Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
CONTEXT: Chlordecone, an environmentally persistent organochlorine insecticide used intensively in banana culture in the French West Indies until 1993, has permanently polluted soils and contaminated foodstuffs. Consumption of contaminated food is the main source of exposure nowadays. We sought to identify main contributors to blood chlordecone concentration (BCC) and to validate an exposure indicator based on food intakes. MATERIAL AND METHODS: We used a food frequency questionnaire (FFQ) completed by a sample of 194 pregnant women to estimate their dietary exposure to chlordecone and compared it to blood levels. In a first approach, chlordecone daily intake was estimated as the product of daily eaten quantity of 214 foodstuffs, multiplied by their chlordecone content, and summed over all items. We then predicted individual blood chlordecone concentration with empirical weight regression models based on frequency of food consumption, and without contamination data. RESULTS: Among the 191 subjects who had BCC determination, 146 (76%) had detectable values and mean BCC was 0.86 ng/mL (range < LOD-13.2). Mean per capita dietary intake of chlordecone was estimated at 3.3 microg/day (range: 0.1-22.2). Blood chlordecone levels were significantly correlated with food exposure predicted from the empirical weight models (r=0.47, p<0.0001) and, to a lesser extent, with chlordecone intake estimated from food consumption and food contamination data (r=0.20, p=0.007). Main contributors to chlordecone exposure included seafood, root vegetables, and Cucurbitaceous. CONCLUSION: These results show that the Timoun FFQ provides valid estimates of chlordecone exposure. Estimates from empirical weight models correlated better with blood levels of chlordecone than did estimates from the dietary intake assessment.
ISSN: 0013-9351

inserm-00517109
http://www.hal.inserm.fr/inserm-00517109
http://www.hal.inserm.fr/inserm-00517109/document
http://www.hal.inserm.fr/inserm-00517109/file/Pesticide_exposureofpregnantwomeninGuadeloupe.pdf
DOI : 10.1016/j.envres.2009.10.015

Éditeur(s) : HAL CCSD Society of Environmental Toxicology and Chemistry Press (SETAC)
Résumé : International audience
Tributyltin (TBT) and triphenyltin (TPT) are emblematic endocrine disruptors, which have been mostly studied in gonochoric prosobranchs. Although both compounds can simultaneously occur in the environment, they have mainly been tested separately for their effects on snail reproduction. Because large discrepancies in experimental conditions occurred in these tests, the present study aimed to compare the relative toxicity of TBT and TPT under similar laboratory conditions in the range of 0 ng Sn/L to 600 ng Sn/L. Tests were performed on the simultaneous hermaphrodite Lymnaea stagnalis, a freshwater snail in which effects of TPT were unknown. Survival, shell length, and reproduction were monitored in a 21-d semistatic test. Frequency of abnormal eggs was assessed as an additional endpoint. Triphenyltin hampered survival while TBT did not. Major effects on shell solidity and reproduction were observed for both compounds, reproductive outputs being more severely hampered by TBT than by TPT. Considering the frequency of abnormal eggs allowed increasing test sensitivity, because snail responses to TBT could be detected at concentrations as low as 19 ng Sn/L. However, the putative mode of action of the 2 compounds could not be deduced from the structure of the molecules or from the response of apical endpoints. Sensitivity of L. stagnalis to TBT and TPT was compared with the sensitivity of prosobranch mollusks with different habitats and different reproductive strategies.
Environmental Toxicology and Chemistry

hal-00877955
https://hal.archives-ouvertes.fr/hal-00877955
DOI : 10.1002/etc.2200
PUBMED : 23450754

Éditeur(s) : HAL CCSD
Résumé : The ovary is not solely the unique source of oocytes necessary for fertilization but also a crucial conductor of endocrine regulations of the reproductive system. In the fetal ovary, oocytes grouped in clusters are surrounded by somatic pre-granulosa cells, altogether delineated by a basement membrane and constituting ovarian cords. The formation of the definitive ovarian functional units requires their fragmentation into follicles formed by a single oocyte surrounded by granulosa cells and delineated by a basement membrane. This partitioning occurs within a tiny period and is dependent on the correct timing of the meiotic process, on an apoptotic wave that specifically targets oocytes and the remodelling of the basement membrane. Follicle formation is a crucial event of ovarian development because the follicle stock formed at the end of this process is non-renewable. Therefore, any disturbance of this process can lead to reproductive abnormalities in adulthood. Recent data on endocrine disruptors displaying estrogenic activity have involved the fragile estrogenic homeostasis in the process. We aimed at better understanding how the endogen estrogen 17b-estradiol (E2) contributes to follicle formation. To assess it, Sprague-Dawley rats were treated with E2 at different doses during follicle formation, /i.e./ in the 3 days following birth. We show that although this treatment impairs the development of the hepatic and ovarian detoxification systems, the female neonate is able to increase its estrogen clearance capabilities. Nevertheless, E2 treatment within this critical period triggers a dose-dependent decrease of oocyte number per ovary. Regardless of the E2 dose, puberty is advanced. All treated females are at least transiently fertile, yet these reproductive capabilities rapidly decline. A high (10 µg/day) dose of E2 leads to a secondary infertility characterized by anovulation that probably result from a dysfunction of the whole reproductive tract. By contrast, a lower (0.1 µg/day) dose of E2, that does not significantly modify neonatal oocyte survival, leads to a progressive reproductive senescence likely due to ovarian failure. Long-term troubles may originate from precocious E2 impact on the ovary since it disturbs ovarian transcriptome and produces many lesions on ovarian cell DNA.
L'ovaire est au cœur de la physiologie de la reproduction féminine. Il est à la fois à l'origine des ovocytes nécessaires à la fécondation et acteur des régulations endocrines du système reproducteur. Les ovocytes de l'ovaire fœtal sont groupés en amas bordés de cellules somatiques et d'une membrane basale, formant les cordons ovariens. Ces cordons ovariens se fragmentent pour former les follicules ovariens: un ovocyte bordé de cellules somatiques et d'une membrane basale. Cette fragmentation se déroule sur une courte période (/in utero/ chez la femme et juste après la naissance chez les rongeurs) et fait intervenir une vague de mort cellulaire programmée touchant les ovocytes pendant leur méiose et un remodelage de la membrane basale. La formation des follicules est une période cruciale du développement ovarien puisque le stock de follicules formés à l'issue de ce processus est non renouvelable. Son altération peut donc être à l'origine de troubles de la fonction de reproduction chez le futur adulte. Il existe une fragile homéostasie œstrogénique en place au moment de la formation folliculaire: chez la femme, l'ovaire se développe /in utero/, sous l'influence des œstrogènes circulants maternels et la production ovarienne fœtale. Chez les rongeurs, les follicules se forment lors de la levée de l'imprégnation hormonale maternelle au moment de la naissance. Nous avons souhaité comprendre comment le 17b-œstradiol (E2), œstrogène endogène, pouvait contribuer à la mise en place des follicules. Pour cela, des rattes Sprague-Dawley ont été traitées pendant la période de formation des follicules avec de l'E2 à différentes doses entre 0.01 et 10 µg/jour. Nos travaux démontrent que le traitement de rattes par des œstrogènes entre leur naissance et 3 jours induit une réduction dose-dépendante de leur nombre d'ovocytes. Bien que le traitement entrave le développement normal du système de détoxication hépatique et ovarien, l'animal est capable d'accroître ses capacités d'élimination des œstrogènes. Ces capacités sont toutefois insuffisantes pour bloquer les effets du traitement. Quelle que soit la dose d'E2 utilisée (0.1 ou 10 µg/jour), la puberté est plus précoce chez les femelles exposées mais toutes sont fertiles, au moins transitoirement. Cependant le traitement induit une dégradation rapide des capacités reproductives. L'E2 modifie la dynamique folliculaire chez l'adulte, longtemps après l'arrêt du traitement. Si une forte dose d'E2 réduit la survie des ovocytes lors de la formation des follicules et conduit à une infertilité secondaire due à un dysfonctionnement général du tractus reproducteur, une dose faible n'affecte pas la survie des ovocytes à court terme mais conduit à une sénescence reproductive précoce vraisemblablement d'origine ovarienne. L'origine de ces troubles pourrait résider dans les effets précoces de l'exposition à E2 : cette molécule altère le transcriptome ovarien et induit de nombreuses lésions de l'ADN des cellules ovariennes.
https://tel.archives-ouvertes.fr/tel-00953657

NNT : 2013REN1S107
tel-00953657
https://tel.archives-ouvertes.fr/tel-00953657
https://tel.archives-ouvertes.fr/tel-00953657/document
https://tel.archives-ouvertes.fr/tel-00953657/file/CHALMEY_Clementine.pdf

Éditeur(s) : HAL CCSD Springer Verlag
Résumé : International audience
Chlordecone (Kepone) is an organochlorine insecticide that has been used as insecticide and fungicide. In the French West Indies, Guadeloupe and Martinique, it was intensively applied to banana fields from 1973 to 1993 to control root borers. This pesticide undergoes no significant biotic or abiotic degradation in the environment and is still present in soils where it was applied. It was only in 1999 that health and environmental authorities became aware of the extent of the chlordecone pollution of environmental media, including soils, waterways, and the food chain. Earlier observations and toxicological studies have demonstrated that chlordecone is a reproductive and developmental toxicant, neurotoxic and carcinogenic in rodents, and is an endocrine-disrupting chemical because of its estrogenic properties both in vitro and in vivo. Several surveys have confirmed that the French West Indian population continues to be exposed to this chemical though consumption of contaminated foodstuffs. Here, we report the findings of various epidemiological studies conducted in the French West Indies to assess the impact of environmental exposure to chlordecone on the health of the population.
ISSN: 0944-1344

hal-01150382
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01150382
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01150382/document
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01150382/file/Chlordecone%20exposure%20and%20adverse%20effects%20in%20French%20West.pdf
DOI : 10.1007/s11356-015-4621-5

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
From 15 to 17 June 2011, a dedicated workshop was held on the subject of in vitro models for mammalian spermatogenesis and their applications in toxicological hazard and risk assessment. The workshop was sponsored by the Dutch ASAT initiative (Assuring Safety without Animal Testing), which aims at promoting innovative approaches toward toxicological hazard and risk assessment on the basis of human and in vitro data, and replacement of animal studies. Participants addressed the state of the art regarding human and animal evidence for compound mediated testicular toxicity, reviewed existing alternative assay models, and brainstormed about future approaches, specifically considering tissue engineering. The workshop recognized the specific complexity of testicular function exemplified by dedicated cell types with distinct functionalities, as well as different cell compartments in terms of microenvironment and extracellular matrix components. This complexity hampers quick results in the realm of alternative models. Nevertheless, progress has been achieved in recent years, and innovative approaches in tissue engineering may open new avenues for mimicking testicular function in vitro. Although feasible, significant investment is deemed essential to be able to bring new ideas into practice in the laboratory. For the advancement of in vitro testicular toxicity testing, one of the most sensitive end points in regulatory reproductive toxicity testing, such an investment is highly desirable.
ISSN: 0890-6238

hal-00876979
https://hal.archives-ouvertes.fr/hal-00876979
DOI : 10.1016/j.reprotox.2013.04.004
PUBMED : 23612449

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
Semi-Volatile Organic Compounds (SVOCs) are commonly present in dwellings and several are suspected of having effects on male reproductive function mediated by an endocrine disruption mode of action. To improve knowledge of the health impact of these compounds, cumulative toxicity indicators are needed. This work derives Benchmark Doses (BMD) and Relative Potency Factors (RPF) for SVOCs acting on the male reproductive system through the same mode of action. We included SVOCs fulfilling the following conditions: detection frequency (>10%) in French dwellings, availability of data on the mechanism/mode of action for male reproductive toxicity, and availability of comparable dose-response relationships. Of 58 SVOCs selected, 18 induce a decrease in serum testosterone levels. Six have sufficient and comparable data to derive BMDs based on 10 or 50% of the response. The SVOCs inducing the largest decrease in serum testosterone concentration are: for 10%, bisphenol A (BMD10= 7.72E-07 mg/kg bw/d; RPF10= 7033679); for 50%, benzo[a]pyrene (BMD50= 0.030 mg/kg bw/d; RPF50= 1630), and the one inducing the smallest one is benzyl butyl phthalate (RPF10 and RPF50= 0.095). This approach encompasses contaminants from diverse chemical families acting through similar modes of action, and makes possible a cumulative risk assessment in indoor environments. The main limitation remains the lack of comparable toxicological data.
ISSN: 0273-2300

hal-01237085
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01237085
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01237085/document
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01237085/file/Multiple%20exposures%20to%20indoor%20contaminants_accepted.pdf
DOI : 10.1016/j.yrtph.2015.11.017

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
The effects of some progestins on fish reproduction have been recently reported revealing the hazard of this class of steroidal pharmaceuticals. However, their effects at the central nervous system level have been poorly studied until now. Notwithstanding, progesterone, although still widely considered primarily a sex hormone, is an important agent affecting many central nervous system functions. Herein, we investigated the effects of a large set of synthetic ligands of the nuclear progesterone receptor on the glial-specific expression of the zebrafish brain aromatase (cyp19a1b) using zebrafish mechanism-based assays. Progesterone and 24 progestins were first screened on transgenic cyp19a1b-GFP zebrafish embryos. We showed that progesterone, dydrogesterone, drospirenone and all the progesterone-derived progestins had no effect on GFP expression. Conversely, all progestins derived from 19-nortesterone induced GFP in a concentration-dependent manner with EC50 ranging from the low nM range to hundreds nM. The 19-nortestosterone derived progestins levonorgestrel (LNG) and norethindrone (NET) were further tested in a radial glial cell context using U251-MG cells co-transfected with zebrafish ER subtypes (zfER alpha, zfER beta 1 or zfER beta 2) and cyp19a1b promoter linked to luciferase. Progesterone had no effect on luciferase activity while NET and LNG induced luciferase activity that was blocked by ICI 182,780. Zebrafish-ERs competition assays showed that NET and LNG were unable to bind to ERs, suggesting that the effects of these compounds on cyp19a1b require metabolic activation prior to elicit estrogenic activity. Overall, we demonstrate that 19-nortestosterone derived progestins elicit estrogenic activity by inducing cyp19a1b expression in radial glial cells. Given the crucial role of radial glial cells and neuro-estrogens in early development of brain, the consequences of exposure of fish to these compounds require further investigation.
ISSN: 0041-008X

hal-01366373
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01366373
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01366373/document
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01366373/file/Several%20synthetic%20progestins%20disrupt%20the%20glial%20cell.pdf
DOI : 10.1016/j.taap.2016.05.019

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
Endocrine disrupting chemicals and especially oestrogen receptor (ER) agonists have been extensively studied over the years due to their potential effects on sexual development and reproduction in vertebrates, notably fish. As ER agonists can exist as complex mixtures in the aquatic environment, evaluating the impact of combined exposure on oestrogenic effects has become increasingly important. Use of predictive models such as concentration addition (CA) and independent action (IA) has allowed assessment of combined estrogenic effects of complex multi-compound mixtures of ER agonists in various fish in vitro and in vivo experimental models. The present work makes use of a transgenic zebrafish strain, tg(cyp19a1b-GFP), which expresses the green fluorescent protein (GFP) under the control of the cyp19a1b (brain aromatase or aromatase B) gene to determine the oestrogenic potency of ER agonists alone or in mixtures. In these studies, tg(cyp19a1b-GFP) zebrafish embryos were exposed for four days (from one to five days post fertilization) to five different oestrogenic chemicals; 17α-ethinylestradiol (EE2), 17β-estradiol (E2), estrone (E1), bisphenol A (BPA) and 4-tert-octylphenol (OP), and three mixtures of up to four of these compounds. The mixture of BPA, OP and E2 was also tested with primary cultures of rainbow trout hepatocytes by analysing the ER-mediated induction of the oestrogenic biomarker vitellogenin in order to compare the performance of the two methods for assessing oestrogenic effects of complex mixtures. The three tested mixtures were predominantly acting in an additive manner on the expression of GFP. Additivity was indicated by the overlap of the 95% confidence interval of the concentration response curves for the observed data with the CA and IA prediction models, and model deviation ratios within a factor of two for a majority of the mixture concentrations. However, minor deviations determined as more than additive effects for the mixture of EE2, E1 and E2 and less than additive effects for the mixture of BPA, OP, EE2 and E1 were observed at the higher mixture concentrations tested. The successful prediction of additivity by CA and IA in tg(cyp19a1b-GFP) zebrafish embryos and deviations at high mixture concentrations seemed to correspond well to results obtained in the rainbow trout hepatocyte assay. The present results clearly show the usefulness of combining predictive modelling and use of in vitro bioassays for rapid screening of oestrogenic effects of complex mixtures and environmental samples.
ISSN: 0166-445X

hal-00877351
https://hal.archives-ouvertes.fr/hal-00877351
DOI : 10.1016/j.aquatox.2013.05.001
PUBMED : 23721851

Éditeur(s) : HAL CCSD Elsevier Elsevier Masson
Résumé : International audience
Prostate cancer is the most frequent cancer affecting men in most Western countries. Certain risk factors have been identified (age, family history, ethnic origin), but the aetiology of this cancer remains largely unknown. However, a role for environmental factors is strongly suspected. Questions have been raised concerning the role of the chemical substances generated by human activities in the occurrence of this disease. Diverse studies have consistently demonstrated a higher risk of prostate cancer in agricultural populations than in the general population. The hypothesis that this higher risk is linked to the use of pesticides has been tested in a number of studies, mostly in North America and Europe. However, to date, with a few possible exceptions, it has been impossible to demonstrate a significant association between exposure to pesticides or a chemical family of pesticides and prostate cancer. Studies have also been carried out on the role of exposure to trace metals, such as cadmium, or to pollutants from industry, such as polychlorobiphenyls. However, no firm conclusions have been drawn. Finally, the effect of chemical substances with endocrine disruptor activity on the occurrence of prostate cancer remains largely unexplored in epidemiological studies. In the face of these uncertainties, rigorous studies are required, with objective measurements of exposure, taking into account confounding factors and individual risk factors, making it possible to assess gene-environment interactions.
ISSN: 1297-9589

inserm-00524579
http://www.hal.inserm.fr/inserm-00524579
DOI : 10.1016/j.gyobfe.2008.07.005
PUBMED : 18693059