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Disturbed phospholipid homeostasis in endoplasmic reticulum initiates tri- o -cresyl phosphate-induced delayed neurotoxicity

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ABSTRACT

Tri-o-cresyl phosphate (TOCP) is a widely used organophosphorus compound, which can cause a neurodegenerative disorder, i.e., organophosphate-induced delayed neurotoxicity (OPIDN). The biochemical events in the initiation of OPIDN were not fully understood except for the essential inhibition of neuropathy target esterase (NTE). NTE, located in endoplasmic reticulum (ER), catalyzes the deacylation of phosphatidylcholine (PC) and lysophosphatidylcholine (LPC) to glycerophosphocholine (GPC). The present study aims to study the changes of ER phospholipids profile as well as levels of important intermediates of phospholipid synthesis such as diacylglycerol (DAG) and phosphatidic acid (PA) at the initiation stage of OPIDN. Hens are the most commonly used animal models of OPIDN. The spinal cord phospholipidomic profiles of hens treated by TOCP were studied by using HPLC-MS-MS. The results revealed that TOCP induced an increase of PC, LPC, and sphingomyelin (SM) levels and a decrease of GPC, phosphatidylethanolamine (PE), lysophosphatidylethanolamine (LPE), lysophosphatidylserine (LPS), phosphatidylglycerol (PG), and phosphatidylinositol (PI) levels., Levels of DAG and PA were also decreased. Pretreatment with phenylmethylsulfonyl fluoride (PMSF) 24 h before TOCP administration prevented OPIDN and restored the TOCP-induced changes of phospholipids except GPC. Thus, the disruption of ER phospholipid homeostasis may contribute to the initiation of organophosphate-induced delayed neurotoxicity.

No MeSH data available.


Related in: MedlinePlus

Summary of the change of phospholipids involved in PC biosynthesis, degradation and conversion in spinal cord ER after TOCP treatment.Adult hens were orally administrated with vehicle (control, C), TOCP (T), or TOCP 24 h after PMSF pretreatment (PT). The spinal cord samples were collected on day 2 after TOCP administration. The key metabolites in phospholipid biosynthesis and the enzymes catalyzing the respective reactions are indicated. NTE was inhibited (in the bracket). Some phospholipids increased after TOCP administration (in red ellipse); while other phospholipids decreased by TOCP (in green box). All of the changed phospholipids except for GPC were restored by the PMSF pretreatment. Abbreviations: CDP: cytidine diphosphate; CDP-DAG, CDP-diacylglycerol; CDS, CDP-DAG synthase; CPT, 1,2-diacylglycerol cholinephosphotransferase; DAG, diacylglycerol; DAGK, DAG kinase; EPT, CDP-ethanolamine:diacylglycerol ethanolaminephosphotransferase; GPC, glycerophosphocholine; LPC, lysophosphatidylcholine; NTE, neuropathy target esterase; PA, phosphatidic acid; PAP, PA phosphatases; PC, phosphatidylcholine; PE, phosphatidylethanolamine; PG, phosphatidylglycerol; PGP, PG phosphate; PGPS, PGP synthase; PGPP, PGP phosphatase; PI, phosphatidylinositol; PIS, PI synthase; PLA1, phospholipase A1; PLA2, phospholipase A2; PLC, phospholipase C; PLD, phospholipase D; PSS1, phosphatidylserine synthase 1; PSS2, phosphatidylserine synthase 2; SM, sphingomyelin; SMS, SM synthase.
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f5: Summary of the change of phospholipids involved in PC biosynthesis, degradation and conversion in spinal cord ER after TOCP treatment.Adult hens were orally administrated with vehicle (control, C), TOCP (T), or TOCP 24 h after PMSF pretreatment (PT). The spinal cord samples were collected on day 2 after TOCP administration. The key metabolites in phospholipid biosynthesis and the enzymes catalyzing the respective reactions are indicated. NTE was inhibited (in the bracket). Some phospholipids increased after TOCP administration (in red ellipse); while other phospholipids decreased by TOCP (in green box). All of the changed phospholipids except for GPC were restored by the PMSF pretreatment. Abbreviations: CDP: cytidine diphosphate; CDP-DAG, CDP-diacylglycerol; CDS, CDP-DAG synthase; CPT, 1,2-diacylglycerol cholinephosphotransferase; DAG, diacylglycerol; DAGK, DAG kinase; EPT, CDP-ethanolamine:diacylglycerol ethanolaminephosphotransferase; GPC, glycerophosphocholine; LPC, lysophosphatidylcholine; NTE, neuropathy target esterase; PA, phosphatidic acid; PAP, PA phosphatases; PC, phosphatidylcholine; PE, phosphatidylethanolamine; PG, phosphatidylglycerol; PGP, PG phosphate; PGPS, PGP synthase; PGPP, PGP phosphatase; PI, phosphatidylinositol; PIS, PI synthase; PLA1, phospholipase A1; PLA2, phospholipase A2; PLC, phospholipase C; PLD, phospholipase D; PSS1, phosphatidylserine synthase 1; PSS2, phosphatidylserine synthase 2; SM, sphingomyelin; SMS, SM synthase.

Mentions: Our result showed that total phospholipids were not affected by TOCP treatment. Hence the increase of PC was accompanied by the decrease of other phospholipids. PE, synthesized via the Kennedy pathway by using ethanolamine and DAG in ER, was remarkably decreased. PG and PI, synthesized by a common precursor PA, were both decreased. The conversion of DAG to PA could contribute to the balance of phospholipid synthesis between the pathway producing PC, PE and PS and that producing PI and PG27. DAG and PA, substrates of phospholipids synthesis and products of phospholipids degradation, were also significantly decreased after TOCP treatment. No alternation was observed in PS, which is synthesized by base-exchange from PC or PE by PS synthases. However, SM, which is synthesized by PC and ceramide28, was significantly increased. These data suggested that TOCP interfered with ER phospholipid homeostasis through disturbing pathways of phospholipid biosynthesis and interconversion in ER (Fig. 5).


Disturbed phospholipid homeostasis in endoplasmic reticulum initiates tri- o -cresyl phosphate-induced delayed neurotoxicity
Summary of the change of phospholipids involved in PC biosynthesis, degradation and conversion in spinal cord ER after TOCP treatment.Adult hens were orally administrated with vehicle (control, C), TOCP (T), or TOCP 24 h after PMSF pretreatment (PT). The spinal cord samples were collected on day 2 after TOCP administration. The key metabolites in phospholipid biosynthesis and the enzymes catalyzing the respective reactions are indicated. NTE was inhibited (in the bracket). Some phospholipids increased after TOCP administration (in red ellipse); while other phospholipids decreased by TOCP (in green box). All of the changed phospholipids except for GPC were restored by the PMSF pretreatment. Abbreviations: CDP: cytidine diphosphate; CDP-DAG, CDP-diacylglycerol; CDS, CDP-DAG synthase; CPT, 1,2-diacylglycerol cholinephosphotransferase; DAG, diacylglycerol; DAGK, DAG kinase; EPT, CDP-ethanolamine:diacylglycerol ethanolaminephosphotransferase; GPC, glycerophosphocholine; LPC, lysophosphatidylcholine; NTE, neuropathy target esterase; PA, phosphatidic acid; PAP, PA phosphatases; PC, phosphatidylcholine; PE, phosphatidylethanolamine; PG, phosphatidylglycerol; PGP, PG phosphate; PGPS, PGP synthase; PGPP, PGP phosphatase; PI, phosphatidylinositol; PIS, PI synthase; PLA1, phospholipase A1; PLA2, phospholipase A2; PLC, phospholipase C; PLD, phospholipase D; PSS1, phosphatidylserine synthase 1; PSS2, phosphatidylserine synthase 2; SM, sphingomyelin; SMS, SM synthase.
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f5: Summary of the change of phospholipids involved in PC biosynthesis, degradation and conversion in spinal cord ER after TOCP treatment.Adult hens were orally administrated with vehicle (control, C), TOCP (T), or TOCP 24 h after PMSF pretreatment (PT). The spinal cord samples were collected on day 2 after TOCP administration. The key metabolites in phospholipid biosynthesis and the enzymes catalyzing the respective reactions are indicated. NTE was inhibited (in the bracket). Some phospholipids increased after TOCP administration (in red ellipse); while other phospholipids decreased by TOCP (in green box). All of the changed phospholipids except for GPC were restored by the PMSF pretreatment. Abbreviations: CDP: cytidine diphosphate; CDP-DAG, CDP-diacylglycerol; CDS, CDP-DAG synthase; CPT, 1,2-diacylglycerol cholinephosphotransferase; DAG, diacylglycerol; DAGK, DAG kinase; EPT, CDP-ethanolamine:diacylglycerol ethanolaminephosphotransferase; GPC, glycerophosphocholine; LPC, lysophosphatidylcholine; NTE, neuropathy target esterase; PA, phosphatidic acid; PAP, PA phosphatases; PC, phosphatidylcholine; PE, phosphatidylethanolamine; PG, phosphatidylglycerol; PGP, PG phosphate; PGPS, PGP synthase; PGPP, PGP phosphatase; PI, phosphatidylinositol; PIS, PI synthase; PLA1, phospholipase A1; PLA2, phospholipase A2; PLC, phospholipase C; PLD, phospholipase D; PSS1, phosphatidylserine synthase 1; PSS2, phosphatidylserine synthase 2; SM, sphingomyelin; SMS, SM synthase.
Mentions: Our result showed that total phospholipids were not affected by TOCP treatment. Hence the increase of PC was accompanied by the decrease of other phospholipids. PE, synthesized via the Kennedy pathway by using ethanolamine and DAG in ER, was remarkably decreased. PG and PI, synthesized by a common precursor PA, were both decreased. The conversion of DAG to PA could contribute to the balance of phospholipid synthesis between the pathway producing PC, PE and PS and that producing PI and PG27. DAG and PA, substrates of phospholipids synthesis and products of phospholipids degradation, were also significantly decreased after TOCP treatment. No alternation was observed in PS, which is synthesized by base-exchange from PC or PE by PS synthases. However, SM, which is synthesized by PC and ceramide28, was significantly increased. These data suggested that TOCP interfered with ER phospholipid homeostasis through disturbing pathways of phospholipid biosynthesis and interconversion in ER (Fig. 5).

View Article: PubMed Central - PubMed

ABSTRACT

Tri-o-cresyl phosphate (TOCP) is a widely used organophosphorus compound, which can cause a neurodegenerative disorder, i.e., organophosphate-induced delayed neurotoxicity (OPIDN). The biochemical events in the initiation of OPIDN were not fully understood except for the essential inhibition of neuropathy target esterase (NTE). NTE, located in endoplasmic reticulum (ER), catalyzes the deacylation of phosphatidylcholine (PC) and lysophosphatidylcholine (LPC) to glycerophosphocholine (GPC). The present study aims to study the changes of ER phospholipids profile as well as levels of important intermediates of phospholipid synthesis such as diacylglycerol (DAG) and phosphatidic acid (PA) at the initiation stage of OPIDN. Hens are the most commonly used animal models of OPIDN. The spinal cord phospholipidomic profiles of hens treated by TOCP were studied by using HPLC-MS-MS. The results revealed that TOCP induced an increase of PC, LPC, and sphingomyelin (SM) levels and a decrease of GPC, phosphatidylethanolamine (PE), lysophosphatidylethanolamine (LPE), lysophosphatidylserine (LPS), phosphatidylglycerol (PG), and phosphatidylinositol (PI) levels., Levels of DAG and PA were also decreased. Pretreatment with phenylmethylsulfonyl fluoride (PMSF) 24 h before TOCP administration prevented OPIDN and restored the TOCP-induced changes of phospholipids except GPC. Thus, the disruption of ER phospholipid homeostasis may contribute to the initiation of organophosphate-induced delayed neurotoxicity.

No MeSH data available.


Related in: MedlinePlus