In vitro human metabolism of permethrin isomers alone or as a mixture and the formation of the major metabolites in cryopreserved primary hepatocytes

Willemin, Marie-Émilie; Sousa, Georges de; Leclerc, Éric; Rahmani, Raphaël; Brochot, Céline

doi:10.1016/j.tiv.2015.03.003

Cited by 18 publications

(10 citation statements)

References 48 publications

(66 reference statements)

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“…However, this hypothesis needs to be evaluated by a proper interaction study in rats, at various ratios. Recently, a similar study was performed on human hepatocytes and highlighted that the interaction was negligible at the ratio 50:50 of isomers but became substantial (50% of interaction) at a ratio 10 times higher (Willemin et al, 2015).…”

Section: Accepted Manuscriptmentioning

confidence: 87%

“…A generic structure of PBPK model for pyrethroids sharing a similar structure as permethrin seems to appear, which includes the description of the kinetic of the insecticide in fat and the sensitive organs like brain and testes. Then, the extended PBPK model developed in this study can be extrapolated to humans for the quantification of the internal exposure, especially in sensitive populations like children, by including data in humans like the recent in vitro results on Caco-2 cells informing on the rate of oral absorption (Zastre et al, 2013), or on microsomes and hepatocytes quantifying the hepatic metabolism (Scollon et al, 2009;Willemin et al, 2015). With the description of the kinetic of the biomarkers of exposure under the chemical form measured in biomonitoring A C C E P T E D M A N U S C R I P T…”

Section: Accepted Manuscriptmentioning

confidence: 99%

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PBPK modeling of the cis- and trans-permethrin isomers and their major urinary metabolites in rats

Willemin

Desmots

Grand

et al. 2016

Toxicology and Applied Pharmacology

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Permethrin, a pyrethroid insecticide, is suspected to induce neuronal and hormonal disturbances in humans. The widespread exposure of the populations has been confirmed by the detection of the urinary metabolites of permethrin in biomonitoring studies. Permethrin is a chiral molecule presenting two forms, the cis and the trans isomers. Because in vitro studies indicated a metabolic interaction between the trans and cis isomers of permethrin, we adapted and calibrated a PBPK model for trans- and cis-permethrin separately in rats. The model also describes the toxicokinetics of three urinary metabolites, cis- and trans-3-(2,2 dichlorovinyl)-2,2-dimethyl-(1-cyclopropane) carboxylic acid (cis- and trans-DCCA), 3-phenoxybenzoic acid (3-PBA) and 4'OH-phenoxybenzoic acid (4'-OH-PBA). In vivo experiments performed in Sprague-Dawley rats were used to calibrate the PBPK model in a Bayesian framework. The model captured well the toxicokinetics of permethrin isomers and their metabolites including the rapid absorption, the accumulation in fat, the extensive metabolism of the parent compounds, and the rapid elimination of metabolites in urine. Average hepatic clearances in rats were estimated to be 2.4 and 5.7 L/h/kg for cis- and trans-permethrin, respectively. High concentrations of the metabolite 4'-OH-PBA were measured in urine compared to cis- and trans-DCCA and 3-PBA. The confidence in the extended PBPK model was then confirmed by good predictions of published experimental data obtained using the isomers mixture. The extended PBPK model could be extrapolated to humans to predict the internal dose of exposure to permethrin from biomonitoring data in urine.

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Section: Accepted Manuscriptmentioning

confidence: 87%

Section: Accepted Manuscriptmentioning

confidence: 99%

PBPK modeling of the cis- and trans-permethrin isomers and their major urinary metabolites in rats

Willemin

Desmots

Grand

et al. 2016

Toxicology and Applied Pharmacology

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“…The concentrations of DDT (Sigma‐Aldrich) and PMT (Supelco Analytical/Sigma‐Aldrich, Saint‐Quentin Fallavier, France) were designed according to the literature data (Leibold & Schwarz, ; Willemin et al, ; Zucchini‐Pascal, Peyre, de Sousa, & Rahmani, ) and rat PBPK mathematical models extracting blood and liver concentrations from in vivo assays in which rat were feed with PMT corn oil (Willemin et al, ). In this work, DDT and PMT were supplied at 15 and 150 μ m .…”

Section: Methodsmentioning

confidence: 99%

“…Endocrine disruptor properties have been reported in vitro and in vivo suggesting that PMT has potential estrogen‐like effects on rodents (Chargui, Haouas, Zaouali, & Ben Cheikh, ; Jin, Wang, Xu, Fu, & Liu, ; Tu et al, ). In liver, the metabolism of PMT involves cytochrome P450 and carboxylesterase families (Willemin et al, ). Previous works have demonstrated that PMT exposure causes severe alterations and cell death by apoptosis in liver and increases hepatic oxidative stress and liver weights (Das et al, ; Kostka, Palut, Kopec‐Szlezak, & Ludwicki, ).…”

Section: Introductionmentioning

confidence: 99%

Metabolomics‐on‐a‐chip approach to study hepatotoxicity of DDT, permethrin and their mixtures

Jellali

Gilard

Pandolfi

et al. 2018

J of Applied Toxicology

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Despite the diversity of studies on pesticide toxicities, there is a serious lack of information concerning the toxic effect of pesticides mixtures. Dichlorodiphenyl-trichloroethane (DDT) and permethrin (PMT) are among the most prevalent pesticides in the environment and have been the subject of several toxicological studies. However, there are no data on the toxicity of their mixtures. In this study, we used an approach combining cell culture in microfluidic biochips with gas chromatography-mass spectrometry metabolomics profiling to investigate the biomarkers of toxicity of DDT, PMT and their mixtures. All parameters observed indicated that no significant effect was observed in hepatocytes cultures exposed to low doses (15 μm) of DDT and PMT. Conversely, combined low doses induce moderate oxidative stress and cell death. The toxic signature of high doses of pesticides (150 μm) was illustrated by severe oxidative stress and cell mortality. Metabolomics profiling revealed that hepatocytes exposure to DDT150, PMT150 and DDT150 and PMT150 cause important modulation in intermediates of glutathione pathway and tricarboxylic acid cycle, amino acids and metabolites associated to hepatic necrosis and inflammation (α-ketoglutarate, arginine and 2-hydroxybutyrate). These changes were more striking in the combined group. Finally, DDT150 led to a significant increase of benzoate, decanoate, octanoate, palmitate, stearate and tetradecanoate, which illustrates the estrogen modulation. This study demonstrates the potential of metabolomics-on-a-chip approach to improve knowledge on the mode of action of pesticides.

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“…The p-pDDT and PMT were supplied at 15 or 150 µM. These concentrations were selected based on literature data of LD50 or IC50 (Willemin et al, 2015;Leibold and Schartz 1993;Zucchini Pascal et al, 2012;Ramos-Chavez et al, 2015) and rat PBPK mathematical models extracting blood and liver concentrations from in vivo assays in which rat were feed with PMT corn oil (Willemin et al, 2014). In these studies, we found values ranging between 2.5 and 125 M. Stock solutions were 50 mM in DMSO, leading to working solution with a DMSO highest concentration of 0.3%.…”

Section: Exposure To Pesticidesmentioning

confidence: 99%

Effects of DDT and permethrin on rat hepatocytes cultivated in microfluidic biochips: Metabolomics and gene expression study

Jellali

Zeller

Gilard

et al. 2018

Environmental Toxicology and Pharmacology

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Dichlorodiphenyl-trichloroethane (DDT) and permethrin (PMT) are amongst most prevalent pesticides in the environment. Although their toxicity has been extensively studied, molecular mechanisms and metabolic effects remain unclear, including in liver where their detoxification occurs. Here, we used metabolomics, coupled to RT-qPCR analysis, to examine effects of DDT and PMT on hepatocytes cultivated in biochips. At 150 μM, DDT caused cell death, cytochrome P450 induction and modulation of estrogen metabolism. Metabolomics analysis showed an increase in some lipids and sugars after 6 h, and a decrease in fatty acids (tetradecanoate, octanoate and linoleate) after 24 h exposure. We also found a change in expression associated with genes involved in hepatic estrogen, lipid, and sugar metabolism. PMT at 150 μM perturbed lipid/sugar homeostasis and estrogen signaling pathway, between 2 and 6 h. After 24 h, lipids and sugars were found to decrease, suggesting continuous energy demand to detoxify PMT. Finally, at 15 μM, DDT and PMT appeared to have a small effect on metabolism and were detoxified after 24 h. Our results show a time-dependent perturbation of sugar/lipid homeostasis by DDT and PMT at 150 μM. Furthermore, DDT at high dose led to cell death, inflammatory response and oxidative stress.

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In vitro human metabolism of permethrin isomers alone or as a mixture and the formation of the major metabolites in cryopreserved primary hepatocytes

Cited by 18 publications

References 48 publications

PBPK modeling of the cis- and trans-permethrin isomers and their major urinary metabolites in rats

PBPK modeling of the cis- and trans-permethrin isomers and their major urinary metabolites in rats

Metabolomics‐on‐a‐chip approach to study hepatotoxicity of DDT, permethrin and their mixtures

Effects of DDT and permethrin on rat hepatocytes cultivated in microfluidic biochips: Metabolomics and gene expression study

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