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1.
J Hazard Mater ; 474: 134721, 2024 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-38843629

RESUMO

The new challenges in toxicology demand novel and innovative in vitro approaches for deriving points of departure (PODs) and determining the mode of action (MOA) of chemicals. Therefore, the aim of this original study was to couple in vitro studies with untargeted metabolomics to model the concentration-response of extra- and intracellular metabolome data on human HepaRG cells treated for 48 h with three pyrrolizidine alkaloids (PAs): heliotrine, retrorsine and lasiocarpine. Modeling revealed that the three PAs induced various monotonic and, importantly, biphasic curves of metabolite content. Based on unannotated metabolites, the endometabolome was more sensitive than the exometabolome in terms of metabolomic effects, and benchmark concentrations (BMCs) confirmed that lasiocarpine was the most hepatotoxic PA. Regarding its MOA, impairment of lipid metabolism was highlighted at a very low BMC (first quartile, 0.003 µM). Moreover, results confirmed that lasiocarpine targets bile acids, as well as amino acid and steroid metabolisms. Analysis of the endometabolome, based on coupling concentration-response and PODs, gave encouraging results for ranking toxins according to their hepatotoxic effects. Therefore, this novel approach is a promising tool for next-generation risk assessment, readily applicable to a broad range of compounds and toxic endpoints.


Assuntos
Metaboloma , Alcaloides de Pirrolizidina , Alcaloides de Pirrolizidina/toxicidade , Alcaloides de Pirrolizidina/metabolismo , Humanos , Metaboloma/efeitos dos fármacos , Linhagem Celular , Metabolômica , Metabolismo dos Lipídeos/efeitos dos fármacos
2.
J Hazard Mater ; 476: 135177, 2024 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-39018595

RESUMO

Chlordecone (CLD) is a pesticide persisting in soils and contaminating food webs. CLD is sequestered in the liver and poorly metabolized into chlordecol (CLDOH). In vitro liver cell models were used to investigate the fate and mechanistic effects of CLD and CLDOH using multiomics. A 3D-cell model was used to investigate whether CLD and CLDOH can affect susceptibility to the metabolic dysfunction-associated steatotic liver disease (MASLD). Hepatocytes were more sensitive to CLD than CLDOH. CLDOH was intensively metabolized into a glucuronide conjugate, whereas CLD was sequestered. CLD but not CLDOH induced a depletion of Septin-2,- 7,- 9,- 10,- 11 due to proteasomal degradation. Septin binding with CLD and CLDOH was confirmed by surface plasmon resonance. CLD disrupted lipid droplet size and increased saturated long-chain dicarboxylic acid production by inhibiting stearoyl-CoA desaturase (SCD) abundance. Neither CLD nor CLDOH induced steatosis, but CLD induced fibrosis in the 3D model of MASLD. To conclude, CLD hepatoxicity is specifically driven by the degradation of septins. CLDOH, was too rapidly metabolized to induce septin degradation. We show that the conversion of CLD to CLDOH reduced hepatotoxicity and fibrosis in liver organoids. This suggests that protective strategies could be explored to reduce the hepatotoxicity of CLD.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Hepatócitos , Complexo de Endopeptidases do Proteassoma , Septinas , Complexo de Endopeptidases do Proteassoma/metabolismo , Humanos , Septinas/metabolismo , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Inseticidas/toxicidade , Inseticidas/metabolismo , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Cirrose Hepática/induzido quimicamente , Fígado/metabolismo , Fígado/efeitos dos fármacos , Fígado/patologia
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