Biology subjects

Mesmar, F.

Publications and source records attributed to Mesmar, F..

3 recordsLinked to original sources

bioRxiv2024

Exposure to the pesticide tefluthrin causes developmental neurotoxicity in zebrafish

BACKGROUNDThe insecticide tefluthrin is widely used in agriculture, resulting in widespread pollution. Tefluthrin is a type I pyrethroid characterized by its high persistence in the environment. Understanding the mechanisms of toxicity of tefluthrin will improve its risk assessment. OBJECTIVESWe aimed to decipher the molecular modes of action of tefluthrin. METHODSPhenotypic developmental toxicity was assessed by exposing zebrafish embryos and larvae to increasing concentrations of tefluthrin. Tg(mnx:mGFP) line was used to assess neurotoxicity. Multi-omics approaches including transcriptomics and lipidomics were applied to analyze RNA and lipid contents, respectively. Finally, an in-silico ligand-protein docking computational method was used to study a possible interaction between tefluthrin and a protein target. RESULTSTefluthrin exposure caused severe morphological malformations in zebrafish larvae, including motor neuron abnormalities. The differentially expressed genes were associated with neurotoxicity and metabolic disruption. Lipidomics analysis revealed a disruption in fatty acid, phospholipid, and lysophospholipid recycling. Protein docking modeling suggested that the LPCAT3 enzyme, which recycles lysophospholipids in the Lands cycle, directly interacts with tefluthrin. CONCLUSIONSTefluthrin exposure causes morphological and neuronal malformations in zebrafish larvae at nanomolar concentrations. Multi-omics results revealed a potential molecular initiating event i.e., inhibition of LPCAT3, and key events i.e., an altered lysophospholipid to phospholipid ratio, leading to the adverse outcomes of neurotoxicity and metabolic disruption.

pharmacology and toxicology↗

bioRxiv2023

The herbicide acetochlor causes lipid peroxidation by inhibition of glutathione peroxidase 4

Obesity is increasing worldwide, particularly in rural communities, where people are likely exposed to high levels of pesticides. We here investigated whether six commonly used agricultural pesticides on corn and soy fields have adipogenic activity and act as obesogens. Exposure to two pesticides, the herbicides acetochlor and metolachlor, induced adipogenesis in vitro in mouse 3T3-L1 preadipocytes. The most potent compound, acetochlor, was selected for further studies in zebrafish. Acetochlor exposure caused morphological malformations and lethality in zebrafish larvae with an EC50 of 7.8 {micro}M and an LC50 of 12 {micro}M. Acetochlor exposure also resulted in lipid accumulation is zebrafish larvae when simultaneously fed a high cholesterol diet. To decipher the molecular mechanisms behind acetochlor action, we preformed transcriptomic and targeted lipidomic analysis of exposed animals. The combined omics results suggested that acetochlor exposure increased Nrf2 activity in response to reactive oxygen species, as well as induced lipid peroxidation and ferroptosis. We further discovered that acetochlor structurally shares a chloroacetamide group with known inhibitors of glutathione peroxidase 4 (GPX4). Computational docking analysis suggested that acetochlor covalently binds to the active site of GPX4. Consequently, Gpx4 activity was efficiently repressed by acetochlor, and lipid peroxidation was increased in zebrafish. We propose that acetochlor disrupts lipid homeostasis by inhibiting Gpx4, resulting in accumulation of lipid peroxidation, 4-hydroxynonenal, and reactive oxygen species in the cells, which in turn activate Nrf2. Because metolachlor, among other acetanilide herbicides, also contain the chloroacetamide group, inhibition of Gpx4 activity may represent a novel, common molecular initiating event of obesogens. SynopsisRural populations have a high prevalence of metabolic disease and are highly exposed to pesticides. This study reports that the herbicide acetochlor, heavily used on soy and corn fields, inhibits an enzyme that protects from oxidation of lipids in the cell membrane, oxidative stress and a type of cell death called ferroptosis, features that are linked to metabolic disruption and obesity.

pharmacology and toxicology↗

bioRxiv2020

Deubiquitinase UCHL1 Maintains Protein Homeostasis through PSMA7-APEH-Proteasome Axis in High-Grade Serous Ovarian Carcinoma

High-grade serous ovarian cancer (HGSOC) is characterized by chromosomal instability, DNA damage, oxidative stress, and high metabolic demand, which exacerbate misfolded, unfolded and damaged protein burden resulting in increased proteotoxicity. However, the underlying mechanisms that maintain protein homeostasis to promote HGSOC growth remain poorly understood. In this study, we report that the neuronal deubiquitinating enzyme, ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) is overexpressed in HGSOC and maintains protein homeostasis. UCHL1 expression was markedly increased in HGSOC patient tumors and serous tubal intraepithelial carcinoma (HGSOC precursor lesions). High UCHL1 levels correlated with higher tumor grade and poor patient survival. UCHL1 inhibition reduced HGSOC cell proliferation and invasion through the outer layers of omentum as well as significantly decreased the in vivo metastatic tumor growth in ovarian cancer xenografts. Transcriptional profiling of UCHL1 silenced HGSOC cells revealed the down-regulation of genes implicated with proteasome activity along with the upregulation of endoplasmic reticulum (ER) stress-induced genes. Reduced expression of proteasome subunit alpha 7 (PSMA7) and acylaminoacyl peptide hydrolase (APEH) resulted in a significant decrease in proteasome activity, impaired protein degradation, and abrogated HGSOC growth. Furthermore, the accumulation of polyubiquitinated proteins in the UCHL1 silenced cells led to attenuation of mTORC1 activity and protein synthesis, and induction of terminal unfolded protein response. Collectively, these results indicate that UCHL1 promotes HGSOC growth by mediating protein homeostasis through the PSMA7-APEH-proteasome axis. O_FIG O_LINKSMALLFIG WIDTH=183 HEIGHT=200 SRC="FIGDIR/small/316810v2_ufig1.gif" ALT="Figure 1"> View larger version (71K): org.highwire.dtl.DTLVardef@d38d5borg.highwire.dtl.DTLVardef@e58513org.highwire.dtl.DTLVardef@83e274org.highwire.dtl.DTLVardef@884ec3_HPS_FORMAT_FIGEXP M_FIG C_FIG ImplicationsThis study identifies the novel links in the proteostasis network to target protein homeostasis in HGSOC. It recognizes the potential of inhibiting UCHL1 and APEH to sensitize cancer cells to proteotoxic stress and as novel alternative therapeutic approaches.

cancer biology↗