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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.

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The levels of each changed phospholipid in different treatments.Adult hens were orally administrated with vehicle (empty capsule) (control, C), TOCP (T), or TOCP 24 h after PMSF pretreatment (PT). The spinal cord samples were collected on day 2 after TOCP administration. Phospholipids profile was detected by HPLC-ESI-MS/MS method. The phospholipids were increased (A) or decreased (B) in TOCP group (white bars) compared to control. Black bars indicate levels of phospholipids in PT group. Data are normalized to those in control group and are expressed as fold change compared to control group. All the phospholipid species were significantly changed in TOCP group compared to control group with P values < 0.05 (n = 5). Data were expressed as mean ± SEM (n = 5). *P < 0.05, and **P < 0.01, compared to TOCP group (n = 5).
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f2: The levels of each changed phospholipid in different treatments.Adult hens were orally administrated with vehicle (empty capsule) (control, C), TOCP (T), or TOCP 24 h after PMSF pretreatment (PT). The spinal cord samples were collected on day 2 after TOCP administration. Phospholipids profile was detected by HPLC-ESI-MS/MS method. The phospholipids were increased (A) or decreased (B) in TOCP group (white bars) compared to control. Black bars indicate levels of phospholipids in PT group. Data are normalized to those in control group and are expressed as fold change compared to control group. All the phospholipid species were significantly changed in TOCP group compared to control group with P values < 0.05 (n = 5). Data were expressed as mean ± SEM (n = 5). *P < 0.05, and **P < 0.01, compared to TOCP group (n = 5).

Mentions: Next, the phospholipids contributing most to the separation of these three groups according to variable importance plot (VIP) values were identified. VIP is a weighed sum of squares of the PLS weight, and VIP values indicate the importance of the variables to the whole model. Fifty-nine phospholipids with VIP values larger than 1.00 and P values less than 0.05 were identified to have significant different levels among the three groups (Fig. 1B). Compared to control, 30 out of 59 phospholipids were increased in TOCP group, which belong to 3 classes: PC (16 phospholipids), LPC (5 phospholipids) and SM (9 phospholipids) (Fig. 2A, white bars). The other 29 phospholipids were decreased in TOCP group, which belong to 5 classes: PE, LPE, PG, PS and LPS. Most of these 29 phospholipids were PE and LPE species (22 and 4, respectively) (Fig. 2B, white bars). Interestingly, levels of all the 59 phospholipids were restored, at least partly, in PMSF plus TOCP group (Fig. 2, black bars).


Disturbed phospholipid homeostasis in endoplasmic reticulum initiates tri- o -cresyl phosphate-induced delayed neurotoxicity
The levels of each changed phospholipid in different treatments.Adult hens were orally administrated with vehicle (empty capsule) (control, C), TOCP (T), or TOCP 24 h after PMSF pretreatment (PT). The spinal cord samples were collected on day 2 after TOCP administration. Phospholipids profile was detected by HPLC-ESI-MS/MS method. The phospholipids were increased (A) or decreased (B) in TOCP group (white bars) compared to control. Black bars indicate levels of phospholipids in PT group. Data are normalized to those in control group and are expressed as fold change compared to control group. All the phospholipid species were significantly changed in TOCP group compared to control group with P values < 0.05 (n = 5). Data were expressed as mean ± SEM (n = 5). *P < 0.05, and **P < 0.01, compared to TOCP group (n = 5).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f2: The levels of each changed phospholipid in different treatments.Adult hens were orally administrated with vehicle (empty capsule) (control, C), TOCP (T), or TOCP 24 h after PMSF pretreatment (PT). The spinal cord samples were collected on day 2 after TOCP administration. Phospholipids profile was detected by HPLC-ESI-MS/MS method. The phospholipids were increased (A) or decreased (B) in TOCP group (white bars) compared to control. Black bars indicate levels of phospholipids in PT group. Data are normalized to those in control group and are expressed as fold change compared to control group. All the phospholipid species were significantly changed in TOCP group compared to control group with P values < 0.05 (n = 5). Data were expressed as mean ± SEM (n = 5). *P < 0.05, and **P < 0.01, compared to TOCP group (n = 5).
Mentions: Next, the phospholipids contributing most to the separation of these three groups according to variable importance plot (VIP) values were identified. VIP is a weighed sum of squares of the PLS weight, and VIP values indicate the importance of the variables to the whole model. Fifty-nine phospholipids with VIP values larger than 1.00 and P values less than 0.05 were identified to have significant different levels among the three groups (Fig. 1B). Compared to control, 30 out of 59 phospholipids were increased in TOCP group, which belong to 3 classes: PC (16 phospholipids), LPC (5 phospholipids) and SM (9 phospholipids) (Fig. 2A, white bars). The other 29 phospholipids were decreased in TOCP group, which belong to 5 classes: PE, LPE, PG, PS and LPS. Most of these 29 phospholipids were PE and LPE species (22 and 4, respectively) (Fig. 2B, white bars). Interestingly, levels of all the 59 phospholipids were restored, at least partly, in PMSF plus TOCP group (Fig. 2, black bars).

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