Academic literature on the topic 'Tri-ortho-cresyl phosphate'

Neuropathy target esterase has been shown to be a lysophospholipase in mouse. The authors investigate the effect of neuropathy target esterase inhibition in mouse nervous tissues in vitro on the homeostasis of phosphatidylcholine and lysophosphatidylcholine by treating the homogenates with tri-ortho-cresyl phosphate, paraoxon, paraoxon plus mipafox, and phenylmethylsulfonyl fluoride. The activity of neuropathy target esterase is significantly inhibited by phenylmethylsulfonyl fluoride and paraoxon plus mipafox but not by paraoxon alone. Tri-ortho-cresyl phosphate slightly but significantly inhibits neuropathy target esterase activity in brain. The levels of phosphatidylcholine and lysophosphatidylcholine in all 3 nervous tissues are not obviously altered after treatment with tri-ortho-cresyl phosphate, paraoxon, or paraoxon plus mipafox. However, phosphatidylcholine and lysophosphatidylcholine levels are clearly enhanced by phenylmethylsulfonyl fluoride. It is concluded that inhibition of neuropathy target esterase in mouse nervous tissues is not enough to disrupt the homeostasis of phosphatidylcholine and lysophosphatidylcholine and that the upregulation by phenylmethylsulfonyl fluoride may be the consequence of combined inhibition of neuropathy target esterase and other phospholipases.

Tri-ortho-cresyl phosphate (TOCP) has been widely used as plasticizers, plastic softeners, and flame retardants in industry and reported to have a deleterious effect on the male reproductive system in animals besides delayed neurotoxicity. Our preliminary results found that TOCP could disrupt the seminiferous epithelium in the testis and inhibit spermatogenesis, but the precise mechanism is yet to be elucidated. This study shows that TOCP inhibited viability of rat spermatogonial stem cells in a dose-dependent manner. TOCP could not lead to cell cycle arrest in the cells; the mRNA levels of p21, p27, p53, and cyclin D1 in the cells were also not affected by TOCP. Meanwhile, TOCP did not induce apoptosis of rat spermatogonial stem cells. After treatment with TOCP, however, both LC3-II and the ratio of LC3-II/LC3-I were markedly increased; autophagy proteins ATG5 and beclin 1 were also increased after treatment with TOCP, indicating that TOCP could induce autophagy in the cells. Ultrastructural observation under the transmission electron microscopy indicated that autophagic vesicles in the cytoplasm containing extensively degraded organelles such as mitochondria and endoplasmic reticulum increased significantly after the cells were treated with TOCP. In summary, we have shown that TOCP can inhibit viability of rat spermatogonial stem cells and induce autophagy of the cells, without affecting cell cycle and apoptosis.

Tri-ortho-cresyl phosphate (TOCP) has been widely used as plasticizers, plastic softeners and flame-retardants in industry and reported to have male reproductive toxicology. However, it is still unknown whether TOCP affects the female reproductive system and its underlying mechanism. In the present study, we found that TOCP exposure significantly decreased ovarian coefficient, caused disintegration and depletion of the granulosa cells in the ovary tissue and significantly inhibited the level of serum estradiol (E2). TOCP markedly increased both LC3-II and the ratio of LC3-II/LC3-I as well as autophagy proteins ATG5 and Beclin1 in the ovary tissue, implying that TOCP could induce autophagy in the ovary tissue. To further investigate the potential mechanism, primary ovarian granulosa cells were isolated in vitro and treated with 0–0.5 mM TOCP for 48 h. We showed that TOCP decreased the number of viable mouse granulosa cells without affecting cell cycle and apoptosis of the cells. Intriguingly, TOCP treatment markedly increased both LC3-II and the ratio of LC3-II/LC3-I as well as ATG5 and Beclin1. Furthermore, transmission electron microscopy (TEM) showed that autophagic vesicles in the cytoplasm increased significantly in the TOCP-treated cells, indicating that TOCP could induce autophagy in the cells. Taken together, TOCP reduces the number of viable cells and induces autophagy in mouse ovarian granulosa cells without affecting cell cycle and apoptosis.

Abstract Environmental exposure to tricresyl phosphate (TCP) may lead to severe neurotoxic effects, including organophosphate (OP)-induced delayed neuropathy. TCP has three symmetric isomers, distinguished by the methyl group position on the aromatic ring system. One of these isomers, tri-ortho-cresyl phosphate (ToCP), has been reported for years as a neuropathic OP, targeting neuropathic target esterase (NTE/PNPLA6), but its mode of toxic action had not been fully elucidated. Zebrafish eleuthero-embryo and larva were used to characterize the differential action of the TCP isomers. The symmetric isomers inhibited phenyl valerate (PV)-NTE enzymatic activity in vivo with different IC50, while no effect was observed on acetylcholinesterase activity. Moreover, the locomotor behavior was also affected by tri-para-cresyl phosphate and tri-meta-cresyl phosphate, only ToCP exposure led to locomotor hyperactivity lasting several hours, associated with defects in the postural control system and an impaired phototactic response, as revealed by the visual motor response test. The electric field pulse motor response test demonstrated that a seizure-like, multiple C-bend-spaghetti phenotype may be significantly induced by ToCP only, independently of any inhibition of PV-NTE activity. Eleuthero-embryos exposed to picrotoxin, a known gamma-aminobutyric acid type-A receptor inhibitor, exhibited similar adverse outcomes to ToCP exposure. Thus, our results demonstrated that the TCP mode of toxic action was isomer specific and not initially related to modulation of PV-NTE activity. Furthermore, it was suggested that the molecular events involved were linked to an impairment of the balance between excitation and inhibition in neuronal circuits.

La prévalence croissante des contaminants chimiques pose d'importants problèmes en matière de santé publique, nécessitant des méthodologies efficaces pour l'évaluation des risques toxicologiques. Un travail initial a été réalisé pour optimiser une nouvelle approche méthodologique (NAM) utilisant des éleuthéroembryons de poisson-zèbre, appelée electric field pulse motor response test (EFPMRT). La méthode vise à effectuer un criblage à haut débit des molécules chimiques induisant des défauts des capacités motrices et du contrôle postural. La robustesse, la reproductibilité, la productivité et la transférabilité de l'EFPMRT ont été améliorées en développant un nouvel outil logiciel, DanioTracker, effectuant l'analyse automatisée de points finaux liés au comportement locomoteur induit par la stimulation électrique. Ensuite, à l'aide d'une batterie de tests, la neurotoxicité induite par des composés organophosphorés (OP) et leurs métabolites a été évaluée. Les perturbations comportementales ont été évaluées en utilisant l'EFPMRT et un test neurocomportemental complémentaire dépendant des fonctions sensorielles, le visual motor response test (VMRT). La contribution de l'inhibition de l'acétylcholinestérase (AChE) et de la neuropathy target esterase (NTE) aux perturbations comportementales a été testée. Le chlorpyrifos, le parathion et le tri-ortho-crésyl-phosphate ont perturbé les fonctions intégratives de contrôle de la nage de manière quantitativement distincte et ont réduit les capacités neuromusculaires des éleuthéroembryons. Leurs métabolites respectifs, le chlorpyrifos-oxon, le paraoxon et le cresyl-saligénine-phosphate, ont intégralement inhibé l'AChE, induisant ainsi un syndrome cholinergique. Une étude comparative de l'efficacité d'un antidote réactivateur de l'AChE, le pralidoxime (2-PAM), pour atténuer certains effets toxiques, a été effectuée. L'antidote a induit une récupération face aux syndromes cholinergiques associés à l'exposition aux métabolites. De façon remarquable, le 2-PAM a également partiellement restauré les hyperactivités induites par les composés parents de manière vraisemblablement indépendante des activités AChE et NTE. Toutefois, il n'a pas restauré les dysfonctionnements neuromusculaires induits par le parathion ou le tri-ortho-crésyl-phosphate. Ceci suggère l’existence d’un ou plusieurs modes d'action (MOA) OP-spécifiques inconnus, associés aux composés parents mais pas aux métabolites correspondants, dont certains sont récupérables par le 2-PAM. Dans l'ensemble, ce travail offre une NAM robuste et transférable qui contribue à une stratégie d'évaluation globale des risques chimiques. Il révèle également des MOA alternatifs potentiels pour les OP sélectionnés, suggérant la nécessité de poursuivre les recherches sur les métabolites dans le cadre réglementaire, et contribue à la compréhension et à la prévention des troubles neurocomportementaux induits par les expositions environnementales seules ou en mixtures
The growing prevalence of chemical contaminants poses major public health concerns, necessitating efficient methodologies for toxicological risk assessment. An initial work was carried out to optimize a new approach methodology (NAM) using zebrafish pre-feeding larvae, called the electric field pulse (EFP) motor response test (EFPMRT). The method aims to perform a high-throughput screening of chemicals inducing motor capabilities and postural control defects. The robustness, reproducibility, productivity, and transferability of EFPMRT were enhanced by developing a novel software tool, DanioTracker, performing the automated analysis of endpoints linked to EFP-induced locomotor behavior. Then, using a battery of tests, the neurotoxicity induced by organophosphorus (OPs) compounds and their metabolites was assessed. Behavioral disruptions were evaluated using EFPMRT and a complementary sensory-dependent neurobehavioral test, the visual motor response test (VMRT). Contributions of acetylcholinesterase (AChE) and neuropathy target esterase (NTE) inhibition to behavioral disruptions were tested. Chlorpyrifos, parathion and tri-ortho-cresyl-phosphate disturbed integrative swimming control functions in quantitatively distinct manners and decreased the neuromuscular capacities of pre-feeding larvae. Their respective metabolites chlorpyrifos-oxon, paraoxon and cresyl-saligenin-phosphate fully inhibited AChE, thus inducing a cholinergic syndrome. Comparative study of the antidotal efficacy of an AChE reactivator, pralidoxime, in mitigating some toxic effects was performed. The antidote induced a recovery of the cholinergic syndromes associated with metabolites exposure. Strikingly, pralidoxime (2-PAM) also partially restored hyperactivities induced by parent compounds apparently independently of the activities of AChE and NTE. However, it did not restore neuromuscular dysfunctions induced by parathion or tri-ortho-cresyl phosphate. This suggests the existence of one or more unknown OP-specific multiple modes of action (MOAs) associated with parent compound but not corresponding metabolites, of which some are restorable by 2-PAM. Overall, this work offers a robust, transferable NAM that contributes to a comprehensive chemical risk assessment strategy. It also uncovers potential alternative MOA for selected OPs, suggesting the need for further research on metabolites within regulatory frameworks, and contributes to understanding and preventing neurobehavioral disorders induced by environmental exposures alone or in mixtures