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

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

Effect of TOCP and PMSF on the GPC (A), DAG (B) and PA (C) levels in spinal cord of hens. 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. GPC content was detected by HPLC-ESI-MS and DAG and PA levels were measured by ELISA assay. GPC and PA concentrations were expressed as ng per mg of spinal cord sample. DAG concentrations were expressed as fmol per mg of spinal cord sample. Data were expressed as mean ± SEM (n = 5). *P < 0.05, and **P < 0.01, compared to the control group. #P < 0.05, compared to TOCP group.
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f4: Effect of TOCP and PMSF on the GPC (A), DAG (B) and PA (C) levels in spinal cord of hens. 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. GPC content was detected by HPLC-ESI-MS and DAG and PA levels were measured by ELISA assay. GPC and PA concentrations were expressed as ng per mg of spinal cord sample. DAG concentrations were expressed as fmol per mg of spinal cord sample. Data were expressed as mean ± SEM (n = 5). *P < 0.05, and **P < 0.01, compared to the control group. #P < 0.05, compared to TOCP group.

Mentions: NTE acts as phospholipase B and catalyzes the deacylation of PC and LPC to GPC. GPC levels in spinal cord were further measured by HPLC-ESI-MS. There was a statistically significant decrease (decreased to 63% of control) of GPC content in TOCP treatment hens (T group). Meanwhile, PMSF pretreatment (PT group) also decreased the GPC content (decreased to 61% of control) (Fig. 4A), which indicated PMSF did not restore the NTE activity inhibited by PMSF, and the decrease of GPC level was not directly related with OPIDN initiation.


Disturbed phospholipid homeostasis in endoplasmic reticulum initiates tri- o -cresyl phosphate-induced delayed neurotoxicity
Effect of TOCP and PMSF on the GPC (A), DAG (B) and PA (C) levels in spinal cord of hens. 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. GPC content was detected by HPLC-ESI-MS and DAG and PA levels were measured by ELISA assay. GPC and PA concentrations were expressed as ng per mg of spinal cord sample. DAG concentrations were expressed as fmol per mg of spinal cord sample. Data were expressed as mean ± SEM (n = 5). *P < 0.05, and **P < 0.01, compared to the control group. #P < 0.05, compared to TOCP group.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5121615&req=5

f4: Effect of TOCP and PMSF on the GPC (A), DAG (B) and PA (C) levels in spinal cord of hens. 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. GPC content was detected by HPLC-ESI-MS and DAG and PA levels were measured by ELISA assay. GPC and PA concentrations were expressed as ng per mg of spinal cord sample. DAG concentrations were expressed as fmol per mg of spinal cord sample. Data were expressed as mean ± SEM (n = 5). *P < 0.05, and **P < 0.01, compared to the control group. #P < 0.05, compared to TOCP group.
Mentions: NTE acts as phospholipase B and catalyzes the deacylation of PC and LPC to GPC. GPC levels in spinal cord were further measured by HPLC-ESI-MS. There was a statistically significant decrease (decreased to 63% of control) of GPC content in TOCP treatment hens (T group). Meanwhile, PMSF pretreatment (PT group) also decreased the GPC content (decreased to 61% of control) (Fig. 4A), which indicated PMSF did not restore the NTE activity inhibited by PMSF, and the decrease of GPC level was not directly related with OPIDN initiation.

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&thinsp;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