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The mechanism of Tetrakis(hydroxymethyl)phosphonium Sulfate (THPS) teratogenicity and fat metabolism in rat precision-cut liver slices (PCLS)

Tan, Jia Lin (2019) The mechanism of Tetrakis(hydroxymethyl)phosphonium Sulfate (THPS) teratogenicity and fat metabolism in rat precision-cut liver slices (PCLS). Research Project 1, Medical Pharmaceutical Sciences.

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Abstract

Tetrakis(hydroxymethyl) phosphonium sulpate (THPS) is a biocide found to cause teratogenicity in rodents, together with liver toxicity. THPS appears to induce acute phase response (APR) at low concentrations, and its teratogenicity is strikingly similar to lipopolysaccharide (LPS). This study aims to understand the mechanism of THPS toxicity by comparing its hepatotoxicity to LPS and another hepatotoxin, acetaminophen (APAP). Thereafter, peroxisome proliferator-activated receptor α (PPARα) agonist, fenofibrate was introduced as an attempt to alleviate THPS liver toxicity. Rat precision cut liver slices (PCLS) was treated with THPS, LPS and APAP, followed by combination treatment of fenofibrate and THPS. PCLS viability was determined by means of ATP content and lactose dehydrogenase (LDH) leakage. The expressions of genes related to APR, nuclear receptors particularly PPARα and downstream genes of PPARα were studied. Morphology study with fat staining was used to study the effect of fenofibrate on THPS induced lipid accumulation. THPS is remarkably toxic to liver slices starting at the concentration of 70μM, with up to 96% reduction in ATP content and 65% LDH leakage at THPS 200μM. There were upregulations of cytokines (IL-1β and TNFα) and acute phase proteins (APP) at THPS concentrations below TC50. Toxic concentration of THPS gradually reduced APP gene expressions corresponds to viability reduction. Fenofibrate 50μM and 100μM caused 10-20% viability increase in THPS 5μM and 10μM treated PCLS. PPARα was downregulated two times by THPS 5μM and 10μM, but slightly upregulated when fenofibrate was co-incubated with THPS. Carnitine palmitoyl transferase 1 (CPT1) was downregulated by THPS, possibly contributing to lipid accumulation in PCLS. Fenofibrate upregulated CPT1 in the presence of THPS. Fat staining did reveal observable decrease in lipid accumulation in one experiment, but it was not repeatable. To summarize, fenofibrate activates PPARα, inflammation pathways and lipogenesis are inhibited. Therefore, inflammatory response and fatty acid metabolism appears to play a partial role in THPS hepatotoxicity, as the administration of fenofibrate improved viability in rat PCLS treated with THPS.

Item Type: Thesis (Research Project 1)
Supervisor:
Supervisor nameSupervisor E mail
Estrada Ortiz, N.N.Estrada.Ortiz@rug.nl
Degree programme: Medical Pharmaceutical Sciences
Thesis type: Research Project 1
Language: English
Date Deposited: 12 Jul 2019
Last Modified: 12 Jul 2019 14:19
URI: http://fse.studenttheses.ub.rug.nl/id/eprint/20172

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