In vivo characterisation of the toxicological properties of DPhP, one of the main degradation product of aryl phosphate esters.

Ruby, S.; Marin-Saez, J.; Fildier, A.; Bulete, A.; Abdallah, M.; Garcia, J.; Deverchere, J.; Spinner, L.; Giroud, B.; Ibanez, S.; Granjon, T.; Bardel-Danjean, C.; Fervers, B.; Puisieux, A.; Vulliet, E.; Payen-Gay, L.; Vigneron, A. M.

doi:10.1101/2019.12.26.888057

bioRxiv · 10.1101/2019.12.26.888057

In vivo characterisation of the toxicological properties of DPhP, one of the main degradation product of aryl phosphate esters.

Ruby, S.·Marin-Saez, J.·Fildier, A.·Bulete, A.·Abdallah, M.·Garcia, J.·Deverchere, J.·Spinner, L.·Giroud, B.·Ibanez, S.·Granjon, T.·Bardel-Danjean, C.·Fervers, B.·Puisieux, A.·Vulliet, E.·Payen-Gay, L.·Vigneron, A. M.

View original source ↗Export metadata ↓

Abstract

BackgroundAryl phosphate esters (APEs), a main class of organophosphorus ester molecules, are widely used and commonly present in the environment. Health hazards associated with these compounds remain largely unknown and the effects of diphenyl phosphate (DPhP), one of their most frequent derivatives in human samples, are poorly characterised. ObjectiveOur aim was to investigate whether DPhP per se may represent a more relevant marker of exposure to APEs and determine its potential deleterious biological effects in chronically exposed mice. MethodsConventional animals (FVB mice) were acutely (intravenous or oral gavage) or chronically (0.1 mg.mL-1, 1 mg.mL-1, 10 mg.mL-1 in drink water) exposed to relevant doses of DPhP or triphenyl phosphate (TPhP), one of its main precursors in the environment. Both molecules were measured in blood and other relevant tissues by liquid chromatography-mass spectrometry (LC-MS). Biological effects of chronic DPhP exposure were addressed through liver multi-omics analysis combining mRNA extraction and sequencing to high resolution LC-MS to determine the corresponding metabolic profile. Deep statistical exploration was performed to extract correlated information, guiding further physiological analyses (immunohistochemistry (IHC) and animal growth measurement). ResultsAcute and chronic exposure to DPhP led to significant levels of this molecule in blood and other tissues, an effect missing with TPhP. Multi-omics analysis confirmed the existence of biological effects of DPhP, even at a very low dose of 0.1 mg.mL-1 in drinking water. Chemical structural homology and pathway mapping demonstrated a clear reduction of the fatty-acid catabolic processes centred on acylcarnitine and mitochondrial {beta}-oxidation. Interestingly, mRNA expression confirmed and extended these observations by demonstrating at all tested doses the overall repression of genes involved in lipid catabolic processes and regulated by PPAR, a master regulator of {beta}-oxidation and its associated ketogenesis. IHC analysis confirmed the alteration of these pathways by showing a specific downregulation of Hmgcs2, a kernel target gene of PPAR, at all doses tested, and surprisingly, a strong reduction of the lipid droplet content only at the highest dose. Overall, DPhP absorption led to weight loss, which was significant using the highest dose. ConclusionsOur results suggest that in mice, the effects of chronic exposure to DPhP, even at a low dose, are not negligible. Fatty acid metabolism in the liver in particular is essential for controlling fast and feast periods with adverse consequences on the overall physiology. Therefore, the impact of DPhP on circulating fat, cardiovascular and metabolic disease incidence deserves, in light of our results, further investigations.

Explore related subjects

pharmacology and toxicology Preprint

Keep this discovery

Explore connections, maps & timelines

BibTeX RIS

Ruby, S., Marin-Saez, J., Fildier, A., Bulete, A., Abdallah, M., Garcia, J., Deverchere, J., Spinner, L., Giroud, B., Ibanez, S., Granjon, T., Bardel-Danjean, C., Fervers, B., Puisieux, A., Vulliet, E., Payen-Gay, L., Vigneron, A. M.. 2019-12-27. In vivo characterisation of the toxicological properties of DPhP, one of the main degradation product of aryl phosphate esters.. https://doi.org/10.1101/2019.12.26.888057

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Lipid-ASO therapeutics exhibit differential tissue targeted delivery upon systemic or local CNS administration

Antisense oligonucleotides (ASOs) are a powerful therapeutic modality, but their full potential is hindered by pharmacokinetic properties that affect tissue and cellular delivery. Lipid conjugation is increasingly used to modulate ASO's biodistribution and promote extrahepatic activity, yet lipid dependent effects on in vivo functional delivery, particularly in the central nervous system (CNS), remain less explored. Here, we performed a side by side in vivo comparison of cholesterol, palmitic acid (C16:0), docosanoic acid (C22:0), and eicosapentaenoic acid (C20:5) conjugated to a fully phosphorothioated 3 10 3 LNA gapmer ASO targeting the Malat1 long non coding RNA. Lipid-ASO conjugates were administered systemically or locally in the brain of mice and evaluated for tissue level and cellular level distribution by imaging, qPCR and single-cell RNA sequencing, simultaneously annotating cell origin and global transcriptional changes within the cell. Following systemic administration in mice, lipid conjugation improved overall multi organ efficacy compared to unconjugated ASO, but with pronounced tissue specific differences. Single cell sequencing of liver and heart transcriptomes revealed lipid dependent cellular uptake patterns and transcriptional responses distinct from administration of unconjugated ASO. After intracerebroventricular administration, selected fatty acid conjugates enhanced silencing in deep brain regions such as the striatum, whereas cholesterol conjugation impaired functional delivery despite increased CNS retention. Light-sheet microscopy showed restricted parenchymal penetration of cholesterol ASOs compared with broader but heterogeneous distribution of palmitic acid conjugate. Together, these findings demonstrate that lipid identity critically determines ASO efficacy, productive cellular uptake, and regional CNS engagement, emphasizing the need for context specific lipid design in ASO therapeutic development.

pharmacology and toxicology↗

bioRxiv2026

Novel Dissymmetric Ionizable Lipid-Assembled Lipid Nanoparticles for Delivery of Ferroptosis-Related siRNA in Diabetic Treatment

Small interfering RNA (siRNA) enables precise post-transcriptional gene silencing for refractory diseases, yet its clinical translation remains limited by the lack of safe and efficient delivery vectors. Inspired by the dissymmetric alkyl chain architecture of natural membrane phospholipids, we designed and synthesized 34 novel ionizable lipids with dissymmetric hydrophobic tails and formulated them into lipid nanoparticles (LNPs). Through systematic physicochemical and biological assessments, we established clear structure-activity relationships and identified two lead LNPs (O14-LNP, H18a-LNP) with superior endosomal escape capacity, enhanced in vivo gene silencing potency, and favorable biosafety relative to the clinical benchmark MC3-LNP. In both streptozotocin-induced and spontaneous db/db type 2 diabetes (T2D) mouse models, lead LNPs delivering ferroptosis-related siRNAs effectively ameliorated glucose and lipid metabolic disorders, restored islet function, and alleviated hepatic steatosis. This study not only lays a theoretical foundation for the rational design of novel ionizable lipids, but also validates the therapeutic potential of siRNA therapy targeting ferroptosis, providing a versatile delivery platform and targeted therapeutic strategy for the treatment of T2D.

pharmacology and toxicology↗

bioRxiv2020

Elucidating Direct Kinase Targets of Compound Danshen Dropping Pills Employing Archived Data and Prediction Models

The research on the direct target of traditional Chinese medicine (TCM) is the key to study the mechanism and material basis of TCM, but there is still no effective technical methods at present. For Compound Danshen dropping pills (CDDP), there is no report about its direct targets. In this study, the direct targets of CDDP were studied for the first time, especially focusing on the protein kinase family, which plays causal roles in a variety of human disease. Firstly, the literature database of CDDP was constructed by literature retrieval, and the important components contained in CDDP were extracted. Secondly, the potential direct targets of important components was obtained through querying public database and predicted by Multi-voting SEA algorithm. Then, the KinomeX system was used to predict and to filter the potential kinase targets of CDDP. Finally, the experimental verification was carried out. In total, 30 active kinase targets was obtained at 25 g/ml concentration of CDDP, and 9 dose-dependent targets were obtained at 250 g/ml concentration of CDDP. This is an efficient and accurate strategy by integrating the targets recorded in several public databases and the targets calculated by two in silico modelling approaches predict potential direct targets of TCM, which can lay an important foundation for the study of the mechanism and material basis of them, promoting the modernization of TCM.

pharmacology and toxicology↗