unravel the origins, causes and mechanisms underlying biological invasions.
Plos One (1932-6203) (Public Library Science), 2013-07 , Vol. 8 , N. 7 , P. -

Droits : 2013 Aires et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
http://archimer.ifremer.fr/doc/00157/26791/24886.pdf
DOI:10.1371/journal.pone.0068429
http://archimer.ifremer.fr/doc/00157/26791/

Éditeur(s) : HAL CCSD American Society for Biochemistry and Molecular Biology
Résumé : International audience
2-Amino-9H-pyrido[2,3-b]indole (AαC) is a carcinogenic heterocyclic aromatic amine (HAA) that arises in tobacco smoke. UDP-glucuronosyltransferases (UGTs) are important enzymes that detoxicate many procarcinogens, including HAAs. UGTs compete with P450 enzymes, which bioactivate HAAs by N-hydroxylation of the exocyclic amine group; the resultant N-hydroxy-HAA metabolites form covalent adducts with DNA. We have characterized the UGT-catalyzed metabolic products of AαC and the genotoxic metabolite 2-hydroxy-amino-9H-pyrido[2,3-b]indole (HONH-AαC) formed with human liver microsomes, recombinant human UGT isoforms, and human hepatocytes. The structures of the metabolites were elucidated by 1H-NMR and mass spectrometry. AαC and HONH-AαC underwent glucuronidation, by UGTs, to form, respectively, N2-(β-D-glucosidurony1)-2-amino-9H-pyrido[2,3-b]indole (AαC-N2-Gl) and N2-(β-D-glucosidurony1)-2-hydroxyamino-9H-pyrido[2,3-b]indole (AαC-HON2-Gl). HONH-AαC also underwent glucuronidation to form a novel O-glucuronide conjugate, O-(β-D-glucosidurony1)-2-hydroxyamino-9H-pyrido[2,3-b]indole (AαC-HN2-O-Gl). AαC-HN2-O-Gl is a biologically reactive metabolite that bound to calf thymus DNA (pH 5.0 or pH 7.0) to form the N-(deoxyguanosin-8-yl)-AαC (dG-C8-AαC) adduct at 20 to 50-fold higher levels than the adduct levels formed with HONH-AαC. Major UGT isoforms were examined for their capacity to metabolize AαC and HONH-AαC. UGT1A4 was the most catalytically efficient enzyme (Vmax/Km) at forming AαC-N2-Gl (0.67 μL mg protein-1 min-1), UGT1A9 was most catalytically efficient at forming AαC-HN-O-Gl (77.1 μL mg protein-1 min-1), whereas, UGT1A1 was most efficient at forming AαC-HON2-Gl (5.0 μL mg protein-1 min-1). Human hepatocytes produced AαC-N2-Gl and AαC-HN2-O-Gl in abundant quantities, but AαC-HON2-Gl was a minor product. Thus, UGTs, usually important enzymes in the detoxication of many procarcinogens, serve as a mechanism of bioactivation of HONH-AαC.
Journal of Biological Chemistry

hal-00688369
https://hal.archives-ouvertes.fr/hal-00688369
DOI : 10.1074/jbc.M111.320093
PUBMED : 22393056

Éditeur(s) : HAL CCSD American Society for Pharmacology and Experimental Therapeutics (ASPET)
Résumé : International audience
Most human hepatocyte cell lines lack a substantial set of liver-specific functions, especially major cytochrome P450 (P450)-related enzyme activities, making them unrepresentative of in vivo hepatocytes. We have used the HepaRG cells, derived from a human hepatocellular carcinoma, which exhibit a high differentiation pattern after 2 weeks at confluency to determine whether they could mimic human hepatocytes for drug metabolism and toxicity studies. We show that when passaged at low density, these cells reversed to an undifferentiated morphology, actively divided, and, after having reached confluency, formed typical hepatocyte-like colonies surrounded by biliary epithelial-like cells. By contrast, when seeded at high density, hepatocyte-like clusters retained their typical differentiated morphology. Transcripts of various nuclear receptors (aryl hydrocarbon receptor, pregnane X receptor, constitutive androstane receptor, peroxisome proliferator-activated receptor alpha), P450s (CYP1A2, 2C9, 2D6, 2E1, 3A4), phase 2 enzymes (UGT1A1, GSTA1, GSTA4, GSTM1), and other liver-specific functions were estimated by reverse transcriptase-quantitative polymerase chain reaction and were found to be expressed, for most of them, at comparable levels in both confluent differentiated and high-density differentiated HepaRG cells and in cultured primary human hepatocytes. For several transcripts, the levels were strongly increased in the presence of 2% dimethyl sulfoxide. Measurement of basal activities of several P450s and their response to prototypical inducers as well as analysis of metabolic profiles and cytotoxicity of several compounds confirmed the functional resemblance of HepaRG cells to primary cultured human hepatocytes. In conclusion, HepaRG cells constitute the first human hepatoma cell line expressing high levels of the major P450s involved in xenobiotic metabolism and represent a reliable surrogate to human hepatocytes for drug metabolism and toxicity studies.
ISSN: 0090-9556

hal-00702085
https://hal.archives-ouvertes.fr/hal-00702085
DOI : 10.1124/dmd.105.006759
PUBMED : 16204462

Éditeur(s) : HAL CCSD Public Library of Science
Résumé : International audience
Pyrethroids are widely-used chemical insecticides, to which humans are commonly exposed, and known to alter functional expression of drug metabolizing enzymes. Limited data have additionally suggested that drug transporters, that constitute key-actors of the drug detoxification system, may also be targeted by pyrethroids. The present study was therefore designed to analyze the potential regulatory effects of these pesticides towards activities of main ATP-binding cassette (ABC) and solute carrier (SLC) drug transporters, using transporter-overexpressing cells. The pyrethroids allethrin and tetramethrin were found to inhibit various ABC and SLC drug transporters, including multidrug resistance-associated protein (MRP) 2, breast cancer resistance protein (BCRP), organic anion transporter polypeptide (OATP) 1B1, organic anion transporter (OAT) 3, multidrug and toxin extrusion transporter (MATE) 1, organic cation transporter (OCT) 1 and OCT2, with IC50 values however ranging from 2.6 muM (OCT1 inhibition by allethrin) to 77.6 muM (OAT3 inhibition by tetramethrin) and thus much higher than pyrethroid concentrations (in the nM range) reached in environmentally pyrethroid-exposed humans. By contrast, allethrin and tetramethrin cis-stimulated OATP2B1 activity and failed to alter activities of OATP1B3, OAT1 and MATE2-K, whereas P-glycoprotein activity was additionally moderately inhibited. Twelve other pyrethoids used at 100 muM did not block activities of the various investigated transporters, or only moderately inhibited some of them (inhibition by less than 50%). In silico analysis of structure-activity relationships next revealed that molecular parameters, including molecular weight and lipophilicity, are associated with transporter inhibition by allethrin/tetramethrin and successfully predicted transporter inhibition by the pyrethroids imiprothrin and prallethrin. Taken together, these data fully demonstrated that two pyrethoids, i.e., allethrin and tetramethrin, can act as regulators of the activity of various ABC and SLC drug transporters, but only when used at high and non-relevant concentrations, making unlikely any contribution of these transporter activity alterations to pyrethroid toxicity in environmentally exposed humans.
ISSN: 1932-6203

hal-01477206
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01477206
DOI : 10.1371/journal.pone.0169480
PUBMED : 28099443