Éditeur(s) : HAL CCSD Wiley
Résumé : International audience
The easy-to-use in vivo model, zebrafish larva, is being increasingly used to screen chemical-induced hepatotoxicity, with a good predictivity for various mechanisms of liver injury. However, nothing is known about its applicability in exploring the mechanism called membrane remodeling, depicted as changes in membrane fluidity or lipid raft properties. The aim of this study was, therefore, to substantiate the zebrafish larva as a suitable in vivo model in this context. Ethanol was chosen as a prototype toxicant because it is largely described, both in hepatocyte cultures and in rodents, as capable of inducing a membrane remodeling leading to hepatocyte death and liver injury. The zebrafish larva model was demonstrated to be fully relevant as membrane remodeling was maintained even after a 1-week exposure without any adaptation as usually reported in rodents and hepatocyte cultures. It was also proven to exhibit a high sensitivity as it discriminated various levels of cytotoxicity depending on the extent of changes in membrane remodeling. In this context, its sensitivity appeared higher than that of WIF-B9 hepatic cells, which is suited for analyzing this kind of hepatotoxicity. Finally, the protection afforded by a membrane stabilizer, ursodeoxycholic acid (UDCA), or by a lipid raft disrupter, pravastatin, definitely validated zebrafish larva as a reliable model to quickly assess membrane remodeling involvement in chemical-induced hepatotoxicity. In conclusion, this model, compatible with a high throughput screening, might be adapted to seek hepatotoxicants via membrane remodeling, and also drugs targeting membrane features to propose new preventive or therapeutic strategies in chemical-induced liver diseases.
ISSN: 0260-437X

hal-01526425
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01526425
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01526425/document
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01526425/file/Zebrafish%20larva%20as%20a%20reliable%20model-Podechard%20JAT%202016%20revised.pdf
DOI : 10.1002/jat.3421

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
Chronic liver damage due to viral or chemical agents leads to a repair process resulting in hepatic fibrosis. Fibrosis may lead to cirrhosis, which may progress to liver cancer or a loss of liver function, with an associated risk of liver failure and death. Chlordecone is a chlorinated pesticide used in the 1990s. It is not itself hepatotoxic, but its metabolism in the liver triggers hepatomegaly and potentiates hepatotoxic agents. Chlordecone is now banned, but it persists in soil and water, resulting in an ongoing public health problem in the Caribbean area. We assessed the probable impact of chlordecone on the progression of liver fibrosis in the population of contaminated areas, by developing a mouse model of chronic co-exposure to chlordecone and a hepatotoxic agent, carbon tetrachloride (CCl4). After repeated administrations of chlordecone and CCl4 by gavage over a 12-week period, we checked for liver damage in the exposed mice, by determining serum liver transaminase (AST, ALT) levels, histological examinations of the liver and measuring the expression of genes encoding extracellular matrix components. The co-exposure of mice to CCl4 and chlordecone resulted in significant increases in ALT and AST levels. Chlordecone also increased expression of the Col1A2, MMP-2, TIMP-1 and PAI-1 genes in CCl4-treated mice. Finally, we demonstrated, by quantifying areas of collagen deposition and alpha-SMA gene expression, that chlordecone potentiated the hepatic fibrosis induced by CCl4. In conclusion, our data suggest that chlordecone potentiates hepatic fibrosis in mice with CCl4-induced chronic liver injury
ISSN: 0378-4274

hal-01274228
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01274228
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01274228/document
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01274228/file/Chlordecone%20potentiates%20hepatic%20fibrosis%20%281%29.pdf
DOI : 10.1016/j.toxlet.2016.02.005

Éditeur(s) : HAL CCSD American Chemical Society
Résumé : International audience
Chlordecone is an organochlorine pesticide that was extensively used in the French West Indies to fight weevils in banana plantations from 1973 to 1993. This has led to a persistent pollution of the environment and to the contamination of the local population for several decades with effects demonstrated on human health. Chlordecone accumulates mainly in the liver where it is known to potentiate the action of hepatotoxic agents. However, there is currently no information on its in situ localization in the liver. We have thus evaluated a matrix-assisted laser desorption ionization (MALDI) imaging quantification method based on labeled normalization for the in situ localization and quantification of chlordecone. After validating the linearity and the reproducibility of this method, quantitative MALDI imaging was used to study the accumulation of chlordecone in the mouse liver. Our results revealed that normalized intensities measured by MALDI imaging could be first converted in quantitative units. These quantities appeared to be different from absolute quantities of chlordecone determined by gas chromatography (GC), but they were perfectly correlated (R(2) = 0.995). The equation of the corresponding correlation curve was thus efficiently used to convert quantities measured by MALDI imaging into absolute quantities. Our method combining labeled normalization and calibration with an orthogonal technique allowed the in situ absolute quantification of chlordecone by MALDI imaging. Finally, our results obtained on the pathological mouse liver illustrate the advantages of quantitative MALDI imaging which preserves information on in situ localization without radioactive labeling and with a simple sample preparation.
ISSN: 0003-2700

hal-01118103
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01118103
PUBMED : 24837422
DOI : 10.1021/ac500313s