Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
In order to perform a human and ecological risk assessment of pharmaceutical products (PPs) in natural waters, it is necessary to accurately quantify a broad variety of PPs at low concentrations. Although numerous currently implemented analytical methodologies, less is known about the preservation of PPs in natural water samples within the period before analysis (holding time, storage conditions). This paper is the first literature review about the stability of PPs in natural waters (surface and groundwaters) during sample storage. The current work focuses on a comparison of the performances of the available preservation techniques (filtration, container materials, storage temperature, preservative agents, etc.) for PPs in samples. All 58 reviewed PPs may be successfully stabilized during 7 days in surface waters by at least one appropriate methodology regarding temperature, acidic and non-acidic preservatives. When temperature is not a sufficient preservation parameter f! or some PPs (hormones and fluoxetine) its combination with the addition of chemical agents into the samples may prolong the integrity of the PPs during storage in surface water. There is a strong need to use standard protocols to assess and compare the stability of PPs in environmental water matrices during storage as well as during analytical preparation or analysis (European criteria 2002/657/EC). Since the stability of PPs during sample storage is a critical parameter that could call into question the quality of the data provided for the concentrations, the design of stability studies should rigorously take into account all critical parameters that could impact the concentrations of the PPs with time.
Talanta

insu-00839186
https://hal-insu.archives-ouvertes.fr/insu-00839186
DOI : 10.1016/j.talanta.2013.01.042

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
Ethnopharmacological relevancePsidium acutangulum Mart. ex DC is a small tree used by the Wayana Amerindians from the Upper-Maroni in French Guiana for the treatment of malaria.Aim of the studyIn a previous study, we highlighted the in vitro antiplasmodial, antioxidant and anti-inflammatory potential of the traditional decoction of P. acutangulum aerial parts. Our goal was then to investigate on the origin of the biological activity of the traditional remedy, and eventually characterize active constituents.Materials and methodsLiquid-liquid extractions were performed on the decoction, and the antiplasmodial activity evaluated against chloroquine-resistant FcB1 ([3H]-hypoxanthine bioassay) and 7G8 (pLDH bioassay) P. falciparum strains, and on a chloroquine sensitive NF54 ([3H]-hypoxanthine bioassay) P. falciparum strain. The ethyl acetate fraction (D) was active and underwent bioguided fractionation. All the isolated compounds were tested on P. falciparum FcB1 strain. In vitro anti-inflammatory activity (IL-1β, IL-6, IL-8, TNFα) of the ethyl acetate fraction and of an anti-Plasmodium active compound, was concurrently assessed on LPS-stimulated human PBMC and NO secretion inhibition was measured on LPS stimulated RAW murine macrophages. Cytotoxicity of the fractions and pure compounds was measured on VERO cells, L6 mammalian cells, PBMCs, and RAW cells.ResultsFractionation of the ethyl acetate soluble fraction (IC50 ranging from 3.4 to <1 µg/mL depending on the parasite strain) led to the isolation of six pure compounds: catechin and five glycosylated quercetin derivatives. These compounds have never been isolated from this plant species. Two of these compounds (wayanin and guaijaverin) were found to be moderately active against P. falciparum FcB1 in vitro (IC50 5.5 and 6.9 µM respectively). We proposed the name wayanin during public meetings organized in June 2015 in the Upper-Maroni villages, in homage to the medicinal knowledge of the Wayana population. At 50 µg/mL, the ethyl acetate fraction (D) significantly inhibited IL-1β secretion (−46%) and NO production (−21%), as previously observed for the decoction. The effects of D and guiajaverin (4) on the secretion of other cytokines or NO production were not significant.ConclusionsThe confirmed antiplasmodial activity of the ethyl acetate soluble fraction of the decoction and of the isolated compounds support the previous results obtained on the P. acutangulum decoction. The antiplasmodial activity might be due to a mixture of moderately active non-toxic flavonoids. The anti-inflammatory activities were less marked for ethyl acetate fraction (D) than for the decoction.
ISSN: 0378-8741

hal-01313006
http://hal.upmc.fr/hal-01313006
http://hal.upmc.fr/hal-01313006/document
http://hal.upmc.fr/hal-01313006/file/Houel_Wayanin_and.pdf
DOI : 10.1016/j.jep.2016.04.053

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
This paper proposes a new approach for the on-site detection of micropollutants in water in case of accidental or intentional contamination (characterized by high concentration). The technique is based on the use of an automatic multiple solid phase extraction step (MSPE) followed by direct or indirect UV spectrometry (MSPE/UV) for the detection of organic contaminants in water (such as regulated molecules (pesticides ...) as well as emerging pollutants (pharmaceutical products, endocrine disruptors ...)). The development of the system supposes firstly the choice of the most appropriate sorbent(s) and secondly conditions for the detection of targeted micropollutants, from several solid phase extraction cartridges and eluting solvents. Two different extraction sorbents were chosen. These sorbents and several eluting solvents allow the first separation of the compounds based on the physico-chemical properties of each substance (pKa, log Kow) and on the specific interactions with the sorbent. Finally, a UV analysis (either at the maximum of absorbance using a calibration curve or from the whole spectrum using a multicomponent (deconvolution) exploitation method) of each fraction allows a determination and a quantification of each compound. The method is rapid (less than 2 h), sensitive enough for an accidental/intentional contamination (between 5 and 40 μg*L− 1 according to the substances) and with a good precision (between 4 and 14%).
ISSN: 0026-265X

hal-00878024
https://hal.archives-ouvertes.fr/hal-00878024
DOI : 10.1016/j.microc.2012.10.025

Éditeur(s) : HAL CCSD IWA Publishing
Résumé : International audience
Anti-cancer drugs are an important class of pharmaceutical products. Methotrexate (MTX) is a folic acid antagonist used in high doses as antimetabolite in anti-cancer treatment as well as in low doses for the treatment of rheumatoid arthritis and adults' psoriasis. In the past, several anti-cancer drugs, including methotrexate, have been found in the environment. Their presence in water, especially if used for the production of drinking water, is even in low concentrations of particular interest, due to the risk to retrieve them in the consumed water and their high activity and grave effects. But prior to usage as drinking water, raw waters are treated and chlorination is a common practice in several countries. As such a treatment can lead to the formation of organochlorine in water, the study of the fate of MTX during chlorination in a batch trial was carried out. The reaction was monitored by dissolved organic carbon (DOC) and by fluorescence and UV spectroscopy. Investigation of by-products formed was done with liquid chromatography/mass spectrometry (LC/MS). Under the given experimental conditions, Methotrexate was eliminated rapidly (t1/2 around 21 min). However, DOC elimination was incomplete. Monitoring with LC-MS showed the formation of a monochlorinated transformation product of MTX. In silico analysis of the proposed transformation products for different carcinogenic, mutagenic and genotoxic endpoints with different software platforms provided no clear evidence that the possible transformation products after chlorination might be more toxic than the parent compound. However, since a number of alerts is altered after chlorination, it cannot be excluded that the toxicity of these transformation products might be modulated compared with the parent compound.
ISSN: 0043-1354

hal-01016617
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01016617
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01016617/document
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01016617/file/Monitoringsur methotrexate_final.pdf
DOI : 10.1016/j.watres.2014.03.008

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
Veterinary pharmaceuticals, widely used in intensive livestock production, may contaminate surface waters. Identifying their sources and pathways in watersheds is difficult because i) most veterinary pharmaceuticals are used in human medicine as well and ii) septic or sewer wastewater treatment plants (WWTP) can release pharmaceuticals into surface water, even in agricultural headwater watersheds. This study aimed to analyze the spatiotemporal variability of animal-specific, mixed-use, and human-specific pharmaceuticals, from agricultural headwaters with intensive livestock production and a WWTP to a watershed used for Water Framework Directive monitoring. Grab sampling was performed during one hydrological year upstream and downstream from a WWTP and at three dates in seven nested watersheds with areas of 1.9-84.1km2. Twenty pharmaceuticals were analyzed. Animal-specific pharmaceuticals were detected at all sampling dates upstream and downstream from the WWTP and at concentrations higher than those of human-specific pharmaceuticals. The predominance of animal-specific and mixed-use pharmaceuticals vs. human-specific pharmaceuticals observed at these sampling points was confirmed at the other sampling points. Animal-specific pharmaceuticals were detected mainly during runoff events and periods of manure spreading. A large percentage of mixed-use pharmaceuticals could come from animal sources, but it was difficult to determine. Mixed-use and human-specific pharmaceuticals predominated in the largest watersheds when runoff decreased. In areas of intensive livestock production, mitigation actions should focus on agricultural headwater watersheds to decrease the number of pathways and the transfer volume of veterinary pharmaceuticals, which can be the main contaminants
ISSN: 0048-9697

insu-01574739
https://hal-insu.archives-ouvertes.fr/insu-01574739
DOI : 10.1016/j.scitotenv.2017.07.206
PUBMED : 28783916

Éditeur(s) : HAL CCSD Wiley
Résumé : International audience
More than half the pregnant women in the Western world report taking mild analgesics. These pharmaceutical compounds have been associated with congenital cryptorchidism in humans, the best-known risk factor for low semen quality and testicular germ cell cancer. Furthermore, some of these mild analgesics exert potent anti-androgenic effects in the male rat and several endocrine-disrupting compounds, known to alter masculinization, have also been shown to be potent inhibitors of prostaglandin (PG) synthesis similar to mild analgesics. Using a 3-day ex vivo organotypic model system based on gestational day 14.5 rat testes, we herein show that testosterone production was inhibited by paracetamol, at doses of 0.1 μm to 100 μm. Similar results were obtained for aspirin (1-100 μm) and indomethacin (10 μm). The production of the other Leydig cell hormone, Insl3, was not disrupted by exposure to paracetamol. Investigations of the gross anatomy of the testis as well as Leydig cells number and rate of gonocyte apoptosis after the 3 days of ex vivo differentiation showed no significant effect of the analgesics tested compared with controls. These data indicate therefore that mild analgesics specifically inhibit testosterone production in rat foetal testes in vitro and that these compounds had no effect on gonocyte survival. Parallel determinations of prostaglandin D2 (PGD2) production indicated that the effects of paracetamol and aspirin on PGD2 and testosterone were not connected, whereas the effects of indomethacin were correlated. We conclude that mild analgesics exert direct and specific anti-androgenic effects in rat foetal testis in our experimental setup and that the mechanism of action is probably uncoupled from the inhibition of PG synthesis.
ISSN: 0105-6263

hal-00876956
https://hal.archives-ouvertes.fr/hal-00876956
DOI : 10.1111/j.1365-2605.2012.01282.x
PUBMED : 22612476

Éditeur(s) : HAL CCSD
Résumé : International audience
Industrial use of aniline is increasing worldwide with production estimated to surpass 5.6 million metric tons in 2016. Exposure to aniline occurs via air, diet and water augmenting the risk of exposing a large number of individuals. Early observations suggest that aniline is metabolised to paracetamol/acetaminophen, likely explaining the omnipresence of low concentrations of paracetamol in European populations. This is of concern as recent studies implicate paracetamol as a disrupter of reproduction. Here we show through steroidogenic profiling that exposure to aniline led to increased levels of the Δ4 steroids, suggesting that the activity of CYP21 was decreased. By contrast, paracetamol decreased levels of androgens likely through inhibition of CYP17A1 activity. We confirm that aniline in vivo is rapidly converted to paracetamol by the liver. Intrauterine exposure to aniline and paracetamol in environmental and pharmaceutical relevant doses resulted in shortening of the anogenital distance in mice, a sensitive marker of fetal androgen levels that in humans is associated with reproductive malformations and later life reproductive disorders. In conclusion, our results provide evidence for a scenario where aniline, through its conversion into anti-androgenic paracetamol, impairs male reproductive development
Toxicological Sciences: An Official Journal of the Society of Toxicology

hal-01187305
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01187305
DOI : 10.1093/toxsci/kfv179
PUBMED : 26259604

Éditeur(s) : HAL CCSD Nature Publishing Group
Résumé : International audience
Among pregnant women ibuprofen is one of the most frequently used pharmaceutical compounds with up to 28% reporting use. Regardless of this, it remains unknown whether ibuprofen could act as an endocrine disruptor as reported for fellow analgesics paracetamol and aspirin. To investigate this, we exposed human fetal testes (7-17 gestational weeks (GW)) to ibuprofen using ex vivo culture and xenograft systems. Ibuprofen suppressed testosterone and Leydig cell hormone INSL3 during culture of 8-9 GW fetal testes with concomitant reduction in expression of the steroidogenic enzymes CYP11A1, CYP17A1 and HSD17B3, and of INSL3. Testosterone was not suppressed in testes from fetuses younger than 8 GW, older than 10-12 GW, or in second trimester xenografted testes (14-17 GW). Ex vivo, ibuprofen also affected Sertoli cell by suppressing AMH production and mRNA expression of AMH, SOX9, DHH, and COL2A1. While PGE2 production was suppressed by ibuprofen, PGD2 production was not. Germ cell transcripts POU5F1, TFAP2C, LIN28A, ALPP and KIT were also reduced by ibuprofen. We conclude that, at concentrations relevant to human exposure and within a particular narrow â €' early window' of sensitivity within first trimester, ibuprofen causes direct endocrine disturbances in the human fetal testis and alteration of the germ cell biology. © The Author(s) 2017.
ISSN: 2045-2322

hal-01517095
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01517095
DOI : 10.1038/srep44184
PUBMED : 28281692

Éditeur(s) : HAL CCSD American Chemical Society
Résumé : International audience
Four bicyclic and three pentacyclic guanidine alkaloids (1–7) were isolated from a French Polynesian Monanchora n. sp. sponge, along with the known alkaloids monalidine A (8), enantiomers 9–11 of known natural product crambescins, and the known crambescidins 12–15. Structures were assigned by spectroscopic data interpretation. The relative and absolute configurations of the alkaloids were established by analysis of 1H NMR and NOESY spectra and by circular dichroism analysis. The new norcrambescidic acid (7) corresponds to interesting biosynthetic variation within the pentacyclic core. All compounds exhibited antiproliferative and cytotoxic efficacy against KB, HCT116, HL60, MRC5, and B16F10 cancer cells, with IC50 values ranging from 4 nM to 10 μM.
ISSN: 0163-3864

hal-01584556
https://hal.archives-ouvertes.fr/hal-01584556
DOI : 10.1021/acs.jnatprod.6b00168

Éditeur(s) : HAL CCSD MDPI
Résumé : International audience
Marine micro-and macroorganisms are well known to produce metabolites with high biotechnological potential. Nearly 40 years of systematic prospecting all around the New Caledonia archipelago and several successive research programs have uncovered new chemical leads from benthic and planktonic organisms. After species identification, biological and/or pharmaceutical analyses are performed on marine organisms to assess their bioactivities. A total of 3582 genera, 1107 families and 9372 species have been surveyed and more than 350 novel molecular structures have been identified. Along with their bioactivities that hold promise for therapeutic applications, most of these molecules are also potentially useful for cosmetics and food biotechnology. This review highlights the tremendous marine diversity in New Caledonia, and offers an outline of the vast possibilities for natural products, especially in the interest of pursuing collaborative fundamental research programs and developing local biotechnology programs.
EISSN: 1660-3397

Droits : http://creativecommons.org/licenses/by/
hal-01292225
http://hal.upmc.fr/hal-01292225
http://hal.upmc.fr/hal-01292225/document
http://hal.upmc.fr/hal-01292225/file/marinedrugs-14-00058.pdf
DOI : 10.3390/md14030058

Éditeur(s) : HAL CCSD Endocrine Society
Résumé : International audience
: Context:Masculinization depends on the fetal testis. Exposure of the human fetus during pregnancy to paracetamol or/and to other mild-analgesics is associated with an increased risk of cryptorchidism.Objective:We aimed at determining whether mild analgesics disrupted the morphology and endocrine function of the human testis.Design:We used an in vitro system based on the culture of human fetal testes exposed or not to paracetamol, its metabolite AM404, aspirin, indomethacin, ketoconazole at 10(-4) M to 10(-7) M.Setting:The study was conducted at the University of Rennes I.Patients/Participants:Human fetal testes were from pregnant women following induced abortion, between 7 and 12 weeks of gestation (GW).Main Outcome Measures:Testosterone (radioimmunoassay: RIA), Anti-Müllerian Hormone (AMH; ELISA), insulin-like factor 3 (INSL3; RIA), prostaglandin D2 and E2 (PGD2 and PGE2, respectively; ELISA), were assayed in the media. Testicular cells were counted using histology and image analysis. The possible nuclear receptor-mediated activities of the analgesics were investigated using reporter cell lines expressing estrogen (ERs), androgen (AR) and peroxysome proliferator-activated γ ( PPARγ) receptors.Results:Indomethacin and aspirin stimulated testosterone production, particularly by the younger testes (8-9 GW vs 10-12 GW). Paracetamol, AM404 and ketoconazole decreased INSL3 levels. Aspirin stimulated, whereas ketoconazole inhibited AMH production. PGE2 levels were inhibited by paracetamol, and aspirin in the 7-12 GW testes, and by indomethacin but only in 7-9.86 GW old testes. The inhibitory trends seen for PGD2 were not statistically significant.Conclusions:Analgesics at concentrations relevant to human exposure cause endocrine disturbances in the fetal testis. We suggest that the fetal human testis displays slight critical age windows for sensitivity to direct exposure to aspirin, indomethacin and paracetamol. The analgesic-induced inhibition of INSL3 may be the mechanism by which analgesics increase the risk of cryptorchidism. Greater caution is required concerning consumption of analgesics during pregnancy.
ISSN: 0021-972X

inserm-00876125
http://www.hal.inserm.fr/inserm-00876125
DOI : 10.1210/jc.2013-2531
PUBMED : 24030937

Éditeur(s) : HAL CCSD Water Quality Research Journal of Canada
Résumé : International audience
The adsorption of some major pharmaceutical products (sulfamethoxazole, caffeine, iopromide and carbamazepine) in water was evaluated using four types of activated carbon, three powdered activated carbon (PAC) and one fluidized, coagulated and flocculated activated carbon (FAC) extracted from a Carboplus®P pilot. These substances were the most frequently quantified (in 50% of samples at least) in surface waters of the Vilaine's basin (Brittany, France) during three sampling campaigns. Jar test experiments were carried out in order to assess the removal efficiency of the four activated carbons. Carbamazepine and caffeine were well removed with PAC with a maximum removal rate of 80% whereas it was more difficult for sulfamethoxazole and iopromide with a maximum of 39%. For each molecule, removal rates are clearly dependent on PAC nature. The overall results with FAC are clearly distinguishable from PAC tests with gains of performance on all target molecules (from 80 to >95%).
Water Quality Research Journal of Canada

hal-00878098
https://hal.archives-ouvertes.fr/hal-00878098
DOI : 10.2166/wqrjc.2013.138

Éditeur(s) : HAL CCSD
Résumé : International audience
Diffuse contamination of surface water by veterinary pharmaceuticals (VP) has been poorly studied in intensive breeding context. Recycling animal waste on soil is supported to fertilize crops and reduce utilization of mineral fertilizer but may have some environmental impact by recycling pollutants on soils and transferring pollutants from soils to rivers. Most of pharmaceuticals are consumed indifferently by human and animal, especially antibiotics. This study aims to quantify veterinary pharmaceuticals (VP) in superficial water in two agricultural catchments. One is dedicated to the production of drinkable water. Agriculture but also waste water treatment plant may contribute to the contamination of water and it is difficult to distinguish animal versus human source of contamination
1ere conférence internationale sur l’évaluation des risques des résidus de médicament dans l’environnement
Paris, France

insu-01467591
https://hal-insu.archives-ouvertes.fr/insu-01467591