Expression of Neuropathy Target Esterase in mouse embryonic stem cells during differentiation

Pamies, David; Reig, Juan A.; Vilanova, Eugenio; Sogorb, Miguel A.

doi:10.1007/s00204-010-0518-8

Cited by 18 publications

(9 citation statements)

References 37 publications

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“…58 In accordance with its embryotoxic nature, we found elevated expression in ES cells after treatment with statins at all concentrations and at each time window of exposure. The probable physiologic functions of Afp in the directing developmental events such as erthyropoiesis, histogenesis/organogenesis, fetal growth and differentiation, and the fetal defects associated with the symptom of elevated levels of Afp are very well explained by Mizejewski.…”

Section: Discussionsupporting

confidence: 76%

Genetic basis for developmental toxicity due to statin intake using embryonic stem cell differentiation model

Jyoti

Tandon

2015

Hum Exp Toxicol

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The in utero environment is a key factor controlling the fate of the growing embryo. The deleterious effects of statins during the fetal development are still not very well understood. Data from animal studies and retrospective studies performed in pregnant women give conflicting reports. In this study, using in vitro differentiation model of embryonic stem cells, which mimic the differentiation process of the embryo, we have systematically exposed the cells to lipophilic statins, simvastatin, and atorvastatin at various doses and at critical times during differentiation. The analysis of key genes controlling the differentiation into ecto-, meso- and endodermal lineages was assessed by quantitative polymerase chain reaction. Our results show that genes of the mesodermal lineage were most sensitive to statins, leading to changes in the transcript levels of brachyury, Flk-1, Nkx2.5, and α/β-myosin heavy chain. In addition, changes to endodermal marker α-fetoprotein, along with ectodermal Nes and Neurofilament 200 kDa, imply that during early differentiation exposure to these drugs leads to altered signaling, which could translate to the congenital abnormalities seen in the heart and limbs.

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Section: Discussionsupporting

confidence: 76%

Genetic basis for developmental toxicity due to statin intake using embryonic stem cell differentiation model

Jyoti

Tandon

2015

Hum Exp Toxicol

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“…There is a transmembrane domain near the N-terminus that anchors the protein to the endoplasmic reticulum membrane, and three homologous tandem domains to cyclic nucleotide-binding proteins, suggesting a possible regulatory or signal transduction role. PNPLA 6 is highly expressed throughout the brain, peripheral nerve and some cells (Pamies et al, 2010). A truncated form of PNPLA 6 (NTE), containing the esterase domain, has been shown to hydrolyze phospholipids and lysophospholipids (Glynn., 2005).…”

Section: Nte Lysophosphatidyl Choline Hydrolasementioning

confidence: 99%

“…A peak in gene expression has been demonstrated in the early cell differentiation stage (Pamies et al, 2010). The relative inhibition of NTE and AChE has been used for in vitro tests for predicting delayed neurotoxicity (Romero et al 2015); the comparison of the exposure needed for AChE and NTE inhibition with that causing alteration in cell differentiation in vitro, has been proposed and applied for predicting developmental toxicity (Estevan et al 2013) NTE(+/-) mice survive, but exhibit increased sensitivity to an acute effect of OP compounds, which is distinct from OPIDN.…”

Section: Nte Lysophosphatidyl Choline Hydrolasementioning

confidence: 99%

“…Future studies should extend the scope of work to encompass the cyclic nucleotide-binding domains and their possible role in the regulation of NTE or its interacting partners, which have yet to be defined (Richardson et al, 2013). The inhibition by OP of NTE enzymatic activity is a triggering mechanism causing toxic neurodegenerative effects in adults, The protein has a critical role in early embryonic development as silencing the expression is causing strong alteration in gene biomarkers of cell differentiation in in vitro models of neurodevelopment (Pamies et al 2010(Pamies et al , 2014. However in similar conditions and models the inhibition of NTE enzymatic activity is not causing significant alteration, suggesting that the protein is needed in the development but not its carboxylesterase catalytic activity (Sogorb,2016) …”

Section: Nte Lysophosphatidyl Choline Hydrolasementioning

confidence: 99%

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New insights on molecular interactions of organophosphorus pesticides with esterases

et al. 2017

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Organophosphorus compounds (OPs) are a large and diverse class of chemicals mainly used as pesticides and chemical weapons. People may be exposed to OPs in several occasions, which can produce several distinct neurotoxic effects depending on the dose, frequency of exposure, type of OP, and the host factors that influence susceptibility and sensitivity. These neurotoxic effects are mainly due to the interaction with enzyme targets involved in toxicological or detoxication pathways. In this work, the toxicological relevance of known OPs targets is reviewed. The main enzyme targets of OPs have been identified among the serine hydrolase protein family, some of them decades ago (e.g. AChE, BuChE, NTE and carboxylesterases), others more recently (e.g. lysophospholipase, arylformidase and KIA1363) and others which are not molecularly identified yet (e.g. phenylvalerate esterases). Members of this family are characterized by displaying serine hydrolase activity, containing a conserved serine hydrolase motif and having an alpha-beta hydrolase fold. Improvement in Xray-crystallography and in silico methods have generated new data of the interactions between OPs and esterases and have established new methods to study new inhibitors and reactivators of cholinesterases. Mass spectrometry for AChE, BChE and APH have characterized the active site serine adducts with OPs being useful to detect biomarkers of OPs exposure and inhibitory and postinhibitory reactions of esterases and OPs. The purpose of this review is focus specifically on the interaction of OP with esterases, mainly with type B-esterases, which are able to hydrolyze carboxylesters but inhibited by OPs by covalent phosphorylation on the serine or tyrosine residue in the active sites. Other related esterases in some cases with no-irreversible effect are also discussed. The understanding of the multiple molecular interactions is the basis we are proposing for a multi-target approach for understanding the organophosphorus toxicity.

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“…In this context, it seems to be relevant that perfluoroalkylated compounds affect protein kinase C signalling that is known as a key factor of cell migration (Stewart et al 2012), a process of particular relevance during the development of the nervous system. Neurotoxicity (Takahashi et al 2011;Nakamura et al 2011;Li et al 2011;Sriram et al 2010;Liu et al 2010) as well as developmental neurotoxicity (Pamies et al 2010;Frimat et al 2010;Hardelauf et al 2011;Kadereit et al 2012;Kuegler et al 2010;Hartung et al 2011) represent cutting-edge topics in toxicology, reflected by the particularly high number of articles in this field. However, little has been published discussing the neurotoxicity of perfluoroalkylated compounds, although they are still widely used in pesticides, paints, clothes treatment, fire-fighting foams, carpets and leather products.…”

mentioning

confidence: 99%

Developmental neurotoxicity: the case of perfluoroalkylated compounds

Thriel

Stewart

2012

Arch Toxicol

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Expression of Neuropathy Target Esterase in mouse embryonic stem cells during differentiation

Cited by 18 publications

References 37 publications

Genetic basis for developmental toxicity due to statin intake using embryonic stem cell differentiation model

Genetic basis for developmental toxicity due to statin intake using embryonic stem cell differentiation model

New insights on molecular interactions of organophosphorus pesticides with esterases

Developmental neurotoxicity: the case of perfluoroalkylated compounds

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